A prospective randomized controlled study of the effects of probiotics on intestinal microecology and gastrointestinal side effects in patients undergoing postoperative chemotherapy for breast cancer

A prospective randomized controlled study of the effects of probiotics on intestinal microecology and gastrointestinal side effects in patients undergoing postoperative chemotherapy for breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A prospective randomized controlled study of the effects of probiotics on intestinal microecology and gastrointestinal side effects in patients undergoing postoperative chemotherapy for breast cancer Juhang Chu, Yaru Wang, Luyao Huang, Yixiang Huang, Mingping Qian This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6914811/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Breast cancer poses a serious threat to women's health, and chemotherapy is a classic treatment for it. However, chemotherapy-induced gastrointestinal toxicity can lead to disease aggravation, treatment failure and even death. Bifico is a commonly used probiotic. This study aimed to explore the effects of Bifico on gastrointestinal side effects caused by chemotherapy. Methods A total of 50 breast cancer patients were enrolled and randomly divided into a treatment group (TG) and a control group (CG) using a 1:1 randomization method. Blood and stool samples were collected and analyzed before the first and third chemotherapy treatment course. The fecal microbiota was analyzed through 16S ribosomal RNA sequencing. The level of serum zonulin was detected before and after chemotherapy. Results After two cycles, the TG showed a richer gut microbiota with increased beneficial bacteria and reduced pathogenic bacteria compared to the CG. Functional analysis indicated the TG's microbiota was involved in polyamine synthesis, while the CG's microbiota was linked to teichoic acid production. Serum zonulin levels decreased significantly in the TG, reflecting improved intestinal barrier function. The TG also had fewer gastrointestinal side effects, particularly constipation and oral mucositis. Additionally, the TG exhibited higher IgG levels and lower triglyceride and small dense low-density lipoprotein levels. Immune function was enhanced in the TG, with increased total T cells, Th cells, and B cells. Conclusion This study revealed that Bifico can maintain intestinal barrier function, reducing chemotherapy-induced gastrointestinal side effects, and modulate gut microbiota in breast cancer patients. Breast cancer Chemotherapy-induced gastrointestinal side effects Zonulin Gut microbiota Probiotics Figures Figure 1 Figure 2 Introduction The most common malignant tumor worldwide is now breast cancer, surpassing lung cancer. Worldwide, there were 2.3 million new cases of breast cancer in 2020, and the disease claimed the lives of over 680,000 people. Chemotherapy has been used alone or in combination with other therapies for the treatments of breast cancer for a long time and has achieved good clinical results. Although the development of therapeutic drugs has made the treatments of breast cancer diversified and individualized, there are still 30% of breast cancer patients die of tumor metastasis and recurrence. It is worth noting that dose reduction, delay and termination of treatments caused by adverse reactions of antineoplastic drugs are also key factors affecting the prognosis of breast cancer patients [1–3] . The human intestinal tract is rich in microbial species, up to 10 14 in total, and is widely distributed in various parts of the intestine. The bacteria are mainly divided into four phyla, namely Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. The composition and distribution of intestinal microbiota are affected by many factors, including age, genetic factors, immunity, microflora interaction, etc. Under normal physiological conditions, microbiota and host coexist in homeostasis, and the imbalance of homeostasis is closely related to host diseases, such as intestinal inflammation, tumors, and immune system diseases [4] . The chemotherapy drug cyclophosphamide (CTX) has the potential to disrupt the gut microbiota by selectively eliminating certain components of the gut flora, inhibiting the proliferation of beneficial bacteria, and consequently altering both the abundance and diversity of the microbial community within the patient's gastrointestinal tract. Some patients receiving CTX treatments will experience serious adverse reactions, mainly including immunosuppression and gastrointestinal reactions. Previous studies [5, 6] have confirmed that CTX can damage the intestinal mucosal barrier, increasing intestinal permeability and the colonization of pathogenic bacteria. In addition, CTX can cause damage to intestinal mucosal epithelial cells, reducing the level of short-chain fatty acids (SCFAs) in the intestine, and increase the concentration of ammonia. Probiotics can promote the production of SCFAs and inhibit the formation of ammonia as well as improve intestinal metabolic disorders [7] . Consequently, studying the quantity and composition of intestinal flora in patients with malignant tumor chemotherapy can understand the influence of chemotherapy drugs on intestinal flora from the perspective of microecology. Zonulin is the only physiological protein known to regulate intestinal permeability. Many studies [8, 9] have confirmed that the increase of serum level of zonulin is accompanied by the increase of intestinal permeability. As one of the important regulatory pathways in tight junction, the zonulin pathway mainly regulates the flow of blood and fluid in the intestinal lumen, and affects the function of macromolecular substances and white blood cells. In consequence, zonulin has also become one of the biomarkers for the diagnosis of “leaky gut syndrome” (Fig. 1 A) Combined with previous studies, it is reasonable to infer that CTX can change the composition of intestinal flora, increase the number of pathogenic bacteria. Metabolites secreted by pathogenic bacteria activate the zonulin pathway, which opens tight junctions, increasing the permeability of the intestinal barrier, leading to gastrointestinal side effects. Previous studies have shown that the adjuvant intervention of microecological bacterial agents during chemotherapy can reduce gastrointestinal adverse reactions in patients [10] . On account of this, we hypothesized that oral administration of probiotics (Bifico) to patients undergoing chemotherapy could maintain intestinal barrier function and reduce gastrointestinal adverse reactions on the basis of regulating the structure of intestinal flora. Methods Patients A total of 50 breast cancer patients who underwent breast surgery and received CTX containing regimen chemotherapy for the first time in Shanghai Tenth People's Hospital from October 2022 to March 2023 were enrolled. Inclusion criteria were as follows: (1) breast cancer was the first primary tumor; (2) patients received chemotherapy for the first time after surgery and the regimen contained CTX. Exclusion criteria were as follows: (1) severe systemic diseases, including heart, liver, and kidney dysfunction; (2) previous chemotherapy or other anti-cancer treatments; (3) treatments with probiotics, prebiotics, or antibiotics within 2 months before recruitment; (4) allergic to probiotics; (5) previous irritable bowel syndrome and inflammatory bowel disease; (6) pregnant and lactating women; And (7) inability to provide informed consent. This study was approved by the Ethics Committee of Shanghai Tenth People's Hospital (Approval No. SHSY-IEC-4.1/21–298/01), and conducted in strict accordance with the ethical principles of the Declaration of Helsinki. All participants provided written informed consent prior to their enrollment, ensuring compliance with international standards for human subject protection. Study design This study was a prospective randomized controlled trial and followed the CONSORT Statement rules. At the first postoperative chemotherapy, the enrolled patients who received chemotherapy containing CTX were randomly divided into CG and TG using a random number table method. The CG was treated with chemotherapy alone, and the TG was treated with two courses of Bifico (Bifidobacterium triple viable capsules) orally, three capsules once, twice a day. Patients' stool and blood samples were collected before the first and third chemotherapy. This work was supported by National Natural Fund Cultivation Project (YNCR2C026). Clinical trial number: not applicable. Record of adverse effects Chemotherapy-induced gastrointestinal adverse effects include nausea, vomiting, diarrhea, constipation, and oral mucositis (OM). The above grades of gastrointestinal side effects are shown in Table 1 . This grade classification refers to the Common Terminology Criteria for Adverse Events (CTCAE). The occurrence of chemotherapy-induced gastrointestinal side effects was recorded by filling out questionnaires and regular telephone follow-up. Table 1 Grading of chemotherapy-induced gastrointestinal side effects Grading of gastrointestinal side effects Grade I Grade II Grade III Grade IV Nausea and vomiting Appetite was normal and vomit occurred 1 to 2 times/day Appetite decreased and vomit occurred 3 to 5 times/day Vomit more than 5 times per day Unable to eat and vomit more than 10 times per day Diarrhea Defecation was < 4 times/day Defecation was 4–6 times/day Defecation was ≥ 7 times/day Life-threatening Constipation Occasional symptoms Persistent symptoms that require Regular treatments with laxatives or enema Symptoms affect daily life and Require manual dredging of constipation Life-threatening OM Erythema, but does not interfere with eating Erythema, ulcers, but able to eat solid food Severe erythema and ulcers Unable to eat Sample collection Fresh fecal samples (approximately 2 to 4 g) were placed in sterile tubes containing preservation solution, frozen at -20 ̊C within 5 min and stored to -80 ̊C freezer within 24 h. Patients in both groups were instructed to fast for at least 8 hours before each blood collection, and 5 mL of fasting venous blood was drawn the next morning. The whole blood sample was immediately centrifuged at 5000 RPM for 10 minutes at room temperature, and 1 mL of the upper layer of serum was extracted in a 2 mL sterile frozen storage tube. The sample was transferred to a -80°C refrigerator within 2 hours for storage. Measuring of serum zonulin, humoral immunity, blood lipids, cytokines and cellular immunity Serum zonulin content was measured by enzyme linked immunosorbent assay (ELISA) using a commercial kit (human zonulin ELISA kit, Wuhan Elabscience, China) with a sensitivity of 0.47 ng/mL, The detection range was 0.78 ng/mL to 50 ng/mL. Cytokines and humoral immunity were measured by ELISA. The sample to be tested is conjugated to a specific antibody, an enzyme-labeled secondary antibody is added, and the concentration of interleukins and immunoglobulins is quantified by a chromogenic reaction. Cellular immunity was measured by flow cytometry. Cells are sorted and counted using the light scattering and fluorescence properties of flow cytometry by fluorescently labeled antibodies binding to cell surface antigens, resulting in percentage and absolute counts of different cell subpopulations. Blood lipids are measured using different methods. Total cholesterol (TC) and triglyceride (TG) were determined by enzymatic method. Serum samples were mixed with enzyme reagents and incubated at 37°C for 15 min, after which absorbance was determined and the content calculated. The precipitation method was used to determine the contents of high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Density gradient ultracentrifugation was used to determine the content of small dense low-density lipoprotein (SD-LDL). Stool specimens test methods Microbial genomic DNA was extracted from the samples of each group using nucleic acid extraction reagents. Qubit2.0 was used to detect the concentration and purity of DNA, and the integrity of DNA was detected by 1% agarose gel electrophoresis. Primers were designed to amplify the V3-V4 hypervariable region of 16S rRNA gene, and the PCR products were quantified and paired for sequencing. FASTP software was used for quality control of the original sequencing sequence, and FLASH software was used for assembly. The Silva 16S rRNA database (SSU123) was used to establish a confidence threshold of 70%. Statistical analysis Qiime2 software was used to analyze microbial α-diversity, and β-diversity was assessed by principal co-ordinates analysis (PCoA) based on weighted and unweighted distances. Linear discriminant analysis effect size (LEfSe) analysis considered LDA values > 2 as significant differences in relative abundance. Normally distributed data were presented as mean ± standard deviation, and skewed data as median. Statistical significance was set at p < 0.05. Results Clinical characteristics of breast cancer patients undergoing postoperative chemotherapy A total of 50 breast cancer patients who received postoperative chemotherapy containing CTX regimen were included in this study, and they were randomly divided into TG and CG. The clinicopathological indicators of the two groups are shown in Table 2 . There was no significant difference in the basic clinicopathological data of the two groups ( p > 0.05), which was comparable. Table 2 Clinicopathological data of patients in TG and CG Clinical Measures TG (N = 25) CG (N = 25) p Age ( ) 53.88 ± 8.60 55.20 ± 10.90 0.637 BMI ( ) 23.34 ± 1.84 23.94 ± 2.56 0.343 Menstrual status 0.771 Menopause 15 16 Premenopausal 10 9 Underlying illness 0.306 Yes 7 4 No 18 21 Chemotherapy regimens 0.683 TAC 22 21 TEC 3 4 Surgical approach 0.733 Modified radical mastectomy 19 20 Breast conserving surgery 6 5 Molecular typing 0.827 Luminal A 7 6 Luminal B 9 11 HER2 positive 4 5 Triple negative 5 3 Type of pathology 0.440 Invasive ductal carcinoma 20 22 Others 5 3 Pathological grading 0.461 1 1 2 2 11 7 3 13 16 Clinical staging 0.490 I 13 12 II 12 12 III 0 1 A and β diversity analysis of intestinal flora in breast cancer patients undergoing postoperative chemotherapy In this study, the rarefaction curve of each sample was drawn to evaluate the sequencing depth (Fig. 1 B). Most samples reached the platform at the expected detection depth, confirming the adequacy of sequencing. Chao, Shannon and Simpson index were used to analyze the α diversity of intestinal flora in the TG and the CG before and after two courses of chemotherapy. At the phylum and genus levels, the Chao index of the CG was significantly lower than that of the TG ( p < 0.001; p = 0.031) (Fig. 1 C-D) PCoA showed that there was no statistically significant difference in the β diversity of the gut microbiota between the two groups before chemotherapy (Fig. 1 E). Under the same condition of receiving two cycles of chemotherapy, the β diversity of intestinal flora in the TG was statistically significantly higher than that in the CG (Fig. 1 F). Differences of intestinal flora in breast cancer patients after chemotherapy Wilcoxon rank sum test was used to analyze the composition of intestinal flora between the TG and the CG after two courses of chemotherapy. The results showed that the relative abundance of Tyzzerella was significantly increased in the CG without oral Bifico ( p = 0.024). The relative abundance of Ruminococcus, Clostridia_UCG-014, Eubacterium_coprostanoligenes_group, Christensenellaceae R-7 group were significantly increased in the TG ( p = 0.016; p = 0.042; p = 0.046; p = 0.009). LEfSe analysis showed that, Prevotella, Eubacterium_coprostanoligenes_group, Clostridla_UCG_014, Ruminococcus, Syntrophobacteria, NK4A214_group, Christensenellaceae R-7 group, Pyramidobacter and Anaerovoracaceae were significantly enriched in the gut microbiota of the TG, and the difference was statistically significant ( p < 0.05). Tyzzerella was significantly enriched in the intestinal flora of the CG, and the difference was statistically significant ( p < 0.05) (Fig. 2A-B). Functional analysis of intestinal flora in breast cancer patients undergoing postoperative chemotherapy Picrust2 was used to analyze the intestinal flora function of the TG and the CG after two courses of chemotherapy and compared with the MetaCyc database. It was found that the intestinal flora function of the TG was mainly involved in the synthesis of polyamines, 1, 4-dihydroxy-6-naphthoate, and methylnaphthoquinone (Fig. 2C). The intestinal flora of breast cancer patients who did not take Bifico orally plays a pathological role by promoting the synthesis of teichoic acid and methane. Analysis of changes in serum zonulin and clinical laboratory indicators in breast cancer patients receiving postoperative chemotherapy Compared with the CG, the level of serum zonulin in the TG was significantly decreased after two cycles of chemotherapy, and the difference was statistically significant ( p < 0.001). There was also a statistically significant difference in the serum level of zonulin before and after chemotherapy in the CG ( p < 0.05) (Fig. 2F). Comparing the levels of lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), neutrophil/monocyte ratio (NMR), platelet/lymphocyte ratio (PLR) before and after chemotherapy in the TG and the CG, it can be found that NLR increased and LMR decreased in the CG after two courses of chemotherapy, and the difference was statistically significant ( p < 0.05). In the TG, the systemic inflammatory response was reduced after chemotherapy compared with before, but the difference was not statistically significant, indicating that chemotherapy increased the systemic inflammatory level of patients, and oral Bifico can effectively reduce the inflammatory response during chemotherapy (Fig. 2D-E). After statistical analysis and summary of the clinical indicators of the enrolled patients, Table 3 showed that the IgG of the TG was significantly higher than the CG after chemotherapy ( p = 0.031). Table 4 shows that the levels of TG and SD-LDL in the TG after chemotherapy were significantly lower than the CG ( p = 0.001; p = 0.005). In the CG, the levels of TG, TC and SD-LDL after chemotherapy were significantly higher than before chemotherapy ( p = 0.002; p = 0.037; p = 0.004). Table 5 shows that chemotherapy can increase the level of inflammatory response. After oral administration of Bifico, the levels of IL-6 and IL-8 in the TG were significantly lower than the CG ( p = 0.044; p = 0.025), and the level of IL-10 was significantly higher than the CG ( p = 0.003). Table 6 shows that chemotherapy significantly reduced the levels of total T cells, Th cells, B cells and Tregs, and inhibited the cellular immunity of the body. Compared with before chemotherapy, the levels of total T cells and Th cells in the TG were significantly increased after oral Bifico treatments ( p = 0.032; p = 0.029). Compared with the CG, the levels of total T cells, Th cells and B cells in the TG after chemotherapy were significantly increased ( p = 0.024; p = 0.013; p = 0.026). Table 3 Humoral immune indexes of the two groups at different periods ( ) Humoral immunity Grouping Time point p Before the first chemotherapy Before the third chemotherapy IgG (g/L) TG 14.16 ± 2.76 13.02 ± 1.90 0.082 CG 12.78 ± 2.94 11.59 ± 2.67 0.190 p 0.095 0.031 IgA (g/L) TG 2.47 ± 1.10 2.34 ± 0.78 0.488 CG 2.66 ± 1.10 2.54 ± 0.97 0.701 p 0.549 0.693 IgM (g/L) TG 1.42 ± 0.68 1.49 ± 0.74 0.727 CG 1.48 ± 0.86 1.37 ± 0.69 0.621 p 0.792 0.465 IgE (IU/mL) TG 186.6 ± 532.06 226.75 ± 44.47 0.175 CG 257.45 ± 728.32 301.82 ± 60.36 0.214 p 0.694 0.465 Table 4 Blood lipid indexes of the two groups in different periods ( ) Blood lipids Grouping Time point p Before the first chemotherapy Before the third chemotherapy TC (mmol/L) TG 5.14 ± 1.14 5.01 ± 0.88 0.653 CG 5.11 ± 0.89 5.50 ± 0.89 0.037 p 0.896 0.053 TG (mmol/L) TG 1.44 ± 1.08 1.11 ± 0.57 0.174 CG 1.36 ± 0.80 1.92 ± 0.95 0.002 p 0.771 0.001 LDL (mmol/L) TG 2.91 ± 0.75 2.97 ± 0.73 0.713 CG 2.99 ± 0.71 3.14 ± 0.68 0.181 p 0.682 0.394 HDL (mmol/L) TG 1.36 ± 0.31 1.42 ± 0.29 0.246 CG 1.30 ± 0.23 1.31 ± 0.29 0.697 p 0.405 0.182 SD-LDL (mmol/L) TG 0.88 ± 0.28 0.79 ± 0.20 0.268 CG 0.84 ± 0.29 1.04 ± 0.35 0.004 p 0.710 0.005 Table 5 Cytokine indexes of the two groups at different periods ( ) Cytokines Grouping Time point p Before the first chemotherapy Before the third chemotherapy IL-6 (pg/mL) TG 5.39 ± 3.56 5.70 ± 3.42 0.100 CG 5.08 ± 5.37 9.47 ± 8.30 0.007 p 0.808 0.044 IL-8 (pg/mL) TG 23.80 ± 51.85 13.28 ± 13.43 0.815 CG 22.70 ± 33.45 27.89 ± 28.10 0.395 p 0.903 0.025 IL-1β (pg/mL) TG 1.28 ± 1.37 2.83 ± 4.59 0.133 CG 1.88 ± 2.48 2.11 ± 2.22 0.271 p 0.296 0.474 IL-10 (pg/mL) TG 2.59 ± 1.27 2.70 ± 0.93 0.228 CG 2.10 ± 1.08 1.98 ± 0.69 0.663 p 0.152 0.003 IFN-a (pg/mL) TG 1.75 ± 0.97 4.05 ± 7.61 0.156 CG 1.94 ± 1.04 2.06 ± 1.25 0.759 p 0.516 0.274 TNF-a (pg/mL) TG 4.80 ± 6.62 7.46 ± 12.78 0.233 CG 5.51 ± 11.01 9.36 ± 17.58 0.012 p 0.797 0.836 IFN-γ (pg/mL) TG 2.54 ± 2.02 2.59 ± 1.35 0.982 CG 2.96 ± 1.15 2.74 ± 1.13 0.300 p 0.369 0.678 Table 6 Cellular immune indexes of the two groups at different periods ( ) Cellular immunity Grouping Time point p Before the first chemotherapy Before the third chemotherapy Total T cells (uL) TG 1043.64 ± 294.21 1298.23 ± 575.16 0.032 CG 1163.04 ± 384.01 972.60 ± 408.37 0.007 p 0.223 0.024 Th cells (uL) TG 559.32 ± 136.73 739.04 ± 391.89 0.029 CG 639.76 ± 238.41 509.92 ± 217.35 0.001 p 0.150 0.013 B cells (uL) TG 186.04 ± 63.51 267.62 ± 204.89 0.064 CG 228.2 ± 161.96 155.44 ± 134.90 0.001 p 0.232 0.026 NK cells (uL) TG 270.80 ± 146.70 361.08 ± 230.94 0.115 CG 283.37 ± 193.64 269.92 ± 99.54 0.513 p 0.797 0.139 CD4 + /CD8 + ratio TG 1.52 ± 0.56 1.62 ± 0.68 0.551 CG 1.42 ± 0.47 1.32 ± 0.45 0.322 p 0.504 0.068 Tregs TG 7.14 ± 2.00 7.07 ± 1.36 0.866 CG 7.64 ± 1.48 6.63 ± 0.98 0.006 p 0.320 0.191 Correlation analysis between gut microbiota and clinical laboratory indicators and zonulin Among the dominant flora in the TG, Christensenellaceae R-7 group was positively correlated with IL-10 and Tregs (r = 0.373, p = 0.020; r = 0.334, p = 0.041), and negatively correlated with the levels of serum zonulin, IL-6, IL-8 and NLR (r=-0.387, p = 0.016; r=-0.436, p = 0.006; r=-0.352, p = 0.030; r=-0.350, p = 0.031) (Fig. 2G). Eubacterium_coprostanoligenes_group was positively correlated with IgG and Tregs (r = 0.423, p = 0.008; r = 0.476, p = 0.003), and negatively correlated with TG (r=-0.352, p = 0.030). Ruminococcaceae_NK4A214_group was positively correlated with IL-10 and Tregs (r=-0.454, p = 0.004; r= -0.352, p = 0.030). r=-0.476, p = 0.003). Synergistota was positively correlated with IL-10 and Tregs (r = 0.420, p = 0.009; r = 0.436, p = 0.006), and negatively correlated with serum zonulin, IL-6 and TG (r=-0.337, p = 0.039; r=-0.385, p = 0.017; r=-0.398, p = 0.013). Tyzzerella was positively correlated with serum zonulin (r = 0.387, p = 0.016) and negatively correlated with IL-10 (r=-0.471, p = 0.003). Analysis of the occurrence of gastrointestinal side effects in breast cancer patients undergoing postoperative chemotherapy The results showed that the incidence and severity of nausea, vomiting, constipation, diarrhea, and OM were decreased in different degrees after taking Bifico during chemotherapy. The symptoms of constipation and OM in the TG were significantly reduced after chemotherapy ( p = 0.026; p = 0.013), as shown in Table 7 . Table 7 Analysis of gastrointestinal side effects in breast cancer patients undergoing postoperative chemotherapy Side effects of digestive tract TG (n = 25) CG (n = 25) p Nausea [n(%)] 16 (64%) 23 (92%) 0.807 Level 1 14 (87.5%) 17 (73.9%) Grade 2 2 (12.5%) 5 (21.7%) Grade 3 0 (0.0%) 1 (4.4%) Vomiting [n(%)] 12 (48%) 19 (76%) 0.935 Level 1 9 (75%) 14 (73.7%) Grade 2 3 (25%) 5 (26.3%) ≥ grade 3 0 (0.0%) 0 (0.0%) Diarrhea [n(%)] 7 (28%) 11 (44%) 0.952 Level 1 5 (71.4%) 8 (72.7%) Grade 2 2 (28.6%) 3 (27.3%) Grade ≥ 3 0 (0.0%) 0 (0.0%) Constipation [n(%)] 18 (72%) 24 (96%) 0.026 Level 1 16 (88.9%) 13 (54.2%) Level 2 2 (11.1%) 10 (41.7%) Grade ≥ 3 0 (0.0%) 1 (4.1%) OM [n(%)] 18 (72%) 22 (88%) 0.013 Level 1 11 (61.1%) 4 (18.2%) Level 2 7 (38.9%) 16 (72.7%) Grade ≥ 3 0 (0.0%) 2 (9.1%) Discussion Probiotics alter the composition and function of intestinal flora in breast cancer patients undergoing postoperative chemotherapy The gut is a complex environment where bacteria, fungi and viruses coexist. Gut microbiota is considered to be the forgotten organ in human health and diseases. It can maintain intestinal homeostasis through a variety of complex mechanisms, further play a role in preventing pathogenic bacteria colonization, immune regulation, inhibition of inflammation, and maintenance of intestinal mucosal barrier [4] . According to their different functions, the various bacteria in the gut microbiota can be divided into probiotics, opportunistic pathogens and pathogenic bacteria [11] . Probiotics refer to microorganisms that are beneficial to the health of the host, including Bifidobacterium, Lactobacillus, Clostridium butyricum, etc. By colonizing the gut's surface, the good bacteria in the gut microbiota create a physical barrier that stops bad bacteria from adhering and growing. The number of dangerous bacteria and the harm they do to the intestinal mucosa are decreased by this competitive inhibitory process. Certain probiotics generate antimicrobial compounds, like organic acids and antimicrobial peptides, which have the ability to kill dangerous bacteria directly and stop them from penetrating the intestinal mucosa. They can also improve immunological function, synthesis vitamins, make SCFAs, and aid in the digestion of meals. According to studies, Clostridium species can prevent excessive immune system activation, maintain immunological homeostasis, and increase the generation of Tregs in the gut. Furthermore, colonization with segmented filamentous bacteria restored T-cell numbers [12] . SCFAs, including acetic acid, propionic acid and butyric acid, are mainly produced by bacteria such as Bacteroides, Coprococcus, Rectobacter, and Rochella. They are the main energy source of colonic cells, promote the proliferation of colonic epithelial cells, protect the intestinal mucosa, and inhibit the development of tumors through a variety of mechanisms, such as inhibiting the proliferation of pathogenic bacteria and cancer cells, inducing cancer cell apoptosis, and inhibiting inflammatory response [13] . As 16S rDNA sequencing and metagenomics technology advance quickly, we have discovered that intestinal flora plays a role in controlling intestinal function, shielding the intestinal mucosa from intestinal pathogen invasion, and stopping harmful bacteria from spreading from the intestine to other tissues. It is also closely related to metabolic syndrome, depression, Alzheimer's disease, inflammatory bowel disease, tumor and other diseases. In addition, the gut microbiota can also influence the efficacy of anti-tumor therapy while reducing its toxicity. Chemotherapy causes harmful side effects such nausea, vomiting, diarrhea, constipation, mouth ulcers, rashes, hair loss, and immunosuppression in addition to their cytotoxic impact on cancer cells. Chemotherapy side effects and toxicity can be considerably reduced by the gut flora and its products. Numerous studies have demonstrated that taking different probiotics and prebiotics together can help with chemotherapy-induced mucositis, lessen diarrhea and abdominal pain, and lower the risk of postoperative complications like pneumonia, infection, and anastomotic leakage [14–16] . Animal studies have also shown consistent outcomes, with probiotic-treated colorectal tumor model mice showing decreased 5-fluorouracil-induced colitis and decreased induction of proinflammatory cytokines [17] . In the present study, we found that the alpha diversity of gut microbiota was significantly decreased in the CG after two cycles of chemotherapy. Compared with the CG, the Bifico plus chemotherapy group had a significant increase in the β diversity of gut microbiota. These results suggest that chemotherapeutic drugs can change the composition of intestinal flora and reduce the abundance and diversity of intestinal microorganisms. Oral administration of Bifico can effectively reverse this trend. Tyzzerella was significantly enriched in the CG after two courses of chemotherapy; Ruminococcus, Prevotella, Eubacterium_coprostanoligenes_group, Clostridla_UCG_014, Syntrophobacteria, NK4A214_group, Christensenellaceae R-7 group, Pyramidobacter and Anaerovoracaceae were significantly enriched in the TG. In the functional study of gut microbiota, teichoic acid and methane synthesis pathways were mainly involved in the CG, while polyamines, 1, 4-dihydroxy-6-naphthoate and methylnaphthoquinone synthesis pathways were mainly involved in the TG. In addition, in the correlation analysis of intestinal flora and clinical laboratory indicators, Tyzzerella was positively correlated with serum zonulin and negatively correlated with IL-10, suggesting that it may be involved in the destruction of intestinal barrier and play a pro-inflammatory role. Long et [18] found a causal relationship between Tyzzerella-3 and lung adenocarcinoma through two-sample Mendelian randomization analysis. Dong et [19] found that the relative abundance of Tyzzerella-3 in the group responding to antidepressant treatment for major depressive disorder decreased significantly after receiving antidepressant treatment. In addition, studies have also shown that Tyzzerella is related to the severity of depressive symptoms [20] . Zhang et [21] constructed a mouse constipation model using loperamide hydrochloride to evaluate the ability of four different proportions of multi-strain probiotic combinations of Bifidobacterium and Lactobacillus to regulate intestinal flora. After four weeks of probiotic intervention, Bifidobacteria-based formulations BM1, BM2 and Lactobacillus based formulations PB2 significantly reduced the abundance of Tyzzerella in stool, down-regulated serum proinflammatory cytokine levels and effectively relieved constipation. Probiotics can change the composition of intestinal flora in breast cancer patients undergoing chemotherapy, affecting the systemic inflammatory state and intestinal barrier function. However, how the microbiota participate in the regulation of the body's physiological function still needs to be verified in more basic experiments. Whether even changes in the abundance of the same bacteria can alter their role in the host needs further study. Probiotics protect the intestinal mucosal barrier and improve intestinal permeability The human body interacts with the environment through the gut mucosa. Toxins and germs cannot cross the intestinal barrier and enter the body through the gastrointestinal mucosa. Each layer of the intestinal barrier normally carries out its own duty to maintain the body's health. Both transcellular and paracellular pathways can be used by the gut to absorb water and nutrients [6] . Inflammation is brought on by intestinal erosion, ulceration, and epithelial cell death, which permit bigger particles to flow through the epithelium of the gastrointestinal tract without restriction. The intestinal barrier is destroyed by adverse events such medications, trauma, and sepsis. Pathogenic bacteria can enter the bloodstream through damaged intestinal barriers and increased vascular permeability, leading to systemic inflammation and even multiple organ failure. Numerous illnesses, including inflammatory bowel disease, diabetes, non-alcoholic fatty liver disease, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and other mental illnesses, as well as malignancies, have been linked to intestinal barrier failure, according to evidence [22] . Toxins and harmful microorganisms cannot harm the gut if the gut barrier is intact. In the early 21st century, some scholars studied Vibrio cholerae and found that cholera toxin secreted by Vibrio cholerae could rapidly open the tight junctions between intestinal epithelial cells, leading to an increase in the permeability of the intestinal barrier. A protein produced by human intestinal cells is almost identical to cholera toxin. They named the protein zonulin. To date, zonulin remains the only functional protein known to be involved in regulating the loose and tight state of intestinal epithelial cells functional protein [23] . Celiac disease is a disease involving the breakdown of the intestinal barrier. In this disease, gluten from wheat and other grains has been identified as an environmental trigger for autoimmune responses in genetically susceptible individuals. Gliadin, found in gluten, induces the release of the intestinal epithelial protein zonulin, so zonulin can be used as one of the markers of intestinal permeability in patients with celiac disease [24] . In addition to celiac disease, increased intestinal permeability has been reported in other autoimmune diseases. Many studies [24–26] have shown that in the acute phase of some chronic inflammatory diseases, zonulin is overexpressed, and blocking its pathway can prevent the occurrence of autoimmune responses, suggesting that zonulin is involved in the pathogenesis of these diseases. Ramezani et [27] selected 9 studies on the influence of probiotic intake and serum zonulin level, and conducted a meta-analysis involving a total of 496 intervention patients and 443 control patients. The results showed that probiotic preparations had a significant effect on reducing serum zonulin compared with the control group. This was confirmed by the results of our study, in which we found that taking probiotics maintained the integrity of the intestinal barrier, reduced intestinal mucosal permeability, and reduced the serum level of zonulin. In addition, the incidence of chemotherapy-induced gastrointestinal side effects in the TG was significantly lower than the CG, suggesting that serum zonulin has the potential to predict gastrointestinal side effects in breast cancer patients receiving chemotherapy. Probiotics can alleviate chemotherapy-induced nausea and vomiting According to the time of onset, CINV can be divided into three categories: acute, delayed and expected. In addition, chemotherapy drugs can be divided into four grades according to their emetogenicity, among which CTX is a drug with high emetogenic risk. Drug therapy is the most commonly used clinical strategy to alleviate CINV, including ondansetron, palonosetron, aprepitant, dexamethasone, etc [28] . Some studies have found that adding olanzapine, dopamine, and serotonin receptor inhibitors to standard antiemetic regimens reduces the occurrence of CINV [29] . In one study, Yeo et [30] found that olanzapine combined with the standard triple antiemetic regimen significantly reduced the incidence of acute and delayed CINV in breast cancer patients. At present, many clinicians consider acupuncture therapy, aromatherapy and probiotics as new strategies for the treatments of CINV. In patients receiving highly emetogenic chemotherapy, prophylactic antiemetics combined with acupuncture before and during treatments significantly reduced the incidence of CINV [31] . But some scholars have not observed the effect of acupuncture therapy on CINV [32] . Therefore, acupuncture and moxibustion therapy still needs to be further verified in large sample randomized controlled trials. In a recent study, Efe Erturk et [33] confirmed that peppermint aromatherapy combined with standard antiemetics could reduce the frequency and severity of CINV, and this conclusion was also confirmed in another study. Zhao et [34] used azomethane oxide and sodium glucan sulfate to induce a mouse model of colorectal cancer to evaluate the improved effects of Thalidomide (THD) and Clostridium butyricum combined therapy on tumor inhibition and CINV. The results showed that the combined treatments of THD and Clostridium butyricum significantly enhanced the anticancer effects of cisplatin by activating the caspase-3 apoptotic pathway, and improved CINV by inhibiting neurotransmitters (such as 5-HT) and their receptors in the brain and colon. In addition, combined treatments of THD and Clostridium butyricum reversed gut microbiota dysbiosis in mice with colorectal cancer by increasing the genus-level abundance of Clostridium, Lactobacillus, Bifidobacterium and Ruminococcus. At the same time, it can reduce the mRNA expression of IL-6, IL-1β and TNF-α, increase the expression of tight junction protein in the colon, and protect the intestinal barrier function. In this study, we found that oral Bifico treatments at the same time as chemotherapy in breast cancer patients could appropriately reduce the incidence and severity of CINV, but the difference was not statistically significant, which should be further confirmed in follow-up clinical studies with longer probiotic treatments cycles. Probiotics alleviate chemotherapy-induced diarrhea and constipation Diarrhea and constipation seriously affect the quality of life and treatments effects of breast cancer patients undergoing chemotherapy. The pathophysiology of chemotherapy-induced diarrhea (CID) and chemotherapy-induced constipation (CIC) is complex and involves a variety of mechanisms, including changes in gastrointestinal secretion, absorption, and innervation. The current treatments available for CID and CIC are dietary changes and pharmacological interventions. Common drugs used to treat CID include loperamide, montmorillonite powder, octreotide, etc. Commonly used drugs for CIC include lactulose, polyethylene glycol, mosapride, etc. With the in-depth study of intestinal flora, the efficacy and safety of probiotics in the treatments of CID and CIC have become a research hotspot. Amiri et [35] collected randomized clinical trials conducted in adult cancer patients with CID from 2018 to 2020 and studies on the efficacy of probiotic supplements in preventing or treating CID, calculated the relative risk or odds ratio of patients with diarrhea incidence and severity during the intervention period, and included a total of 13 randomized clinical trials. These reports were based on a total of 18 randomized controlled trials reporting the combined effect size of CID, and meta-analyses showed that probiotics had a statistically significant beneficial effect on all outcomes except fecal viscosity. Huang et [36] divided 100 patients with diagnosed colorectal cancer into TG and CG. The intervention time was about 6 weeks from the third day after operation to the end of the first chemotherapy course. Probiotics were found to be effective in reducing CID and CIC. Our results showed that probiotic preparations significantly reduced the incidence and severity of CIC. The incidence of CID was low in TG patients and was further controlled with probiotic preparations, but the efficacy was not statistically significant. Probiotics alleviate chemotherapy-induced OM OM refers to the inflammatory and ulcerative lesions of oral mucosal epithelium, which are mainly manifested as oral mucosal hyperemia, erythema, edema, erosion, and different degrees of ulceration. For patients with malignant tumors, radiotherapy, chemotherapy, targeted therapy or immunotherapy are the main causes of OM. The treatments of OM usually include cryotherapy and drug therapy, such as chlorhexidine mouthrinse, Kangfuxin solution, and lidocaine gel. In recent years, many studies have found that taking probiotics can effectively relieve OM. Guo et [37] found that Bifidobacterium tablets could significantly reduce the incidence of chemotherapy-induced OM in patients receiving hematopoietic stem cell transplantation, mainly reducing the incidence of 1 ~ 2 grade OM, and the median duration of OM in the probiotic group was shorter. Gupta et [38] confirmed for the first time that Lactobacillus reuteri has a protective effect on OM caused by chemotherapy. Among the 50 patients included in this study, the incidence of OM in the CG was 88%, and the incidence of OM in the TG was 72%. The incidence of OM at all grades in the TG was also significantly lower than the CG, indicating that probiotics have potential preventive and therapeutic effects on OM. Conclusion This study is a prospective randomized controlled study. By comparing the gastrointestinal side effects of the TG group and the CG group, and analyzing the intestinal microbiota and blood indexes of the TG group and the CG group, it was shown that Bifico could maintain the intestinal barrier function and alleviate the gastrointestinal side effects caused by chemotherapy on the basis of regulating the structure of the intestinal microbiota. Providing more effective options and potential targets for alleviating chemotherapy-induced gastrointestinal side effects. The limited sample size of this study may not adequately represent the situation of all postoperative chemotherapy patients with breast cancer, resulting in limited generalizability of the study results. In addition, although there have been some studies on the mechanism of probiotics regulating intestinal microbiota and immune function, their specific action pathways and interactions with other factors still need to be further explored. Declarations Funding: This work was supported by National Natural Fund Cultivation Project, China (YNCR2C026) Conflict of Interest Statements: The authors declare that there is no conflict of interest regarding the publication of this article. Author Contribution Juhang Chu and Yaru Wang were responsible for data analysis and manuscript writing. Luyao Huang was responsible for collecting data. Yixiang Huang and Mingping Qian were responsible for selecting patients and editing manuscripts. All authors reviewed the manuscript. Ethical Statement: This study was approved by the Ethics Committee of Shanghai Tenth People's Hospital (Approval number: SHSY-IEC-4.1/21-298/01). All participants provided written informed consent. References GAO X, ZHANG F, ZHOU Q, et al. Metastasis, characteristic, and treatment of breast cancer in young women and older women: A study from the Surveillance, Epidemiology, and End Results registration database [J]. PLoS One, 2023, 18(11): e0293830. 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XIE J H, FAN S T, NIE S P, et al. Lactobacillus plantarum NCU116 attenuates cyclophosphamide-induced intestinal mucosal injury, metabolism and intestinal microbiota disorders in mice [J]. Food Funct, 2016, 7(3): 1584-92. ASBJORNSDOTTIR B, SIGURDSSON S, MIRANDA-RIBERA A, et al. Evaluating Prophylactic Effect of Bovine Colostrum on Intestinal Barrier Function in Zonulin Transgenic Mice: A Transcriptomic Study [J]. Int J Mol Sci, 2023, 24(19). VERES-SZéKELY A, SZáSZ C, PAP D, et al. Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions [J]. Int J Mol Sci, 2023, 24(8). WANG Y, WIESNOSKI D H, HELMINK B A, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis [J]. Nat Med, 2018, 24(12): 1804-8. FENG P, XUE X, BUKHARI I, et al. Gut microbiota and its therapeutic implications in tumor microenvironment interactions [J]. Front Microbiol, 2024, 15: 1287077. BRABEC T, SCHWARZER M, KOVáČOVá K, et al. Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover [J]. J Exp Med, 2024, 221(1). THIRUVENGADAM M, SUBRAMANIAN U, VENKIDASAMY B, et al. Emerging role of nutritional short-chain fatty acids (SCFAs) against cancer via modulation of hematopoiesis [J]. Crit Rev Food Sci Nutr, 2023, 63(6): 827-44. KHAZAEI Y, BASI A, FERNANDEZ M L, et al. The effects of synbiotics supplementation on reducing chemotherapy-induced side effects in women with breast cancer: a randomized placebo-controlled double-blind clinical trial [J]. BMC Complement Med Ther, 2023, 23(1): 339. WEI H, YUE Z, HAN J, et al. Oral compound probiotic supplements can improve the quality of life for patients with lung cancer during chemotherapy: A randomized placebo-controlled study [J]. Thorac Cancer, 2024, 15(2): 182-91. MOTOORI M, YANO M, MIYATA H, et al. Randomized study of the effect of synbiotics during neoadjuvant chemotherapy on adverse events in esophageal cancer patients [J]. Clin Nutr, 2017, 36(1): 93-9. LóPEZ-GóMEZ L, ALCORTA A, ABALO R. Probiotics and Probiotic-like Agents against Chemotherapy-Induced Intestinal Mucositis: A Narrative Review [J]. J Pers Med, 2023, 13(10). LONG Y, TANG L, ZHOU Y, et al. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study [J]. BMC Med, 2023, 21(1): 66. DONG Z, SHEN X, HAO Y, et al. Gut microbiome: A potential indicator for predicting treatment outcomes in major depressive disorder [J]. Front Neurosci, 2022, 16: 813075. WANG R, CAI Y, LU W, et al. Exercise effect on the gut microbiota in young adolescents with subthreshold depression: A randomized psychoeducation-controlled Trial [J]. Psychiatry Res, 2023, 319: 115005. ZHANG C, WANG L, LIU X, et al. The Different Ways Multi-Strain Probiotics with Different Ratios of Bifidobacterium and Lactobacillus Relieve Constipation Induced by Loperamide in Mice [J]. Nutrients, 2023, 15(19). IACUCCI M, SANTACROCE G, MAJUMDER S, et al. Opening the doors of precision medicine: novel tools to assess intestinal barrier in inflammatory bowel disease and colitis-associated neoplasia [J]. Gut, 2024, 73(10): 1749-62. FASANO A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications [J]. Clin Gastroenterol Hepatol, 2012, 10(10): 1096-100. DAFONTE T M, VALITUTTI F, KENYON V, et al. Zonulin as a Biomarker for the Development of Celiac Disease [J]. Pediatrics, 2024, 153(1). KABAKCHIEVA P, GATEVA A, VELIKOVA T, et al. Meteorin-like Protein and Zonulin in Polycystic Ovary Syndrome: Exploring Associations with Obesity, Metabolic Parameters, and Inflammation [J]. Biomedicines, 2024, 12(1). GARGARI G, MANTEGAZZA G, CREMON C, et al. Collinsella aerofaciens as a predictive marker of response to probiotic treatment in non-constipated irritable bowel syndrome [J]. Gut Microbes, 2024, 16(1): 2298246. RAMEZANI AHMADI A, SADEGHIAN M, ALIPOUR M, et al. The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as a Biomarker of Intestinal Permeability: A Systematic Review and Meta-Analysis [J]. Iran J Public Health, 2020, 49(7): 1222-31. YING Y, WU H, CHEN X, et al. Electrical acupoint stimulation for the treatment of chemotherapy-induced nausea and vomiting: A systematic review and meta-analysis [J]. Heliyon, 2024, 10(10): e30965. ULLAH I, AYAZ M. A re-consideration of neural/receptor mechanisms in chemotherapy-induced nausea and vomiting: current scenario and future perspective [J]. Pharmacol Rep, 2023, 75(5): 1126-37. YEO W, LAU T K, LI L, et al. A randomized study of olanzapine-containing versus standard antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting in Chinese breast cancer patients [J]. Breast, 2020, 50: 30-8. YAN Y, LóPEZ-ALCALDE J, ZHANG L, et al. Acupuncture for the prevention of chemotherapy-induced nausea and vomiting in cancer patients: A systematic review and meta-analysis [J]. Cancer Med, 2023, 12(11): 12504-17. MORAIS S F M, TURRINI R N T. Evaluation of acupuncture and auriculotherapy in the control of chemotherapy-induced nausea and vomiting: a Pilot Study [J]. Rev Esc Enferm USP, 2023, 57: e20230191. EFE ERTüRK N, TAŞCı S. The Effects of Peppermint Oil on Nausea, Vomiting and Retching in Cancer Patients Undergoing Chemotherapy: An Open Label Quasi-Randomized Controlled Pilot Study [J]. Complement Ther Med, 2021, 56: 102587. ZHAO X, WU H, ZHU R, et al. Combination of thalidomide and Clostridium butyricum relieves chemotherapy-induced nausea and vomiting via gut microbiota and vagus nerve activity modulation [J]. Front Immunol, 2023, 14: 1220165. AMIRI KHOSROSHAHI R, ZERAATTALAB-MOTLAGH S, SARSANGI P, et al. Effect of probiotic supplementation on chemotherapy- and radiotherapy-related diarrhoea in patients with cancer: an umbrella review of systematic reviews and meta-analyses [J]. Br J Nutr, 2023, 130(10): 1754-65. HUANG F, LI S, CHEN W, et al. Postoperative Probiotics Administration Attenuates Gastrointestinal Complications and Gut Microbiota Dysbiosis Caused by Chemotherapy in Colorectal Cancer Patients [J]. Nutrients, 2023, 15(2). GUO J, ZHANG H, LU X, et al. Viable Bifidobacterium tablets for the prevention of chemotherapy-/radiation-induced mucositis in patients undergoing haematopoietic stem cell transplantation [J]. Support Care Cancer, 2023, 31(5): 282. GUPTA N, FERREIRA J, HONG C H L, et al. Lactobacillus reuteri DSM 17938 and ATCC PTA 5289 ameliorates chemotherapy-induced oral mucositis [J]. Sci Rep, 2020, 10(1): 16189. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 23 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviewers agreed at journal 27 Sep, 2025 Reviews received at journal 26 Sep, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers invited by journal 18 Aug, 2025 Editor invited by journal 22 Jul, 2025 Editor assigned by journal 27 Jun, 2025 Submission checks completed at journal 27 Jun, 2025 First submitted to journal 17 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6914811","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":504589323,"identity":"992b26ea-3dc1-4c4b-b52f-3b0b73dbcdbc","order_by":0,"name":"Juhang Chu","email":"","orcid":"","institution":"Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Juhang","middleName":"","lastName":"Chu","suffix":""},{"id":504589324,"identity":"533bc0ac-3d28-432f-b21f-529e41cb1862","order_by":1,"name":"Yaru Wang","email":"","orcid":"","institution":"Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yaru","middleName":"","lastName":"Wang","suffix":""},{"id":504589325,"identity":"1bac9220-7a6d-44a1-b702-3ab1b4a29102","order_by":2,"name":"Luyao Huang","email":"","orcid":"","institution":"Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Luyao","middleName":"","lastName":"Huang","suffix":""},{"id":504589326,"identity":"68135666-2bf2-4121-a5eb-72dea79ab487","order_by":3,"name":"Yixiang Huang","email":"","orcid":"","institution":"Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yixiang","middleName":"","lastName":"Huang","suffix":""},{"id":504589327,"identity":"2a642b14-c994-4caa-9c72-e2e857968ebd","order_by":4,"name":"Mingping Qian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYDACZgjFw8/MfPABSVpkJNvZkg1IsszG4DyPmQBRSvmOMz97wJhzh8f4MIMZA0ONTTRBLZKH2cwNGLc94zE7zJD2gOFYWm4DIS0GQMMlGLcdBmk5bsDYcJgYLezfwFqMmxnbJIjUwgOxxYCZmY04LZKHecokQH6ROMzGbJBAjF/4zh/fBtRyx56///zHBx9qbAhrYTgAjM0/IBIEEggqh2qBk6NgFIyCUTAKsAIAqjs6ne5F+LYAAAAASUVORK5CYII=","orcid":"","institution":"Tongji University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Mingping","middleName":"","lastName":"Qian","suffix":""}],"badges":[],"createdAt":"2025-06-17 13:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6914811/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6914811/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89987099,"identity":"b3df9099-242e-45b1-8c30-8c2e1d30ea8d","added_by":"auto","created_at":"2025-08-27 06:57:17","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":138346,"visible":true,"origin":"","legend":"\u003cp\u003eThe influence of probiotics on gut microbiota. (A) Schematic diagram of the interaction of intestinal barrier with pathogenic bacteria, chemotherapeutic drugs, and zonulin. (B) Rarefaction curve. (C-D) Chao index analysis of the intestinal flora at the genus and phylum levels. (E-F) β diversity analysis of intestinal flora in the two groups before and after chemotherapy. TGbase, treatment group before the first chemotherapy; CGbase, control group before the first chemotherapy; TG3cycle, treatment group before the third chemotherapy; CG3cycle, control group before the third chemotherapy.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6914811/v1/2a3d5208605c13d385f9f671.jpg"},{"id":89987107,"identity":"14479de2-62c4-420f-aeac-052213173321","added_by":"auto","created_at":"2025-08-27 06:57:17","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":169662,"visible":true,"origin":"","legend":"\u003cp\u003eThe changes of intestinal flora, clinical laboratory indicators and Zonulin. (A-B) The difference of intestinal flora between the TG and the CG after two courses of chemotherapy. A: LEfSe analysis of gut microbiota in the two groups. B: Wilcoxon rank-sum test box plot of the differences in gut microbiota groups between the two groups. (C) Functional analysis of intestinal flora in the two groups of patients after two courses of chemotherapy. (D-E) Levels of NLR and LMR in the two groups at different periods. (F) Serum levels of zonulin in the two groups at different periods. (G) Spearman correlation heat map between intestinal flora and clinical laboratory indicators.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6914811/v1/e0fdaaeaef2916f98a606012.jpg"},{"id":89988673,"identity":"28f80581-bf1d-496b-adce-07d189b15efc","added_by":"auto","created_at":"2025-08-27 07:05:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1960035,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6914811/v1/69c82439-cee6-47db-a941-f156f36b6ed0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A prospective randomized controlled study of the effects of probiotics on intestinal microecology and gastrointestinal side effects in patients undergoing postoperative chemotherapy for breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe most common malignant tumor worldwide is now breast cancer, surpassing lung cancer. Worldwide, there were 2.3\u0026nbsp;million new cases of breast cancer in 2020, and the disease claimed the lives of over 680,000 people. Chemotherapy has been used alone or in combination with other therapies for the treatments of breast cancer for a long time and has achieved good clinical results. Although the development of therapeutic drugs has made the treatments of breast cancer diversified and individualized, there are still 30% of breast cancer patients die of tumor metastasis and recurrence. It is worth noting that dose reduction, delay and termination of treatments caused by adverse reactions of antineoplastic drugs are also key factors affecting the prognosis of breast cancer patients\u003csup\u003e[1\u0026ndash;3]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe human intestinal tract is rich in microbial species, up to 10\u003csup\u003e14\u003c/sup\u003e in total, and is widely distributed in various parts of the intestine. The bacteria are mainly divided into four phyla, namely Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. The composition and distribution of intestinal microbiota are affected by many factors, including age, genetic factors, immunity, microflora interaction, etc. Under normal physiological conditions, microbiota and host coexist in homeostasis, and the imbalance of homeostasis is closely related to host diseases, such as intestinal inflammation, tumors, and immune system diseases\u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe chemotherapy drug cyclophosphamide (CTX) has the potential to disrupt the gut microbiota by selectively eliminating certain components of the gut flora, inhibiting the proliferation of beneficial bacteria, and consequently altering both the abundance and diversity of the microbial community within the patient's gastrointestinal tract. Some patients receiving CTX treatments will experience serious adverse reactions, mainly including immunosuppression and gastrointestinal reactions. Previous studies\u003csup\u003e[5, 6]\u003c/sup\u003e have confirmed that CTX can damage the intestinal mucosal barrier, increasing intestinal permeability and the colonization of pathogenic bacteria. In addition, CTX can cause damage to intestinal mucosal epithelial cells, reducing the level of short-chain fatty acids (SCFAs) in the intestine, and increase the concentration of ammonia. Probiotics can promote the production of SCFAs and inhibit the formation of ammonia as well as improve intestinal metabolic disorders\u003csup\u003e[7]\u003c/sup\u003e. Consequently, studying the quantity and composition of intestinal flora in patients with malignant tumor chemotherapy can understand the influence of chemotherapy drugs on intestinal flora from the perspective of microecology.\u003c/p\u003e\u003cp\u003eZonulin is the only physiological protein known to regulate intestinal permeability. Many studies\u003csup\u003e[8, 9]\u003c/sup\u003e have confirmed that the increase of serum level of zonulin is accompanied by the increase of intestinal permeability. As one of the important regulatory pathways in tight junction, the zonulin pathway mainly regulates the flow of blood and fluid in the intestinal lumen, and affects the function of macromolecular substances and white blood cells. In consequence, zonulin has also become one of the biomarkers for the diagnosis of \u0026ldquo;leaky gut syndrome\u0026rdquo; (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA)\u003c/p\u003e\u003cp\u003eCombined with previous studies, it is reasonable to infer that CTX can change the composition of intestinal flora, increase the number of pathogenic bacteria. Metabolites secreted by pathogenic bacteria activate the zonulin pathway, which opens tight junctions, increasing the permeability of the intestinal barrier, leading to gastrointestinal side effects. Previous studies have shown that the adjuvant intervention of microecological bacterial agents during chemotherapy can reduce gastrointestinal adverse reactions in patients\u003csup\u003e[10]\u003c/sup\u003e. On account of this, we hypothesized that oral administration of probiotics (Bifico) to patients undergoing chemotherapy could maintain intestinal barrier function and reduce gastrointestinal adverse reactions on the basis of regulating the structure of intestinal flora.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eA total of 50 breast cancer patients who underwent breast surgery and received CTX containing regimen chemotherapy for the first time in Shanghai Tenth People's Hospital from October 2022 to March 2023 were enrolled.\u003c/p\u003e\u003cp\u003eInclusion criteria were as follows: (1) breast cancer was the first primary tumor; (2) patients received chemotherapy for the first time after surgery and the regimen contained CTX.\u003c/p\u003e\u003cp\u003eExclusion criteria were as follows: (1) severe systemic diseases, including heart, liver, and kidney dysfunction; (2) previous chemotherapy or other anti-cancer treatments; (3) treatments with probiotics, prebiotics, or antibiotics within 2 months before recruitment; (4) allergic to probiotics; (5) previous irritable bowel syndrome and inflammatory bowel disease; (6) pregnant and lactating women; And (7) inability to provide informed consent.\u003c/p\u003e\u003cp\u003e This study was approved by the Ethics Committee of Shanghai Tenth People's Hospital (Approval No. SHSY-IEC-4.1/21\u0026ndash;298/01), and conducted in strict accordance with the ethical principles of the Declaration of Helsinki. All participants provided written informed consent prior to their enrollment, ensuring compliance with international standards for human subject protection.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eThis study was a prospective randomized controlled trial and followed the CONSORT Statement rules. At the first postoperative chemotherapy, the enrolled patients who received chemotherapy containing CTX were randomly divided into CG and TG using a random number table method. The CG was treated with chemotherapy alone, and the TG was treated with two courses of Bifico (Bifidobacterium triple viable capsules) orally, three capsules once, twice a day. Patients' stool and blood samples were collected before the first and third chemotherapy. This work was supported by National Natural Fund Cultivation Project (YNCR2C026). Clinical trial number: not applicable.\u003c/p\u003e\n\u003ch3\u003eRecord of adverse effects\u003c/h3\u003e\n\u003cp\u003eChemotherapy-induced gastrointestinal adverse effects include nausea, vomiting, diarrhea, constipation, and oral mucositis (OM). The above grades of gastrointestinal side effects are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This grade classification refers to the Common Terminology Criteria for Adverse Events (CTCAE). The occurrence of chemotherapy-induced gastrointestinal side effects was recorded by filling out questionnaires and regular telephone follow-up.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGrading of chemotherapy-induced gastrointestinal side effects\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrading of gastrointestinal side effects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGrade I\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGrade II\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGrade III\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGrade IV\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea and vomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAppetite was normal and vomit occurred 1 to 2 times/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAppetite decreased and vomit occurred 3 to 5 times/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eVomit more than 5 times per day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnable to eat and vomit more than 10 times per day\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDefecation was \u0026lt;\u0026thinsp;4 times/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDefecation was 4\u0026ndash;6 times/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDefecation was \u0026ge;\u0026thinsp;7 times/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLife-threatening\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConstipation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOccasional symptoms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePersistent symptoms that require Regular treatments with laxatives or enema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSymptoms affect daily life and Require manual dredging of constipation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLife-threatening\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eErythema, but does not interfere with eating\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eErythema, ulcers, but able to eat solid food\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSevere erythema and ulcers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnable to eat\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSample collection\u003c/h3\u003e\n\u003cp\u003eFresh fecal samples (approximately 2 to 4 g) were placed in sterile tubes containing preservation solution, frozen at -20 ̊C within 5 min and stored to -80 ̊C freezer within 24 h. Patients in both groups were instructed to fast for at least 8 hours before each blood collection, and 5 mL of fasting venous blood was drawn the next morning. The whole blood sample was immediately centrifuged at 5000 RPM for 10 minutes at room temperature, and 1 mL of the upper layer of serum was extracted in a 2 mL sterile frozen storage tube. The sample was transferred to a -80\u0026deg;C refrigerator within 2 hours for storage.\u003c/p\u003e\n\u003ch3\u003eMeasuring of serum zonulin, humoral immunity, blood lipids, cytokines and cellular immunity\u003c/h3\u003e\n\u003cp\u003eSerum zonulin content was measured by enzyme linked immunosorbent assay (ELISA) using a commercial kit (human zonulin ELISA kit, Wuhan Elabscience, China) with a sensitivity of 0.47 ng/mL, The detection range was 0.78 ng/mL to 50 ng/mL.\u003c/p\u003e\u003cp\u003eCytokines and humoral immunity were measured by ELISA. The sample to be tested is conjugated to a specific antibody, an enzyme-labeled secondary antibody is added, and the concentration of interleukins and immunoglobulins is quantified by a chromogenic reaction.\u003c/p\u003e\u003cp\u003eCellular immunity was measured by flow cytometry. Cells are sorted and counted using the light scattering and fluorescence properties of flow cytometry by fluorescently labeled antibodies binding to cell surface antigens, resulting in percentage and absolute counts of different cell subpopulations.\u003c/p\u003e\u003cp\u003eBlood lipids are measured using different methods. Total cholesterol (TC) and triglyceride (TG) were determined by enzymatic method. Serum samples were mixed with enzyme reagents and incubated at 37\u0026deg;C for 15 min, after which absorbance was determined and the content calculated. The precipitation method was used to determine the contents of high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Density gradient ultracentrifugation was used to determine the content of small dense low-density lipoprotein (SD-LDL).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStool specimens test methods\u003c/h2\u003e\u003cp\u003eMicrobial genomic DNA was extracted from the samples of each group using nucleic acid extraction reagents. Qubit2.0 was used to detect the concentration and purity of DNA, and the integrity of DNA was detected by 1% agarose gel electrophoresis. Primers were designed to amplify the V3-V4 hypervariable region of 16S rRNA gene, and the PCR products were quantified and paired for sequencing. FASTP software was used for quality control of the original sequencing sequence, and FLASH software was used for assembly. The Silva 16S rRNA database (SSU123) was used to establish a confidence threshold of 70%.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eQiime2 software was used to analyze microbial α-diversity, and β-diversity was assessed by principal co-ordinates analysis (PCoA) based on weighted and unweighted distances. Linear discriminant analysis effect size (LEfSe) analysis considered LDA values\u0026thinsp;\u0026gt;\u0026thinsp;2 as significant differences in relative abundance. Normally distributed data were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and skewed data as median. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eClinical characteristics of breast cancer patients undergoing postoperative chemotherapy\u003c/h2\u003e\u003cp\u003eA total of 50 breast cancer patients who received postoperative chemotherapy containing CTX regimen were included in this study, and they were randomly divided into TG and CG. The clinicopathological indicators of the two groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. There was no significant difference in the basic clinicopathological data of the two groups (\u003cem\u003ep\u0026thinsp;\u0026gt;\u003c/em\u003e\u0026thinsp;0.05), which was comparable.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinicopathological data of patients in TG and CG\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical Measures\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG (N\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCG (N\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.88\u0026thinsp;\u0026plusmn;\u0026thinsp;8.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55.20\u0026thinsp;\u0026plusmn;\u0026thinsp;10.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.637\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.94\u0026thinsp;\u0026plusmn;\u0026thinsp;2.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.343\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMenstrual status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.771\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMenopause\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePremenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnderlying illness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.306\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChemotherapy regimens\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.683\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical approach\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.733\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModified radical mastectomy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBreast conserving surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMolecular typing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.827\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuminal B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHER2 positive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTriple negative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eType of pathology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.440\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInvasive ductal carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePathological grading\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.461\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical staging\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.490\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eA and β diversity analysis of intestinal flora in breast cancer patients undergoing postoperative chemotherapy\u003c/h2\u003e\u003cp\u003eIn this study, the rarefaction curve of each sample was drawn to evaluate the sequencing depth (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Most samples reached the platform at the expected detection depth, confirming the adequacy of sequencing.\u003c/p\u003e\u003cp\u003eChao, Shannon and Simpson index were used to analyze the α diversity of intestinal flora in the TG and the CG before and after two courses of chemotherapy. At the phylum and genus levels, the Chao index of the CG was significantly lower than that of the TG (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC-D)\u003c/p\u003e\u003cp\u003ePCoA showed that there was no statistically significant difference in the β diversity of the gut microbiota between the two groups before chemotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). Under the same condition of receiving two cycles of chemotherapy, the β diversity of intestinal flora in the TG was statistically significantly higher than that in the CG (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eDifferences of intestinal flora in breast cancer patients after chemotherapy\u003c/h2\u003e\u003cp\u003eWilcoxon rank sum test was used to analyze the composition of intestinal flora between the TG and the CG after two courses of chemotherapy. The results showed that the relative abundance of Tyzzerella was significantly increased in the CG without oral Bifico (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024). The relative abundance of Ruminococcus, Clostridia_UCG-014, Eubacterium_coprostanoligenes_group, Christensenellaceae R-7 group were significantly increased in the TG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009).\u003c/p\u003e\u003cp\u003eLEfSe analysis showed that, Prevotella, Eubacterium_coprostanoligenes_group, Clostridla_UCG_014, Ruminococcus, Syntrophobacteria, NK4A214_group, Christensenellaceae R-7 group, Pyramidobacter and Anaerovoracaceae were significantly enriched in the gut microbiota of the TG, and the difference was statistically significant (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.05). Tyzzerella was significantly enriched in the intestinal flora of the CG, and the difference was statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;2A-B).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eFunctional analysis of intestinal flora in breast cancer patients undergoing postoperative chemotherapy\u003c/h2\u003e\u003cp\u003ePicrust2 was used to analyze the intestinal flora function of the TG and the CG after two courses of chemotherapy and compared with the MetaCyc database. It was found that the intestinal flora function of the TG was mainly involved in the synthesis of polyamines, 1, 4-dihydroxy-6-naphthoate, and methylnaphthoquinone (Fig.\u0026nbsp;2C). The intestinal flora of breast cancer patients who did not take Bifico orally plays a pathological role by promoting the synthesis of teichoic acid and methane.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnalysis of changes in serum zonulin and clinical laboratory indicators in breast cancer patients receiving postoperative chemotherapy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCompared with the CG, the level of serum zonulin in the TG was significantly decreased after two cycles of chemotherapy, and the difference was statistically significant (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). There was also a statistically significant difference in the serum level of zonulin before and after chemotherapy in the CG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;2F).\u003c/p\u003e\u003cp\u003eComparing the levels of lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), neutrophil/monocyte ratio (NMR), platelet/lymphocyte ratio (PLR) before and after chemotherapy in the TG and the CG, it can be found that NLR increased and LMR decreased in the CG after two courses of chemotherapy, and the difference was statistically significant (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.05). In the TG, the systemic inflammatory response was reduced after chemotherapy compared with before, but the difference was not statistically significant, indicating that chemotherapy increased the systemic inflammatory level of patients, and oral Bifico can effectively reduce the inflammatory response during chemotherapy (Fig.\u0026nbsp;2D-E).\u003c/p\u003e\u003cp\u003eAfter statistical analysis and summary of the clinical indicators of the enrolled patients, Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e showed that the IgG of the TG was significantly higher than the CG after chemotherapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031). Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows that the levels of TG and SD-LDL in the TG after chemotherapy were significantly lower than the CG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). In the CG, the levels of TG, TC and SD-LDL after chemotherapy were significantly higher than before chemotherapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows that chemotherapy can increase the level of inflammatory response. After oral administration of Bifico, the levels of IL-6 and IL-8 in the TG were significantly lower than the CG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025), and the level of IL-10 was significantly higher than the CG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e shows that chemotherapy significantly reduced the levels of total T cells, Th cells, B cells and Tregs, and inhibited the cellular immunity of the body. Compared with before chemotherapy, the levels of total T cells and Th cells in the TG were significantly increased after oral Bifico treatments (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029). Compared with the CG, the levels of total T cells, Th cells and B cells in the TG after chemotherapy were significantly increased (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHumoral immune indexes of the two groups at different periods (\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHumoral immunity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGrouping\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eTime point\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBefore the first chemotherapy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBefore the third chemotherapy\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgG (g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.16\u0026thinsp;\u0026plusmn;\u0026thinsp;2.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.082\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.59\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.190\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.095\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgA (g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.488\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.66\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.701\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.549\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.693\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgM (g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.727\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.621\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.792\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.465\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgE (IU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e186.6\u0026thinsp;\u0026plusmn;\u0026thinsp;532.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e226.75\u0026thinsp;\u0026plusmn;\u0026thinsp;44.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.175\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e257.45\u0026thinsp;\u0026plusmn;\u0026thinsp;728.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e301.82\u0026thinsp;\u0026plusmn;\u0026thinsp;60.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.214\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.694\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.465\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBlood lipid indexes of the two groups in different periods (\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eBlood lipids\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGrouping\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eTime point\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eBefore the first chemotherapy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBefore the third chemotherapy\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTC (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e5.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.653\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e5.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.896\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.053\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTG (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.44\u0026thinsp;\u0026plusmn;\u0026thinsp;1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.174\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.771\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDL (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.713\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e3.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.181\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.682\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.394\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHDL (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.246\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.697\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.405\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.182\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSD-LDL (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.268\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.710\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCytokine indexes of the two groups at different periods (\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCytokines\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGrouping\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eTime point\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eBefore the first chemotherapy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBefore the third chemotherapy\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-6 (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.39\u0026thinsp;\u0026plusmn;\u0026thinsp;3.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e5.70\u0026thinsp;\u0026plusmn;\u0026thinsp;3.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e9.47\u0026thinsp;\u0026plusmn;\u0026thinsp;8.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.808\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.044\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-8 (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.80\u0026thinsp;\u0026plusmn;\u0026thinsp;51.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e13.28\u0026thinsp;\u0026plusmn;\u0026thinsp;13.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.815\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.70\u0026thinsp;\u0026plusmn;\u0026thinsp;33.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e27.89\u0026thinsp;\u0026plusmn;\u0026thinsp;28.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.395\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.903\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-1β (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.28\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.83\u0026thinsp;\u0026plusmn;\u0026thinsp;4.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.133\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.11\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.271\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.296\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.474\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-10 (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.228\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.10\u0026thinsp;\u0026plusmn;\u0026thinsp;1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.663\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.152\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIFN-a (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e4.05\u0026thinsp;\u0026plusmn;\u0026thinsp;7.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.156\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.94\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.759\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.516\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.274\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNF-a (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.80\u0026thinsp;\u0026plusmn;\u0026thinsp;6.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e7.46\u0026thinsp;\u0026plusmn;\u0026thinsp;12.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.233\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.51\u0026thinsp;\u0026plusmn;\u0026thinsp;11.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e9.36\u0026thinsp;\u0026plusmn;\u0026thinsp;17.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.797\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.836\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIFN-γ (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.982\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.96\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e2.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.300\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.369\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e0.678\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCellular immune indexes of the two groups at different periods (\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCellular immunity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGrouping\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eTime point\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBefore the first chemotherapy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBefore the third chemotherapy\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal T cells (uL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1043.64\u0026thinsp;\u0026plusmn;\u0026thinsp;294.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1298.23\u0026thinsp;\u0026plusmn;\u0026thinsp;575.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.032\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1163.04\u0026thinsp;\u0026plusmn;\u0026thinsp;384.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e972.60\u0026thinsp;\u0026plusmn;\u0026thinsp;408.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.223\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTh cells (uL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e559.32\u0026thinsp;\u0026plusmn;\u0026thinsp;136.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e739.04\u0026thinsp;\u0026plusmn;\u0026thinsp;391.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.029\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e639.76\u0026thinsp;\u0026plusmn;\u0026thinsp;238.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e509.92\u0026thinsp;\u0026plusmn;\u0026thinsp;217.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB cells (uL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e186.04\u0026thinsp;\u0026plusmn;\u0026thinsp;63.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e267.62\u0026thinsp;\u0026plusmn;\u0026thinsp;204.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.064\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e228.2\u0026thinsp;\u0026plusmn;\u0026thinsp;161.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e155.44\u0026thinsp;\u0026plusmn;\u0026thinsp;134.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.232\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNK cells (uL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e270.80\u0026thinsp;\u0026plusmn;\u0026thinsp;146.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e361.08\u0026thinsp;\u0026plusmn;\u0026thinsp;230.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.115\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e283.37\u0026thinsp;\u0026plusmn;\u0026thinsp;193.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e269.92\u0026thinsp;\u0026plusmn;\u0026thinsp;99.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.513\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.797\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.139\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD4\u003csup\u003e+\u003c/sup\u003e/CD8\u003csup\u003e+\u003c/sup\u003eratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.551\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.322\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.068\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTregs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.14\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.07\u0026thinsp;\u0026plusmn;\u0026thinsp;1.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.866\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.320\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCorrelation analysis between gut microbiota and clinical laboratory indicators and zonulin\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAmong the dominant flora in the TG, Christensenellaceae R-7 group was positively correlated with IL-10 and Tregs (r\u0026thinsp;=\u0026thinsp;0.373, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020; r\u0026thinsp;=\u0026thinsp;0.334, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041), and negatively correlated with the levels of serum zonulin, IL-6, IL-8 and NLR (r=-0.387, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; r=-0.436, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006; r=-0.352, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030; r=-0.350, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031) (Fig.\u0026nbsp;2G). Eubacterium_coprostanoligenes_group was positively correlated with IgG and Tregs (r\u0026thinsp;=\u0026thinsp;0.423, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008; r\u0026thinsp;=\u0026thinsp;0.476, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), and negatively correlated with TG (r=-0.352, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030). Ruminococcaceae_NK4A214_group was positively correlated with IL-10 and Tregs (r=-0.454, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004; r= -0.352, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030). r=-0.476, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Synergistota was positively correlated with IL-10 and Tregs (r\u0026thinsp;=\u0026thinsp;0.420, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009; r\u0026thinsp;=\u0026thinsp;0.436, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006), and negatively correlated with serum zonulin, IL-6 and TG (r=-0.337, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039; r=-0.385, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017; r=-0.398, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013). Tyzzerella was positively correlated with serum zonulin (r\u0026thinsp;=\u0026thinsp;0.387, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) and negatively correlated with IL-10 (r=-0.471, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eAnalysis of the occurrence of gastrointestinal side effects in breast cancer patients undergoing postoperative chemotherapy\u003c/h2\u003e\u003cp\u003eThe results showed that the incidence and severity of nausea, vomiting, constipation, diarrhea, and OM were decreased in different degrees after taking Bifico during chemotherapy. The symptoms of constipation and OM in the TG were significantly reduced after chemotherapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAnalysis of gastrointestinal side effects in breast cancer patients undergoing postoperative chemotherapy\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSide effects of digestive tract\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTG (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCG (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea [n(%)]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (92%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.807\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (87.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (73.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (21.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (4.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting [n(%)]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (48%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19 (76%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.935\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (75%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (73.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (26.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge; grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhea [n(%)]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (44%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.952\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (72.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (27.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConstipation [n(%)]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (72%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (96%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (88.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (54.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (41.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (4.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOM [n(%)]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (72%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (88%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (61.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (18.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (38.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (72.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cb\u003eProbiotics alter the composition and function of intestinal flora in breast cancer patients undergoing postoperative chemotherapy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe gut is a complex environment where bacteria, fungi and viruses coexist. Gut microbiota is considered to be the forgotten organ in human health and diseases. It can maintain intestinal homeostasis through a variety of complex mechanisms, further play a role in preventing pathogenic bacteria colonization, immune regulation, inhibition of inflammation, and maintenance of intestinal mucosal barrier\u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAccording to their different functions, the various bacteria in the gut microbiota can be divided into probiotics, opportunistic pathogens and pathogenic bacteria\u003csup\u003e[11]\u003c/sup\u003e. Probiotics refer to microorganisms that are beneficial to the health of the host, including Bifidobacterium, Lactobacillus, Clostridium butyricum, etc. By colonizing the gut's surface, the good bacteria in the gut microbiota create a physical barrier that stops bad bacteria from adhering and growing. The number of dangerous bacteria and the harm they do to the intestinal mucosa are decreased by this competitive inhibitory process. Certain probiotics generate antimicrobial compounds, like organic acids and antimicrobial peptides, which have the ability to kill dangerous bacteria directly and stop them from penetrating the intestinal mucosa. They can also improve immunological function, synthesis vitamins, make SCFAs, and aid in the digestion of meals.\u003c/p\u003e\u003cp\u003eAccording to studies, Clostridium species can prevent excessive immune system activation, maintain immunological homeostasis, and increase the generation of Tregs in the gut. Furthermore, colonization with segmented filamentous bacteria restored T-cell numbers\u003csup\u003e[12]\u003c/sup\u003e. SCFAs, including acetic acid, propionic acid and butyric acid, are mainly produced by bacteria such as Bacteroides, Coprococcus, Rectobacter, and Rochella. They are the main energy source of colonic cells, promote the proliferation of colonic epithelial cells, protect the intestinal mucosa, and inhibit the development of tumors through a variety of mechanisms, such as inhibiting the proliferation of pathogenic bacteria and cancer cells, inducing cancer cell apoptosis, and inhibiting inflammatory response\u003csup\u003e[13]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAs 16S rDNA sequencing and metagenomics technology advance quickly, we have discovered that intestinal flora plays a role in controlling intestinal function, shielding the intestinal mucosa from intestinal pathogen invasion, and stopping harmful bacteria from spreading from the intestine to other tissues. It is also closely related to metabolic syndrome, depression, Alzheimer's disease, inflammatory bowel disease, tumor and other diseases. In addition, the gut microbiota can also influence the efficacy of anti-tumor therapy while reducing its toxicity.\u003c/p\u003e\u003cp\u003eChemotherapy causes harmful side effects such nausea, vomiting, diarrhea, constipation, mouth ulcers, rashes, hair loss, and immunosuppression in addition to their cytotoxic impact on cancer cells. Chemotherapy side effects and toxicity can be considerably reduced by the gut flora and its products. Numerous studies have demonstrated that taking different probiotics and prebiotics together can help with chemotherapy-induced mucositis, lessen diarrhea and abdominal pain, and lower the risk of postoperative complications like pneumonia, infection, and anastomotic leakage \u003csup\u003e[14\u0026ndash;16]\u003c/sup\u003e. Animal studies have also shown consistent outcomes, with probiotic-treated colorectal tumor model mice showing decreased 5-fluorouracil-induced colitis and decreased induction of proinflammatory cytokines\u003csup\u003e[17]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn the present study, we found that the alpha diversity of gut microbiota was significantly decreased in the CG after two cycles of chemotherapy. Compared with the CG, the Bifico plus chemotherapy group had a significant increase in the β diversity of gut microbiota. These results suggest that chemotherapeutic drugs can change the composition of intestinal flora and reduce the abundance and diversity of intestinal microorganisms. Oral administration of Bifico can effectively reverse this trend.\u003c/p\u003e\u003cp\u003eTyzzerella was significantly enriched in the CG after two courses of chemotherapy; Ruminococcus, Prevotella, Eubacterium_coprostanoligenes_group, Clostridla_UCG_014, Syntrophobacteria, NK4A214_group, Christensenellaceae R-7 group, Pyramidobacter and Anaerovoracaceae were significantly enriched in the TG. In the functional study of gut microbiota, teichoic acid and methane synthesis pathways were mainly involved in the CG, while polyamines, 1, 4-dihydroxy-6-naphthoate and methylnaphthoquinone synthesis pathways were mainly involved in the TG. In addition, in the correlation analysis of intestinal flora and clinical laboratory indicators, Tyzzerella was positively correlated with serum zonulin and negatively correlated with IL-10, suggesting that it may be involved in the destruction of intestinal barrier and play a pro-inflammatory role.\u003c/p\u003e\u003cp\u003eLong et\u003csup\u003e[18]\u003c/sup\u003e found a causal relationship between Tyzzerella-3 and lung adenocarcinoma through two-sample Mendelian randomization analysis. Dong et\u003csup\u003e[19]\u003c/sup\u003e found that the relative abundance of Tyzzerella-3 in the group responding to antidepressant treatment for major depressive disorder decreased significantly after receiving antidepressant treatment. In addition, studies have also shown that Tyzzerella is related to the severity of depressive symptoms\u003csup\u003e[20]\u003c/sup\u003e. Zhang et\u003csup\u003e[21]\u003c/sup\u003e constructed a mouse constipation model using loperamide hydrochloride to evaluate the ability of four different proportions of multi-strain probiotic combinations of Bifidobacterium and Lactobacillus to regulate intestinal flora. After four weeks of probiotic intervention, Bifidobacteria-based formulations BM1, BM2 and Lactobacillus based formulations PB2 significantly reduced the abundance of Tyzzerella in stool, down-regulated serum proinflammatory cytokine levels and effectively relieved constipation.\u003c/p\u003e\u003cp\u003eProbiotics can change the composition of intestinal flora in breast cancer patients undergoing chemotherapy, affecting the systemic inflammatory state and intestinal barrier function. However, how the microbiota participate in the regulation of the body's physiological function still needs to be verified in more basic experiments. Whether even changes in the abundance of the same bacteria can alter their role in the host needs further study.\u003c/p\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eProbiotics protect the intestinal mucosal barrier and improve intestinal permeability\u003c/h2\u003e\u003cp\u003eThe human body interacts with the environment through the gut mucosa. Toxins and germs cannot cross the intestinal barrier and enter the body through the gastrointestinal mucosa. Each layer of the intestinal barrier normally carries out its own duty to maintain the body's health. Both transcellular and paracellular pathways can be used by the gut to absorb water and nutrients\u003csup\u003e[6]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eInflammation is brought on by intestinal erosion, ulceration, and epithelial cell death, which permit bigger particles to flow through the epithelium of the gastrointestinal tract without restriction. The intestinal barrier is destroyed by adverse events such medications, trauma, and sepsis. Pathogenic bacteria can enter the bloodstream through damaged intestinal barriers and increased vascular permeability, leading to systemic inflammation and even multiple organ failure. Numerous illnesses, including inflammatory bowel disease, diabetes, non-alcoholic fatty liver disease, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and other mental illnesses, as well as malignancies, have been linked to intestinal barrier failure, according to evidence\u003csup\u003e[22]\u003c/sup\u003e. Toxins and harmful microorganisms cannot harm the gut if the gut barrier is intact.\u003c/p\u003e\u003cp\u003eIn the early 21st century, some scholars studied Vibrio cholerae and found that cholera toxin secreted by Vibrio cholerae could rapidly open the tight junctions between intestinal epithelial cells, leading to an increase in the permeability of the intestinal barrier. A protein produced by human intestinal cells is almost identical to cholera toxin. They named the protein zonulin. To date, zonulin remains the only functional protein known to be involved in regulating the loose and tight state of intestinal epithelial cells functional protein\u003csup\u003e[23]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCeliac disease is a disease involving the breakdown of the intestinal barrier. In this disease, gluten from wheat and other grains has been identified as an environmental trigger for autoimmune responses in genetically susceptible individuals. Gliadin, found in gluten, induces the release of the intestinal epithelial protein zonulin, so zonulin can be used as one of the markers of intestinal permeability in patients with celiac disease\u003csup\u003e[24]\u003c/sup\u003e. In addition to celiac disease, increased intestinal permeability has been reported in other autoimmune diseases.\u003c/p\u003e\u003cp\u003eMany studies\u003csup\u003e[24\u0026ndash;26]\u003c/sup\u003e have shown that in the acute phase of some chronic inflammatory diseases, zonulin is overexpressed, and blocking its pathway can prevent the occurrence of autoimmune responses, suggesting that zonulin is involved in the pathogenesis of these diseases. Ramezani et\u003csup\u003e[27]\u003c/sup\u003e selected 9 studies on the influence of probiotic intake and serum zonulin level, and conducted a meta-analysis involving a total of 496 intervention patients and 443 control patients. The results showed that probiotic preparations had a significant effect on reducing serum zonulin compared with the control group.\u003c/p\u003e\u003cp\u003eThis was confirmed by the results of our study, in which we found that taking probiotics maintained the integrity of the intestinal barrier, reduced intestinal mucosal permeability, and reduced the serum level of zonulin. In addition, the incidence of chemotherapy-induced gastrointestinal side effects in the TG was significantly lower than the CG, suggesting that serum zonulin has the potential to predict gastrointestinal side effects in breast cancer patients receiving chemotherapy.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eProbiotics can alleviate chemotherapy-induced nausea and vomiting\u003c/h2\u003e\u003cp\u003eAccording to the time of onset, CINV can be divided into three categories: acute, delayed and expected. In addition, chemotherapy drugs can be divided into four grades according to their emetogenicity, among which CTX is a drug with high emetogenic risk. Drug therapy is the most commonly used clinical strategy to alleviate CINV, including ondansetron, palonosetron, aprepitant, dexamethasone, etc\u003csup\u003e[28]\u003c/sup\u003e. Some studies have found that adding olanzapine, dopamine, and serotonin receptor inhibitors to standard antiemetic regimens reduces the occurrence of CINV\u003csup\u003e[29]\u003c/sup\u003e. In one study, Yeo et\u003csup\u003e[30]\u003c/sup\u003e found that olanzapine combined with the standard triple antiemetic regimen significantly reduced the incidence of acute and delayed CINV in breast cancer patients.\u003c/p\u003e\u003cp\u003eAt present, many clinicians consider acupuncture therapy, aromatherapy and probiotics as new strategies for the treatments of CINV. In patients receiving highly emetogenic chemotherapy, prophylactic antiemetics combined with acupuncture before and during treatments significantly reduced the incidence of CINV\u003csup\u003e[31]\u003c/sup\u003e. But some scholars have not observed the effect of acupuncture therapy on CINV\u003csup\u003e[32]\u003c/sup\u003e. Therefore, acupuncture and moxibustion therapy still needs to be further verified in large sample randomized controlled trials.\u003c/p\u003e\u003cp\u003eIn a recent study, Efe Erturk et\u003csup\u003e[33]\u003c/sup\u003e confirmed that peppermint aromatherapy combined with standard antiemetics could reduce the frequency and severity of CINV, and this conclusion was also confirmed in another study. Zhao et\u003csup\u003e[34]\u003c/sup\u003e used azomethane oxide and sodium glucan sulfate to induce a mouse model of colorectal cancer to evaluate the improved effects of Thalidomide (THD) and Clostridium butyricum combined therapy on tumor inhibition and CINV. The results showed that the combined treatments of THD and Clostridium butyricum significantly enhanced the anticancer effects of cisplatin by activating the caspase-3 apoptotic pathway, and improved CINV by inhibiting neurotransmitters (such as 5-HT) and their receptors in the brain and colon. In addition, combined treatments of THD and Clostridium butyricum reversed gut microbiota dysbiosis in mice with colorectal cancer by increasing the genus-level abundance of Clostridium, Lactobacillus, Bifidobacterium and Ruminococcus. At the same time, it can reduce the mRNA expression of IL-6, IL-1β and TNF-α, increase the expression of tight junction protein in the colon, and protect the intestinal barrier function.\u003c/p\u003e\u003cp\u003eIn this study, we found that oral Bifico treatments at the same time as chemotherapy in breast cancer patients could appropriately reduce the incidence and severity of CINV, but the difference was not statistically significant, which should be further confirmed in follow-up clinical studies with longer probiotic treatments cycles.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eProbiotics alleviate chemotherapy-induced diarrhea and constipation\u003c/h2\u003e\u003cp\u003eDiarrhea and constipation seriously affect the quality of life and treatments effects of breast cancer patients undergoing chemotherapy. The pathophysiology of chemotherapy-induced diarrhea (CID) and chemotherapy-induced constipation (CIC) is complex and involves a variety of mechanisms, including changes in gastrointestinal secretion, absorption, and innervation. The current treatments available for CID and CIC are dietary changes and pharmacological interventions. Common drugs used to treat CID include loperamide, montmorillonite powder, octreotide, etc. Commonly used drugs for CIC include lactulose, polyethylene glycol, mosapride, etc.\u003c/p\u003e\u003cp\u003eWith the in-depth study of intestinal flora, the efficacy and safety of probiotics in the treatments of CID and CIC have become a research hotspot. Amiri et\u003csup\u003e[35]\u003c/sup\u003e collected randomized clinical trials conducted in adult cancer patients with CID from 2018 to 2020 and studies on the efficacy of probiotic supplements in preventing or treating CID, calculated the relative risk or odds ratio of patients with diarrhea incidence and severity during the intervention period, and included a total of 13 randomized clinical trials. These reports were based on a total of 18 randomized controlled trials reporting the combined effect size of CID, and meta-analyses showed that probiotics had a statistically significant beneficial effect on all outcomes except fecal viscosity. Huang et\u003csup\u003e[36]\u003c/sup\u003e divided 100 patients with diagnosed colorectal cancer into TG and CG. The intervention time was about 6 weeks from the third day after operation to the end of the first chemotherapy course. Probiotics were found to be effective in reducing CID and CIC.\u003c/p\u003e\u003cp\u003eOur results showed that probiotic preparations significantly reduced the incidence and severity of CIC. The incidence of CID was low in TG patients and was further controlled with probiotic preparations, but the efficacy was not statistically significant.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eProbiotics alleviate chemotherapy-induced OM\u003c/h2\u003e\u003cp\u003eOM refers to the inflammatory and ulcerative lesions of oral mucosal epithelium, which are mainly manifested as oral mucosal hyperemia, erythema, edema, erosion, and different degrees of ulceration. For patients with malignant tumors, radiotherapy, chemotherapy, targeted therapy or immunotherapy are the main causes of OM. The treatments of OM usually include cryotherapy and drug therapy, such as chlorhexidine mouthrinse, Kangfuxin solution, and lidocaine gel.\u003c/p\u003e\u003cp\u003eIn recent years, many studies have found that taking probiotics can effectively relieve OM. Guo et\u003csup\u003e[37]\u003c/sup\u003e found that Bifidobacterium tablets could significantly reduce the incidence of chemotherapy-induced OM in patients receiving hematopoietic stem cell transplantation, mainly reducing the incidence of 1\u0026thinsp;~\u0026thinsp;2 grade OM, and the median duration of OM in the probiotic group was shorter. Gupta et\u003csup\u003e[38]\u003c/sup\u003e confirmed for the first time that Lactobacillus reuteri has a protective effect on OM caused by chemotherapy.\u003c/p\u003e\u003cp\u003eAmong the 50 patients included in this study, the incidence of OM in the CG was 88%, and the incidence of OM in the TG was 72%. The incidence of OM at all grades in the TG was also significantly lower than the CG, indicating that probiotics have potential preventive and therapeutic effects on OM.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study is a prospective randomized controlled study. By comparing the gastrointestinal side effects of the TG group and the CG group, and analyzing the intestinal microbiota and blood indexes of the TG group and the CG group, it was shown that Bifico could maintain the intestinal barrier function and alleviate the gastrointestinal side effects caused by chemotherapy on the basis of regulating the structure of the intestinal microbiota. Providing more effective options and potential targets for alleviating chemotherapy-induced gastrointestinal side effects.\u003c/p\u003e\u003cp\u003eThe limited sample size of this study may not adequately represent the situation of all postoperative chemotherapy patients with breast cancer, resulting in limited generalizability of the study results. In addition, although there have been some studies on the mechanism of probiotics regulating intestinal microbiota and immune function, their specific action pathways and interactions with other factors still need to be further explored.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis work was supported by National Natural Fund Cultivation Project, China (YNCR2C026)\u003c/p\u003e\u003cp\u003eConflict of Interest Statements: The authors declare that there is no conflict of interest regarding the publication of this article.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJuhang Chu and Yaru Wang were responsible for data analysis and manuscript writing. Luyao Huang was responsible for collecting data. Yixiang Huang and Mingping Qian were responsible for selecting patients and editing manuscripts. All authors reviewed the manuscript.\u003c/p\u003e\u003cp\u003eEthical Statement: This study was approved by the Ethics Committee of Shanghai Tenth People\u0026apos;s Hospital (Approval number: SHSY-IEC-4.1/21-298/01). All participants provided written informed consent.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGAO X, ZHANG F, ZHOU Q, et al. Metastasis, characteristic, and treatment of breast cancer in young women and older women: A study from the Surveillance, Epidemiology, and End Results registration database [J]. PLoS One, 2023, 18(11): e0293830.\u003c/li\u003e\n\u003cli\u003eUSHIYAMA Y, HORIMOTO Y, MURAKAMI F, et al. Relationship Between Daily Dose of Everolimus and Treatment Effect in Patients With Luminal HER2-negative Metastatic Breast Cancer [J]. Anticancer Res, 2023, 43(11): 5253-9.\u003c/li\u003e\n\u003cli\u003eZHONG Y, LI T, ZHU Y, et al. 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Lactobacillus reuteri DSM 17938 and ATCC PTA 5289 ameliorates chemotherapy-induced oral mucositis [J]. Sci Rep, 2020, 10(1): 16189.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-microbiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcro","sideBox":"Learn more about [BMC Microbiology](http://bmcmicrobiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mcro","title":"BMC Microbiology","twitterHandle":"#bmcmicrobiology","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, Chemotherapy-induced gastrointestinal side effects, Zonulin, Gut microbiota, Probiotics","lastPublishedDoi":"10.21203/rs.3.rs-6914811/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6914811/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eBreast cancer poses a serious threat to women's health, and chemotherapy is a classic treatment for it. However, chemotherapy-induced gastrointestinal toxicity can lead to disease aggravation, treatment failure and even death. Bifico is a commonly used probiotic. This study aimed to explore the effects of Bifico on gastrointestinal side effects caused by chemotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 50 breast cancer patients were enrolled and randomly divided into a treatment group (TG) and a control group (CG) using a 1:1 randomization method. Blood and stool samples were collected and analyzed before the first and third chemotherapy treatment course. The fecal microbiota was analyzed through 16S ribosomal RNA sequencing. The level of serum zonulin was detected before and after chemotherapy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAfter two cycles, the TG showed a richer gut microbiota with increased beneficial bacteria and reduced pathogenic bacteria compared to the CG. Functional analysis indicated the TG's microbiota was involved in polyamine synthesis, while the CG's microbiota was linked to teichoic acid production. Serum zonulin levels decreased significantly in the TG, reflecting improved intestinal barrier function. The TG also had fewer gastrointestinal side effects, particularly constipation and oral mucositis. Additionally, the TG exhibited higher IgG levels and lower triglyceride and small dense low-density lipoprotein levels. Immune function was enhanced in the TG, with increased total T cells, Th cells, and B cells.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study revealed that Bifico can maintain intestinal barrier function, reducing chemotherapy-induced gastrointestinal side effects, and modulate gut microbiota in breast cancer patients.\u003c/p\u003e","manuscriptTitle":"A prospective randomized controlled study of the effects of probiotics on intestinal microecology and gastrointestinal side effects in patients undergoing postoperative chemotherapy for breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 06:57:12","doi":"10.21203/rs.3.rs-6914811/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-23T23:39:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"22498427328630559823426925269712198899","date":"2025-10-03T13:00:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"248329950181274549373549083164715499797","date":"2025-09-27T15:41:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-26T05:08:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124812201311629197652636969098969646437","date":"2025-08-29T21:59:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-18T13:10:11+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-22T17:41:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-27T13:40:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-27T13:38:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Microbiology","date":"2025-06-17T13:12:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-microbiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcro","sideBox":"Learn more about [BMC Microbiology](http://bmcmicrobiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mcro","title":"BMC Microbiology","twitterHandle":"#bmcmicrobiology","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b9ad68bb-e9fc-4e47-b305-0bdc7397323f","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-08-27T06:57:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-27 06:57:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6914811","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6914811","identity":"rs-6914811","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}