Gut microbiota and ovarian diseases: a new therapeutic perspective.

Ovarian malignancy is the third most common gynecological cancer [ 74 ], after cervical and endometrial tumors [ 75 , 76 ]. However, the mortality rate associated with ovarian malignancy is at the top of female genital tract cancers. It’s also important to note that the recurrence rate of this malignancy after treatment is high, as it continues to increase annually [ 77 , 78 ]. Patients often present clinically with significant lower abdominal discomfort, bloating, and loss of appetite, with gastrointestinal symptoms prominent in the overall course of treatment [ 79 , 80 ]. Humans host a diverse range of microorganisms across various organs, including the gut, respiratory tract, and reproductive tract. These microorganisms are crucial for maintaining health. Microbial diversity imbalances in the reproductive and gut tracts can contribute to the development and progression of diseases such as ovarian cancer. The microbiome may play an incidental or associative role in ovarian cancer, with Proteobacteria being more prevalent in cancer patients than in healthy women. Contrastingly, Firmicutes are predominant in healthy women compared to cancer patients. The estrogen-gut axis is vital for estrogen metabolism and utilization, but dysregulation, which may involve certain bacteria, such as Firmicutes, Actinobacteria, and Proteobacteria, is linked to ovarian cancer. Additionally, microorganisms associated with sexually transmitted diseases can impact the onset and progression of ovarian malignancies. Overall, microbes and their metabolites are considered incidental factors that increase the risk of ovarian cancer [ 24 ]. The gut microbiota significantly affects the environment in your digestive system. It also interacts with hormones such as estrogen, androgens, and insulin, thereby influencing the reproductive endocrine system. The relationship between estrogen levels and the gut microbiota is two-way. This means that estrogen regulates the gut microbiota, and vice versa. Estrogen is crucial for the development and maintenance of the female reproductive system. It mainly acts on the lower female reproductive tract, where it increases epithelial thickness, glycogen concentration, and mucus secretion, in addition to promoting the abundance of lactic acid bacteria. Changes in estrogen levels are linked to conditions like endometrial cancer (particularly Type I), endometriosis, and uterine fibroids. Gut bacteria such as E. coli, Bacteroides fragilis, and Streptococcus agalactiae can uncouple glucuronic acid, leading to the reabsorption of active estrogens, this increases their affinity for estrogen beta (ER-β) receptors and may impact tumor formation in the reproductive system [ 76 ]. A study that investigated the relationship between microbiota and gynecological cancers indicated that gut microbiota is strongly associated with the development of some cancers that affect females. The results from the study also highlighted that microbiota products such as lipopolysaccharides can directly promote the production of pro-inflammatory cytokines and increase tumor tolerance of ovarian cancer cells [ 81 ]. In addition, the well-studied theory of dysbiosis of the PCOS gut microbiota has also been implicated in the development of multiple ovarian microcysts [ 82 , 83 ]. Zhou et al. reported that the diversity and abundance of microbiota in ovarian cancer tissue is significantly reduced when compared to normal fallopian tube tissue. This suggests a link between microbiota and ovarian cancer [ 84 ]. Further research suggests two primary mechanisms through which the gut microbiota interfere with estrogen levels and ultimately contribute to the development and progression of ovarian cancer. The first mechanism is the disruption of hepatic-gut estrogen circulation. In this case, the gut microbiota can influence the circulation of estrogen between the liver and the gut, thereby impacting estrogen levels in the body. The second mechanism is the alteration of β-Glucuronidase activity. In this case, the gut microbiota affects the secretion of β-glucuronidase, an enzyme that increases estrogen activity. Higher estrogen levels may enhance gene transcription and mitotic activity, possibly leading to tumor development. Additionally, high β-glucuronidase activity may cause carcinogens to be produced, further promoting tumorigenesis (Fig.  4 ) [ 85 ].However, this mechanism is still highly controversial. The study also raises the possibility of using microbes as therapeutic tools to enhance immunity and improve anti-tumor responses. It further highlights the potential of using gut microbiota as a novel biomarker for cancer. Wahid et al. have demonstrated that balancing the microbiome composition of gynecological cancers is a promising therapeutic target [ 8 ]. Lactobacillus can lower pH, produce bacteriocins, and competitively exclude other bacteria. The use of prebiotics, probiotics, and fecal microbiota transplants with specific bacterial strains can aid in achieving and maintaining a balanced gut microbiota. These interventions may help to restore or enhance the microbial community, potentially supporting overall health and addressing various conditions that are linked to microbiota imbalances. A healthy microbiome can train and activate the body’s immune response to target various gynecological cancers. Modulating the microbiome may also enhance immuno-oncology therapy. Microorganisms trigger innate and adaptive immune system responses, and this may promote malignancy [ 86 ]. Inflammatory mediators such as cytokines and chemokines have a direct impact on tumors and contribute to several markers of cancer [ 87 ].Bacteria affect carcinogenesis in four ways: stimulating cell proliferation or death, disrupting immune system function, affecting host cell metabolism [ 88 ], and triggering genomic instability and DNA damage [ 89 ]. Bacteria use their components, products, and metabolism to interact with tissues and potentially influence cancer development. Ovarian cancer is one of the main causes of death related to gynecological cancers. Although surgery and platinum-based chemotherapy are standard treatments, most patients will relapse and die from the disease. Chambers LM et al. have shown that the use of antibiotics may affect the efficacy of chemotherapy and immunotherapy in patients with non-gynecological cancers. Through a retrospective single-institution cohort study (2009–2015), 424 newly diagnosed patients with ovarian cancer were included, all of whom received cytoreductive surgery and chemotherapy. The grouping results were patients who received antibiotic treatment, anti-Gram-positive bacteria antibiotics such as vancomycin, and those who did not receive antibiotic treatment. After statistical analysis, it was concluded that patients receiving antibiotic treatment significantly reduced progression-free survival and overall survival. The use of anti-Gram-positive antibiotics had a more significant impact on the survival of patients. Researchers have demonstrated that the use of antibiotics is associated with a shortened progression time of ovarian diseases and a deterioration in overall survival, affecting the response and resistance to platinum-based chemotherapy [ 90 ].The application of antibiotics can disrupt the balance of the gut microbiota. The destruction of the microbiota structure may lead to the aggravation of patients’ symptoms or the occurrence of complications, affecting the ultimate survival time and treatment effect of patients. Chambers LM et al. found that ovarian tumors in mice treated with antibiotics grew faster, resulting in a reduced efficacy of cisplatin and a shortened survival period of mice. Researchers believe that antibiotics significantly disrupt the diversity of the gut microbiota, reduce non-drug-resistant bacterial species, and increase drug-resistant bacteria such as Enterobacteriaceae. Chambers LM et al. transplanted the gut microbiota of control group mice into antibiotic-treated mice, which restored cisplatin sensitivity and prolonged survival. Metabolite detection revealed that antibiotics reduced the metabolites of gut microbiota in plasma (such as indole-3-propionic acid and indoleophenol sulfate), and gut microbiota transplantation could partially restore the levels of these metabolites. Antibiotics lead to drug resistance by reducing DNA damage (down-regulation of 53BP1), enhancing repair (up-regulation of BRCA1), and promoting angiogenesis (up-regulation of CD31). Meanwhile, RNA sequencing revealed that the expression of stem cell-related genes (such as SOX2 and WNT7a) in tumors treated with antibiotic was upregulated, and the epithelial-mesenchymal transition and hypoxia pathways were activated. The research supports the role of the intestinal microbiota in inhibiting tumor growth and maintaining chemotherapy sensitivity, suggesting that antibiotics should be used with caution in clinical practice to avoid disrupting the microbiota. Meanwhile, this also suggests that microbiota transplantation or metabolite intervention may be a new strategy to overcome platinum resistance [ 91 ]. The microbiome’s role in tumor development, particularly estrogen-mediated cancer, is of great interest. Microbes that are associated with cancer can target the Wnt/β-catenin signaling pathway in several ways. Bacteria may attach to epithelial cells through FadA adhesion, and this allows them to invade the host tissue and induce inflammatory responses that contribute to carcinogenesis. FadA activates β-catenin by binding to E-cadherin on the surface of the host cell. This interaction causes differential regulation of inflammatory processes and promotes carcinogenic responses. This stimulates cell growth and supports the development of cancer. Signaling cascades and receptor recognition patterns may be involved in breaking down the boundary between host cells and microbes. The NF-κB and STAT3 signaling pathways are crucial in regulating chronic inflammatory feed-forward loops that are linked to cancer development [ 92 – 94 ]. These pathways contribute to sustained inflammation, which can aid tumorigenesis. Additionally, susceptibility to HIV significantly increases when the vaginal epithelial barrier is disrupted, often due to the influence of vaginal bacteria. These bacteria play a key role in enhancing the secretion of pro-inflammatory cytokines during the epithelial cell response to HIV, thereby exacerbating the infection and its effects [ 95 ]. Fig. 4 Gut microbiota be involved in the development and progression of ovarian cancer by influencing estrogen levels, with the main mechanisms being (1) gut microbiota interfering with the hepatic-gut circulation of estrogen (2) gut microbiota interfering with the secretion of b-glucuronidase, thereby increasing estrogen activity. By Figdraw Gut microbiota be involved in the development and progression of ovarian cancer by influencing estrogen levels, with the main mechanisms being (1) gut microbiota interfering with the hepatic-gut circulation of estrogen (2) gut microbiota interfering with the secretion of b-glucuronidase, thereby increasing estrogen activity. By Figdraw Fig. 5 POI: gut microbiota like Mycobacterium phylum, Butyric acid bacteria, Doriaceae, Lactobacillus genus are more abundant in the POI patients. PCOS: gut microbiota like Clostridium colorless, Clostridium spp and Faecococcus spp are more abundant in the POI patients. Cancer: gut microbiota interfering with the hepatic-gut circulation of estrogen and secretion of b-glucuronidase, elevating estrogen activity. By Figdraw. POI: gut microbiota like Mycobacterium phylum, Butyric acid bacteria, Doriaceae, Lactobacillus genus are more abundant in the POI patients. PCOS: gut microbiota like Clostridium colorless, Clostridium spp and Faecococcus spp are more abundant in the POI patients. Cancer: gut microbiota interfering with the hepatic-gut circulation of estrogen and secretion of b-glucuronidase, elevating estrogen activity. By Figdraw.

Increasingly more research has explored the gut microbiota and its potential effects on human health. Studies indicate that alterations in the gut microbiota may be associated with the development and progression of various diseases (Fig.  5 ). Notably, emerging evidence suggests a strong link between gut microbiota dysbiosis and ovarian-related infertility, possibly mediated through systemic inflammation, hormonal imbalance, and metabolic disturbances [ 96 ]. Empirical evidence from animal models provides strong support for the role of the microbiome in chronic disease conditions. Human diseases are consistently linked to fecal microbiota, with recent systematic reviews highlighting parallel disruptions in both gut and genital tract microbiomes in fertility disorders.The microbiota of diseased individuals significantly differs from that of healthy individuals in terms of taxonomic composition, diversity indices, and/or functional values/abundance. The disease-associated changes in the microbiome are commonly known as the ‘dysbiosis’ microbiome domain. Identifying the etiological components of the complex microbiota responsible for pathology can be quite challenging. This is mainly due to the highly individualized nature of the community, which comprises bacteria, archaea, fungi, viruses, and protozoa. All these microorganisms, along with their metabolites, may significantly contribute to the development of diseases, either individually or in combination. The studies that were highlighted and discussed in this review have clearly established a significant correlation between gut microbiota and ovarian disease. Various ovarian diseases have been observed to cause changes in microbiota. Moreover, animal studies have provided compelling evidence of the causal relationship between microbiota and ovarian disease, mainly through regulatory pathways, immunity, or pathogenic mechanisms. It’s important to note that alterations in the gut microbiota may have potential benefits in disease treatment. Further evidence is needed to determine causality, concomitance, or unrelatedness to the disease. The function of gut microbiota has become increasingly important to various medical fields in recent years. As a result, extensive research is being undertaken concerning the mechanisms of action through which the gut microbiota interferes with diseases. Moreover, the available methods for microbiota analysis have advanced. Characterizing the gut microbiota in various ovarian disease populations provides insight into certain pathological mechanisms. Different drugs alter the gut microbiota, thereby presenting a link and potential target for pharmacological mechanisms of action. Using probiotics to regulate gut microbiota presents a safe and effective therapy for ovarian disease. The introduction of active health in China has made primary prevention of ovarian disease from the gut microbiota a possibility. Further research on the mechanism of action of the gut microbiota is crucial as it positively impacts human health.

Two doctoral researchers systematically reviewed studies published in the past ten years on the relationship between gut microbiota and ovarian diseases, prioritizing those with human clinical data, followed by well-designed animal experiments. The selection criteria focused on studies exploring the associations between gut microbiota composition and common ovarian diseases, such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), endometriosis, and ovarian cancer. Studies were excluded if they: (1) investigated gut microbiota in non-ovarian diseases (e.g., diabetes, cardiovascular disorders); or (2) employed concurrent therapies known to interact with gut microbiota (e.g., antibiotics, probiotics, or fecal microbiota transplantation) without controlling for their confounding effects. Based on the collected evidence, we analyzed the role of gut microbiota dysbiosis in ovarian disease pathogenesis, particularly its impact on inflammatory and metabolic pathways. This review also highlights the potential of gut microbiota modulation as an adjunctive therapeutic strategy for ovarian diseases, providing new perspectives on its clinical applications in reproductive health.

The ovaries secret sex hormones that maintain the normal function of many female organs, thereby playing a crucial role in women’s reproductive and endocrine functions [ 1 – 2 ]. Much research has been done on ovarian inflammation [ 3 – 4 ], polycystic ovary syndrome [ 5 , 6 ], and ovarian tumors [ 7 , 8 ], all of which are prevalent in women. The human gut microbiome is a diverse and intricate community of microorganisms that inhabit the gastrointestinal tract, and these include bacteria, viruses, and fungi [ 9 , 10 ]. This community is composed of approximately 10¹³ to 10 14 microorganisms, including over 1,000 species and more than 7,000 strains [ 11 ]. The gut microbiota is essential in shaping and developing the immune system [ 5 , 12 ], in addition to preventing infection [ 13 ], aiding nutrient supply, and maintaining brain and nervous system function in the host [ 14 ]. Imbalances in the composition [ 15 ] and diversity of the gut microbiota [ 16 ], along with altered metabolic function [ 17 ], can cause inflammation and increased gut permeability, both of which result in disease [ 18 ]. The gut microbiota affects brain function via the gut-brain axis [ 19 ]. It activates neurons through the vagus nerve, endocrine signaling, and immune pathways [ 20 – 22 ]. Significant changes in microbiota were observed in various ovarian diseases. This highlighted a strong association between the gut microbiota and ovarian disease [ 23 ]. Results from animal studies have indicated a potential causal relationship between the gut microbiota and ovarian diseases, possibly through regulatory pathways [ 24 – 27 ], immune responses, or pathogenic mechanisms [ 28 , 29 ]. However, there is no clarity as to whether the alterations in the gut microbiota are a cause, consequence, or mere coincidence in the development of these diseases. Therefore, more research is necessary to confirm the potential benefits of targeting the gut microbiota in disease treatment. This paper reviews the latest advancements in research on gut microbiota and ovarian diseases, to offer new perspectives for preventing and treating these conditions. The findings from this review also unleash more information regarding the pathogenesis of ovarian diseases.