Disentangling the Immune Cell-Mediated Causal Effects of Gut Microbiota on Inflammatory Bowel Disease via Mendelian Randomization

Disentangling the Immune Cell-Mediated Causal Effects of Gut Microbiota on Inflammatory Bowel Disease via Mendelian Randomization | 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 Disentangling the Immune Cell-Mediated Causal Effects of Gut Microbiota on Inflammatory Bowel Disease via Mendelian Randomization Lintao Dong, Jingping Hu, Fang Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6723420/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Inflammatory Bowel Disease (IBD), including Crohn's Disease and Ulcerative Colitis, is a chronic intestinal inflammation that significantly impacts patients' quality of life. Recently, studies have highlighted that the gut microbiota can influence the pathogenesis of IBD by mediating immune cells. Methods :We used a two-sample bidirectional Mendelian Randomization (MR) analysis on genetically predicted gut microbiota and IBD. Additionally, a two-step MR approach was applied to quantify the mediating effect of HLA DR on monocytes on the influence of gut microbiota on IBD. Results :The results indicate that Alistipes shahii significantly reduces the risk of developing IBD (IVW odds ratio [OR] per SD increase in IBD =0.8917/ 0.5944 P =0.0373/0.0389），HLA-DR on monocyte, as the intermediary factor between Alistipes shahii and IBD, can strengthen the protective effect of Alistipes shahii on IBD, and the proportion of mediation effect accounted for 13.9% Conclusion :In summary, our study found that the protective effect of HLA DR On monocytes enhanced the protective effect of Alistipes shahii on IBD in Finland. However, most of the mechanisms by which Alistipes shahii affects IBD on monocytes via HLA DR are unknown.Further research is needed to explore other risk factors as potential mediators. Gastroenterology & Hepatology causal relationship Alistipes shahii HLA DR on monocyte mendelian randomization inflammatory bowel disease Figures Figure 1 Figure 2 Figure 3 1. INTRODUCTION Inflammatory Bowel Disease(IBD) is a type of chronic and relapsing intestinal inflammation disease including Crohn's Disease and Ulcerative Colitis[ 1 ]. The incidence and prevalence rate of IBD continue to increasingly become common diseases that affect severely patients' quality of life and social economy[ 2 ]. The pathogenesis of IBD is not entirely definite[ 3 ]. Various pieces of research indicate that the interaction between genetic susceptibility and environmental factors may play a role in the pathogenesis. Common environmental hazardous factors include smoking, dietary habits, infections, and other factors[ 4 – 6 ]. In addition, impaired immune system function and intestinal barrier function are essential for the progression of IBD[ 7 , 8 ]. The gut microbiota consists of trillions of microbes living in the body's intestine, mainly including bacteria, viruses, fungi, archaea, and other microorganisms, which are vital components in maintaining human health[ 9 , 10 ]. Recently, the increasing number of studies shows that the gut microbiota plays a crucial role in the pathogenic mechanism of IBD[ 11 , 12 ]. The composition of gut microbiota in patients with IBD shows significant differences compared to healthy individuals, not only in terms of microbial species but also in their abundance and function[ 13 , 14 ]. Various metabolites produced by gut microbiota play a key role in regulating intestinal inflammation and immune responses[ 15 , 16 ]. Short-chain fatty acids, such as butyrate, promote the generation of regulatory T cells while inhibiting the release of pro-inflammatory cytokines, effectively suppressing inflammation[ 17 , 18 ]. Additionally, microbial metabolites provide energy to intestinal epithelial cells, promoting their differentiation and helping to maintain the integrity of the gut barrier[ 19 , 20 ]. In recent years, studies have shown a bidirectional interaction between gut microbiota and the host immune system[ 21 , 22 ]. Gut microbes can interact with host immunity, in which immune cells maintain gut microbiota homeostasis and gut microbiota supports host immune function[ 23 ]. Human Leukocyte Antigen D region(HLA-DR) is a major histocompatibility complex class II molecule expressed on antigen-presenting cells (APCs) such as monocytes, macrophages, dendritic cells, and B cells. It plays a crucial role in delivering processed antigens to T cells and activating adaptive immune responses. HLA-DR on monocytes is used as a marker to assess the status of the immune system, which reflects its functional status[ 24 ]. When patients are infected with acute inflammatory diseases (such as injury and sepsis), the expression of HLA-DR on monocytes is reduced. This reduces the innate immune system's responsiveness to pathogens, thereby increasing the risk of secondary infection and poor prognosis in patients[ 25 ]. In addition, some scholars have proposed that the immune response of patients can be restored by improving the expression of HLA-DR[ 26 ]. Gut microbiota can directly interact with intestinal immune cells to modulate the host's immune response[ 27 ]. This complex interaction mechanism plays a crucial role in maintaining intestinal immune homeostasis and regulating inflammation. Previous studies, which were mostly observational, had certain inherent limitations. Their results were influenced by confounding factors and reverse causality. However, compared with previous observational studies, Mendelian randomization (MR) analysis better removes the effect of potential confounding factors such as environmental factors, dietary habits, and lifestyle[ 28 ]. Therefore, MR can better reveal the complex causal relationship between gut microbiota, immune cells, and IBD, which not only deepens our understanding of gut microbiota and immune cells in the pathogenesis of IBD, but also provides important guidance for clinical individualized intervention. MR analysis is a type of analysis that utilizes genetic variation as instrumental variables (IVs), which assesses the causal relationship between hazardous factors and the clinical outcome of observational data[ 29 ]. In addition, compared to traditional observational studies, MR effectively reduces bias caused by confounding factors or reverse causality, ensuring higher reliability and validity of the experimental results[ 30 ]. Recently, researchers have discussed the causal relationship between gut microbiota and IBD by MR analysis[ 31 , 32 ]. However, previous studies were limited in the types of gut microbiota exposure data they collected. In this study, exposure data of 473 types of gut microbiota are used, covering a much wider range of gut microbiota. On this basis, we also add immune cells as mediators to help us more comprehensively understand the complex mechanism of gut microbiota and immune cells in inflammatory bowel disease (IBD). 2. MATERIALS AND METHODS 2.1 Study design All data are from published sources with prior ethical approval; no additional review is needed. Methods followed the STROBE-MR checklist. IBD was the outcome, using FinnGen as the exploration dataset (ED) and European data as validation (VD). We analyzed 473 gut microbiota (exposures) and 731 immune cells (mediators), using SNPs as IVs to assess causality. Cross-population validation was applied to reduce bias and enhance result reliability (In Fig. 1 )[ 33 ]. 2.2 Data sources Our gut microbiota data comes from GWAS of 5959 individuals in the FINRISK 2002 cohort, a Finnish population study conducted every five years since 1972. Participants aged 25–74 were sampled from six regions, and fecal samples were frozen at − 20°C and later sequenced. Summary statistics for 473 microbiota traits (GCST90032172–GCST90032644) are available at EBI GWAS[ 34 ]. We used IBD GWAS data from Finnish (FinnGen R11: 322 cases, 438,277 controls) and European (IIBDGC meta-analysis: 12,882 cases, 21,770 controls) cohorts. The FinnGen project provides detailed participant info[ 35 ],while European data (12.7 million SNPs) are available at IEU GWAS[ 36 ]. We obtained GWAS data on 731 immune cell types from 3,757 Europeans (GCST90001391–GCST90002121). These include absolute counts, surface antigen levels, relative counts, and morphological traits, classified into seven immune cell groups[ 37 ]. 2.3 Instrumental variable selection and data harmonization We involve SNPs(P < 5 × 10^-8)as IVs at the genome-wide significance level. If SNPs do not reach the genome-wide significance level, SNPs with P < 1 × 10^-5 are used as candidate IVs[ 38 ]. Then, these SNPs are clustered based on linkage disequilibrium (window size = 10,000kb and r2 < 0.001). Linkage disequilibrium levels are estimated from the 1000 Genomes Project based on European samples[ 39 ]. We assess the robustness of the selected SNPs as instrumental variables (IVs) by analyzing the F-statistic to mitigate the risk of instrumental variable bias. The F-statistic is calculated using the formula [(N – K – 1)/K]/[R²/(1 – R²)], where K is the number of genetic variants and N is the sample size. We exclude weak instrumental variables (F-statistic < 10)[ 40 ]. 2.4 Statistical analysis In our MR Study, we analyze the data using R software (version 4.3.1) and the "Two-Sample MR "package the "foreach" package and" ggplot2 "package, and inverse variance weighted (IVW) method, MR Egger, Weighted Median, Weighted Mode, and Simple Mode are used to evaluate the causal relationship between gut microbiota and IBD.Because the IVW method produces consistent causal effects without heterogeneity, we chose it as our primary method[ 41 ].If the IVW result is significant (P < 0.05), this confirms the existence of a causal relationship. The direction of causality can be determined by the direction of the estimated effect[ 42 – 44 ]. 2.5 Mediation analysis Figure 1 shows the frame diagram of the analysis. Firstly, we discover a significant causal relationship between Alistipes shahii and IBD through two-sample Mendelian randomization, which is referred to as the direct effect. Then, we conduct a two-sample bidirectional MR analysis to explore the causal relationship between 731 immune cells and ED and VD. Finally, we analyze the causal relationship between Alistipes shahii and immune cells to explore whether HLA DR on monocyte mediates a causal pathway from Alistipes shahii to IBD. Overall effects can be divided into indirect effects (through mediators) and direct effects (without mediators)[ 45 ]. The total effect of Alistipes shahii on IBD can be divided into the direct effect of Alistipes shahii on IBD and the indirect effect of Alistipes shahii mediated through immune cells. We calculate the percentage of the mediation effects by dividing the indirect effect by the total effect[ 46 ]. 2.6 Sensitivity analysis We estimate heterogeneity among IVs by using Cochran’s Q statistic. A P value less than 0.05 indicates statistically significant heterogeneity among IVs[ 47 ]. We test level pleiotropy by using the MR-Egger intercept method and the MR-PRESSO global test. Horizontal pleiotropy is not considered present if the P value is greater than 0.05[ 48 , 49 ]. Finally, leave-one-out analysis is used to validate the effect of each SNP on the overall causal estimates. After detecting outliers, we re-evaluate the causal effect after removing these outliers. 3. RRSULTS 3.1 Association of 473 Gut Microbiota with IBD After removing palindromic and ambiguous SNPs, firstly, the causal relationship between 473 gut microbiota and ED and VD is analyzed at the genome-wide significance level (P < 1 x 10 − 5).19 types of gut microbiota are significantly associated with VD and 23 with ED by IVW (In Fig. 2 ). We use 10–39 SNPs to generate IVs, in which all gut microbiota have F values greater than 10 in gut microbiota associated with VD (In Supplementary Table S1); we also use 9–29 SNPs to generate IVs, in which all gut microbiota have F values greater than 10 in gut microbiota associated with ED. Then we identify overlapping gut microbiota in ED and VD (In Fig. 2 A). To be specific, we discover that Alistipes shahii shows consistent associations in ED and VD. Alistipes shahii significantly reduces the risk of developing IBD (IVW odds ratio [OR] per SD increase in VD = 0.8917 [95% CI, 0.8006 − 0.9933], P = 0.0373);(IVW odds ratio [OR] per SD increase in ED = 0.5944 [95% CI, 0.3628 − 0.9738], P = 0.0389). Additionally, We conduct reverse Mendelian randomization with IBD patients as exposure and Alistipes shahii as outcome, and the results show that there is no reverse causality between genetically predicted IBD and Alistipes shahii(In Supplementary Table S3༉. 3.2 Association of 731 immune cells with IBD We analyze a causal relationship between 731 immune cells and ED and VD at genome-wide significance level (P < 1 x 10 − 5). We obtain 54 types of immune cells associated with VD and 37 types of immune cells associated with ED (In Supplementary Table S5). Then, we identify that HLA DR on monocytes is associated with both ED and VD. (In Fig. 2 B). The genetic instrument for HLA DR on monocyte explained 1.5% and 1.6% of the variance for the ED and VD, respectively, with F-statistic of 57 and 61 (Supplementary Table S5).The IVW method shows that the genetically predicted HLA DR on monocyte has a positive correlation with VD [OR = 1.0759,95% CI, 1.0038 − 1.1533; P = 0.0388]; and a negative correlation with ED [OR = 0.6538,95% CI, 0.4545 − 0.9404; P = 0.0220](In Fig. 3 ). Additionally, we use data from patients with IBD as exposure and HLA DR on monocyte as the outcome to conduct reverse Mendelian randomization, showing no reverse causality between genetically predicted IBD and Alistipes shahii (In Supplementary Table S3). 3.3 Association of Alistipes shahii with HLA DR on monocyte We analyze HLA DR on monocyte as the medium from the Alistipes shahii to the IBD pathway.We find that Alistipes shahii is associated with increased HLA DR on monocyte(In Supplementary Table S4), but HLA DR on monocyte is associated with increased risk of VD (associated with decreased risk of ED ). Based on the beta_all and beta_direct, HLA DR on monocyte weakens part of the protective effect of Alistipes shahii on IBD. (beta_direct=-0.12,beta_all=-0.11,beta1*2: 1.2%; Mediating Effect:NA in the VD ; beta_direct=-0.44,beta_all=-0.52,beta1*2: -0.07%; Mediating Effect:13.9% in the ED). 3.4 Sensitivity analyses We examine heterogeneity in the results using Cochran's Q-test and funnel plot. Thus it can be seen that there is no heterogeneity or asymmetry in the causal relationship between these SNPs (In Supplementary Table S2 and Supplementary Fig. 1). We also examine horizontal pleiotropy using the MR-Egger intercept and MR-PRESSO global test, showing no horizontal pleiotropy (In Supplementary Table S2 ). The effect of each SNP on the overall causal estimate is verified by a leave-one-out analysis (supplementary Figure S2). 3.5 Results after FDR correction The aforementioned results did not demonstrate statistical significance after the implementation of FDR correction for multiple comparisons. 4. DISCUSSION This research discusses the causal relationship between gut microbiota and IBD using a two-sample bidirectional Mendelian randomization method, which using ED and VD confirmed that Alistipes shahii may reduce the risk of IBD. These findings suggest that gut microbiota may have a protective effect against IBD. In recent years, it has been confirmed that the gut microbiota composition of IBD patients differs from that of healthy subjects[ 50 ]. Li et al . suggested that the main manifestation of gut microbiota imbalance in IBD patients was the decrease of Firmicutes and Bacteroidetes, while the bacterial species of Enterobacteriaceae are relatively increased[ 51 ]. Sha et al .also found that the most common pattern of gut microbiota imbalance is the decrease in diversity of symbiotic bacteria, especially in the species of Bacteroidetes[ 52 ]. Alistipes shahii is a bacterial species within the genus Alistipes of the Bacteroidetes phylum.Currently the known Alistipes genus includes the following 13 species: Alistipes finegoldii, Alistipes putredinis, Alistipes onderdonkii, Alistipes shahii, Alistipes indistinctus, Alistipes senegalensis, Alistipes timonensis, Alistipes obesi, Alistipes ihumii, Alistipes inops, Alistipes megaguti, Alistipes provencensis and Alistipes massiliensis[ 53 ]. Interestingly, several studies have investigated changes in the abundance of Alistipes bacteria in human patients and mouse models during the disease. Studies showed that the gut microbiota imbalance of Alistipes is a double-edged sword. Moschen et al. further demonstrated that in WT, LCN 2 KO, and IL-10 KO C57BL/6J mice, oral administration of Alistipes finegoldii for one week induced intestinal inflammation[ 54 ].However, other researchers have observed contradictory findings, where the intervention of Alistipes finegoldii significantly reduced the severity of colitis in mice induced by oral DSS[ 55 ]. In addition, previous studies have shown that the abundance of Alistipes shows an increasing trend in the microbial community spectrum of NOD2 knockout mice. This was confirmed by Butera et al ., who reported that NOD2 knockout mice that were given trinitrobenzene sulfonic acid (TNBS) through the rectum to induce colitis showed milder symptoms of colitis than wild-type mice. It was further found that NOD2 knockout mice showed an increase in Alistipes flora and anti-inflammatory cytokines[ 56 ].This suggests that the imbalance of Alistipes is an important marker of intestinal inflammation; however, the role Alistipes plays in the metabolic mechanisms of the gut microbiota remains unclear.The above studies are consistent with our results obtained through Mendelian randomization, suggesting that Alistipes may play a vital role in IBD. However, most studies are largely concentrated on other species of the genus Alistipes, and less research on Alistipes shahii. A study on mice with hepatocellular carcinoma (HCC) showed that treatment with a probiotic called Prohep resulted in reduced tumor growth and a decrease in Th17 cells, while the anti-inflammatory cell subsets Treg/Tr1 increased. Notably, the abundance of Alistipes in the mice also increased[ 57 , 58 ].Collectively, these studies suggest that Alistipes shahii may influence IBD through immune cell-mediated mechanisms. Several studies have shown that monocytes are potential targets for conventional IBD therapies[ 59 , 60 ]. HLA-DR is an important immune molecule that is widely expressed on the surface of various immune cells, particularly monocytes[ 61 ]. It belongs to the major histocompatibility complex (MHC) class II molecules, which are primarily responsible for presenting exogenous antigens to CD4 + T cells and subsequently initiating and regulating the immune response[ 62 ]. Macrophages and dendritic cells are transformed from monocytes and are an important part of the innate immune system. High expression of HLA-DR usually marks the activation of monocytes. Monocyte levels are significantly increased in IBD patients[ 63 ]. Additionally, previous studies also have observed that elevated levels of functionally suppressed HLA-DR-myeloid-derived cells are found in IBD patients, reflecting the need for immunosuppression in the disease state. L et al. report that CD14(+)HLA-DR(hi) monocytes show a significant increase in the blood of patients with active IBD.” Monocyte subsets not only produce pro-inflammatory cytokines that may trigger or exacerbate an inflammatory response but also guide the migration of monocytes to the inflammatory sites in the colon. This guidance is achieved through the expression of the C-C chemokine receptor 9[ 64 , 65 ]. This is consistent with our study. In addition, Joshi et al. highlight that monocyte HLA-DR has advantages in analytical validity and a direct biological link to mononuclear phagocyte function, making it a potential gold standard for identifying sepsis immune paralysis. They also confirm that Granulocyte-Macrophage Colony-Stimulating Factor therapy can restore immune function and improve patient outcomes by upregulating monocyte HLA-DR expression[ 66 ]. Given that IBD is also an immune system dysfunction-related disease, the regulatory role of HLA-DR⁺ monocytes in the protective effect against Alistipes shahii in this study suggests that they may also have value in "immune status monitoring" or "therapeutic response prediction" in IBD. In the future, we can further explore whether it can be used as a key biomarker in the individualized decision-making of IBD treatment and even become one of the evaluation indicators of immune intervention. Specific Alistipes strains (such as Alistipes onderdonkii) may participate in the occurrence of postoperative poor anastomotic healing by up-regulating the expression of pro-inflammatory factors (such as TNF-α and IL-1β) in the intestinal mucosa. This proinflammatory phenotype is detected preoperatively and could be transferred to mouse models via fecal bacterial transplantation, suggesting that its inflammatory regulation depends on microflora composition[ 67 ]. In addition, the abundance of Alistipes is positively correlated with circulating IL-17 levels in the population, further supporting its possible proinflammatory potential. However, it is worth noting that Alistipes is not a whole proinflammatory, and different strains of Alistipes may play completely different roles in inflammatory response[ 68 ]. In a recent study on coronary atherosclerotic disease (CAD), researchers not only focus on the correlation between Alistipes and the disease but also introduce immune cells and inflammatory factors as mediating mechanisms. Studies have found that Alistipes is significantly reduced in CAD patients, and with the increase of circulating LPS level, it further activates monocytes or macrophages, induces the production of pro-inflammatory factors such as MCP-1, and promotes the adhesion and migration of monocytes to vascular endothelia[ 69 – 71 ]. This study provides a new perspective for understanding Alistipes' mechanism of disease mediated by immune cells and also suggests that many biological pathways involved in immune regulation may have commonalities among different tissues and systems. Therefore, the findings in the CAD model can also provide references for the study of other disease mechanisms. Notably, another study using a breast cancer mouse model found that amino acid–optimized nutritional supplements significantly increased the abundance of Alistipes in the gut, thereby maintaining muscle function during chemotherapy[ 72 ]. Studies have shown that Alistipes can produce short-chain fatty acids(SCFAs), such as butyric acid, propionic acid, and acetic acid, which are not only important sources of energy for intestinal epithelial cells but also regulate immune and inflammatory states through various mechanisms[ 73 , 74 ]. Butyric acid and propionic acid have been shown to exert anti-inflammatory effects by acting on monocytes and their downstream signaling pathways. Butyric acid can inhibit histone deacetylase(HDAC)activity in monocytes, and then inhibit NF-κB mediated inflammatory pathway, and reduce the expression of TNF-α, IL-6 and IL-12[ 75 – 77 ]. In addition, SCFAs can also induce the polarization of monocytes and macrophages towards the anti-inflammatory M2 phenotype by activating G protein-coupled receptors such as free fatty acid receptor 2 and niacin receptor, promote immune tolerance and alleviate inflammation[ 78 – 81 ]. In patients with IBD, downregulation of FFAR2 expression has been linked to persistent inflammation, and SCFA-mediated FFAR2 activation reduces lamina propria monocytes' overresponse to symbiotic bacteria. At the same time, butyrate can activate GPR109A, induce the secretion of anti-inflammatory factor IL-10, promote the differentiation of regulatory T cells (Tregs), and inhibit the activation of inflammatory dendritic cells[ 82 , 83 ]. Therefore, we speculate that Alistipes shahii may be involved in the immune regulation of IBD through two different but interrelated mechanisms in IBD. On the one hand, Alistipes shahii may directly interact with gut innate immune cells (such as monocytes) to influence their activation status or differentiation direction. For example, it may bind to pattern recognition receptors (such as TLR4) via specific bacterial components, like cell wall components or low-toxicity lipopolysaccharides, to induce anti-inflammatory immune cells and thereby reduce mucosal inflammation. On the other hand, A. shahii may also indirectly act on monocytes through its metabolites (such as short-chain fatty acids or indole tryptophan metabolites) to regulate key IBD pathways, including NF-κB, HDAC, FFAR2, GPR109A, and AHR. Interestingly, we find that in Finnish IBD patients, HLA-DR enhances the protective effect of Alistipes shahii on monocytes. However, in the European population, HLA-DR expression weakens this protective effect. In Fig. 3 , Mendelian randomization analysis with HLA-DR expression on monocytes as the exposure variable and IBD as the outcome shows that in the European population: [OR = 1.0759, 95% CI: 1.0038–1.1533, P = 0.0388]. In the Finnish population: [OR = 0.6538, 95% CI: 0.4545–0.9404, P = 0.0220], the effect direction is opposite, and the difference is statistically significant. This difference between populations may be due to the combined effect of multiple factors. First, the HLA-DRB1 allele frequency varies significantly between Finland and other European populations. For example, the Finnish-specific A03-B35-DRB101:01 haplotype is rare elsewhere in Europe, while DRB103:01 (AH 8.1) is more common. These differences may impact the antigen-presenting ability and immunoregulatory mechanisms of HLA-DR molecules in monocytes[ 84 ]. Secondly, the composition of the gut microbiota also varies significantly among different populations. The interactions between microbial communities may indirectly modulate HLA-DR-mediated immune effects, thereby influencing the function of Alistipes shahii. In the early stage of the disease, the immune response is relatively mild, and HLA-DR may play an anti-inflammatory role by regulating the function of monocytes, enhancing the protective effect of Alistipes shahii. In advanced stages, the continuously activated immune system and upregulated HLA-DR may amplify inflammation, weaken Alistipes shahii’s benefits, and exacerbate mucosal damage [ 85 , 86 ]. Notably, studies in Asian populations have shown that the abundance of Alistipes shahii is significantly increased in healthy elderly individuals and may exert potential protective effects in energy metabolism and immune homeostasis through alternative butyrate-producing pathways (such as lysine → butyrate). Aarthi Ravikrishnan et al. not only emphasized the population specificity of gut microbiota functions across different ethnic groups but also provided indirect support for our observation in European populations that Alistipes shahii may reduce the risk of IBD[ 87 ]. Although Alistipes shahii may influence host health through distinct mechanisms in different populations, its consistent association with “anti-inflammatory” or “metabolic health” traits across multiple cohorts suggests that it may possess a relatively conserved beneficial function. This provides both theoretical rationale and population-based support for future investigations into the relationship between Alistipes shahii and IBD, as well as for microbiota-based intervention studies in broader populations. Furthermore, fecal microbiota transplantation (FMT) is an emerging technology to treat disease by transplanting normal fecal microbiota obtained from healthy donors[ 88 , 89 ]. Many animal studies have explored FMT as a potential tool for the treatment of various intestinal diseases and other metabolic disorders[ 90 – 92 ]. However, the number of randomized controlled trials of FMT for IBD is still limited, and the efficacy is affected by many factors, such as the composition of the flora, donor selection and host differences. Although it is unclear whether transplantation of A. shahii can alleviate IBD, previous studies suggest Alistipes may play an important role in maintaining intestinal homeostasis and immune balance. Therefore, further study of the specific mechanisms of Alistipes in IBD, and exploration of its potential protective role via metabolites (such as short-chain fatty acids, tryptophan metabolites, etc.) or immunomodulatory pathways, could provide a theoretical basis for its use as a potential "next-generation probiotic" or FMT target in IBD treatment. Of course, there are still many challenges in translating Alistipes's basic research findings into clinical applications. For example, there is a lack of systematic safety assessment of the bacteria in humans, and its colonization ability and long-term effects are unclear. In addition, how to achieve large-scale cultivation, accurate delivery, and maintain stable ecological functions in different populations is also a problem that must be solved in the future. In the future, it can be combined with metabolomics, single-cell transcriptome and spatial omics technology to screen its key regulatory pathways and action targets, to promote its clinical transformation and provide new ideas for individualized treatment of IBD. Our study has several limitations. First, our study is mainly based on the analysis of the European and Finnish populations, so the universality of the results may be limited to other populations. As Chinese scholars, we should further collect the sequencing data of gut microbiota and IBD patients in the Asian population to explore whether Alistipes shahii has a causal relationship with IBD patients in the Asian population. Second, in this study, although the results did not reach the strict threshold for FDR correction, we believe they may be biologically significant. For example, these results are consistent with existing literature and experimental observations, suggesting a potentially important association. In fact, in many practical biomedical studies, extremely strict statistical thresholds can sometimes reduce sensitivity to potential discoveries, especially in areas of research with complex mechanisms and multiple potentially interfering factors. Finally, this study reveals a potential causal relationship between Alistipes shahii and HLA-DR on monocyte in the development of IBD. However, HLA-DR on monocyte, as the intermediary factor in the protective effect of Alistipes shahii against IBD, only accounted for 13.9% of the mediating effect. This indicates that this pathway could only explain part of the role of Alistipes shahii in the occurrence and development of IBD. However, its specific mechanism remains to be further explored. This indicates that there are still other more important immune regulatory or metabolic pathways in the protective effect of Alistipes shahii on IBD, which need to be further explored and verified. Future studies can use the combination of single-cell transcriptome sequencing and spatial omics to screen possible related immune regulatory factors, to determine which immune cells play a more important role in the process of Alistipes shahii's influence on IBD. In addition, Alistipes shahii may also regulate HLA-DR on monocyte through its metabolites (such as short-chain fatty acids SCFAs, secondary bile acids, tryptophan metabolites, etc.), and possible metabolites can be explored through metabolomics and transcriptomics in the future. Despite these limitations, our study also shows significant advantages. First, in addition to being based on a single dataset, our findings are repeatedly verified by analyzing two different ethnic GWAS datasets. The use of GWAS data with the largest number of participants ensures strong statistical power and minimizes confounding effects common in observational studies. Abbreviations Inflammatory Bowel Disease（IBD) Mendelian randomization (MR) single nucleotide polymorphism（SNPs） Exploration Database(ED) Radiation Database(VD) instrumental variables（IVs） Declarations Data availability statement The datasets used in this study are accessible through online repositories. The article's Table 1 include the repository names and accession numbers. We are deeply appreciative of all participants and researchers who shared these valuable datasets. Author Contributions Lintao Dong,Jingping Hu:Writing original draft,Methodology,Formal analysis, Conceptualization. Fang Wang*:Writing – review & editing, Conceptualization. Funding This work was supported by the National Natural Science Foundation of China (Grant No. 82460563, project title: The mechanism of PFKFB4 inhibition of SIRT2-mediated ketone body degradation regulating Rela/ZZ modification in promoting chemoresistance in colorectal cancer). Acknowledgments The data for the exposure and outcome in this study were obtained from the GWAS database, and both have received ethical approval and participant informed consent. We appreciate all the participants and investigators for sharing these data. Conflict of interest The authors declare that they have no competing interests. References Sartor RB. 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Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39237540&query_hl=1 doi: 10.1038/s41467-024-52097-9 Fanizzi F, D'Amico F, Zanotelli BI, Zilli A, Furfaro F, Parigi TL, et al. The role of fecal microbiota transplantation in IBD. Microorganisms. 2024 2024 Aug 23;12(9). Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39338430&query_hl=1 doi: 10.3390/microorganisms12091755 Kim DY, Lee SY, Lee JY, Whon TW, Lee JY, Jeon CO, et al. Gut microbiome therapy: fecal microbiota transplantation vs live biotherapeutic products. Gut Microbes. 2024 2024 Jan-Dec;16(1):2412376. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39377231&query_hl=1 doi: 10.1080/19490976.2024.2412376 Sbahi H, Di Palma JA. Faecal microbiota transplantation: applications and limitations in treating gastrointestinal disorders. BMJ Open Gastroenterol. 2016 2016;3(1):e000087. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=27239328&query_hl=1 doi: 10.1136/bmjgast-2016-000087 Singh V, Choi SD, Mahra K, Son H, Lee H, Lee YJ, et al. Cultured fecal microbial community and its impact as fecal microbiota transplantation treatment in mice gut inflammation. Appl Microbiol Biotechnol. 2024 2024 Sep 13;108(1):463. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39269473&query_hl=1 doi: 10.1007/s00253-024-13295-z Ye W, Fan J, Wu W, Chen Z, Huang Q, Qian L. Effects of fecal microbiota transplantation on metabolic health of DBA mice. Front Microbiol. 2024 2024;15:1352555. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38444807&query_hl=1 doi: 10.3389/fmicb.2024.1352555 Table Table1 Details of the genome-wide association studies and datasets used in this study. Exposure or outcome Sample size Links for datadownload PMID 473 Gut microbiota 5959 https://www.ebi.ac.uk/gwas/GCST90032172-GCST90032644 35115689 European IBD population 34652 https://gwas.mrcieu.ac.uk/datasets/ieu-a-31/ 26192919 Finnish IBD population 438599 https://storage.googleapis.com/finngen-public-data-r11/summary_stats/finngen_R11_K11_IBD_STRICT_PSC.gz 36653562 731immune cells 3757 https://www.ebi.ac.uk/gwas/GCST90001391-90002121 37582716 Additional Declarations The authors declare no competing interests. Supplementary Files STROBEMRchecklistfillable.docx SupplementaryFigure.docx SupplementaryTable.xlsx Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6723420","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":460345697,"identity":"3e764ff6-5ae4-4ef7-bef7-910a8b187f08","order_by":0,"name":"Lintao Dong","email":"","orcid":"","institution":"The First Clinical Medical School, Ningxia Medical University, Yinchuan, China","correspondingAuthor":false,"prefix":"","firstName":"Lintao","middleName":"","lastName":"Dong","suffix":""},{"id":460345698,"identity":"16b10920-6543-4075-a5c7-d6e4c5adb819","order_by":1,"name":"Jingping Hu","email":"","orcid":"","institution":"The First Clinical Medical School, Ningxia Medical University, Yinchuan, China","correspondingAuthor":false,"prefix":"","firstName":"Jingping","middleName":"","lastName":"Hu","suffix":""},{"id":460345699,"identity":"e55fb3c9-f605-417d-93ce-6cc7357aab0c","order_by":2,"name":"Fang Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYLCCCiDmZ29sfvDBwMaOOC1ngFiy5/AxwxkFacnEazG4kZYgzfPhEGMDIdUGx88efnGg5o7dhjNnDIxtDA4wM7AfProBr5YzeWkWB449S555vMfgcY7BHT4GnrS0G/i0mB3IMTP+wHY4mQ9kS47BM2YGCR4z/FrOvzEzOPDvcDLDjRwDaQuDw4wNBLXcyDF+cLDtsJ0AyPsMxGixv/HGjOFg3+EEcCD3GKQlsxHyi2R/jvGHA98O24Oj8scfGzt+9sPH8GoBAjYJIJHYAOcSUA4CzB9ADiRC4SgYBaNgFIxUAAAGW1jE3evz7AAAAABJRU5ErkJggg==","orcid":"","institution":"The First Clinical Medical School, Ningxia Medical University, Yinchuan, China,Department of Gastroenterology, General Hospital, Ningxia Medical University, Yinchuan ,Ningxia, China","correspondingAuthor":true,"prefix":"","firstName":"Fang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-05-22 09:28:01","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6723420/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6723420/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83440042,"identity":"5f97d5c9-2318-43f0-ab25-068e56916dd3","added_by":"auto","created_at":"2025-05-26 09:20:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":171256,"visible":true,"origin":"","legend":"\u003cp\u003eExperimental flow chart.Step 1 represents the bi-directional causal relationship between gut microbiota and IBD;Step 2 represents the bi-directional causal relationship between immune cells and IBD；Step 3 represents the mediaing analysis of HLA DR on monocyte in the pathway from the Alistipes shahii to Inflammatory bowel disease。The total effect was decomposed into: (i) indirect effect using a two-step approach (where a is the effect of Alistipes shahii on HLA DR on monocyte, and b is the effect of HLA DR on monocyte on IBD) and the mediating effect (a × b) and (ii) direct effect (c-a*b). Proportion mediated was the indirect effect divided by the total effect\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/061bc25ae86f6f1e01a2670d.jpg"},{"id":83440044,"identity":"c630513e-be6d-4d55-88ef-145ca158ed65","added_by":"auto","created_at":"2025-05-26 09:20:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":449682,"visible":true,"origin":"","legend":"\u003cp\u003eThe Venn diagram summarizes and synthesizes the results obtained in this study.(A)The overlapping region in the Venn diagram represents the gut microbiota that are significantly associated with both ED and VD.(B)The overlapping region in the Venn diagram represents the Immune cells that are significantly associated with both ED and VD.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/572243936acbdec4cc16f260.jpg"},{"id":83440050,"identity":"791e427b-a352-4c13-9775-c8b172be4a93","added_by":"auto","created_at":"2025-05-26 09:20:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3072338,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot to visualize the causal effects of HLA DR on monocyte with Alistipes shahii and IBD.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/3a19079db189251fd372d421.jpg"},{"id":83441068,"identity":"d99087d7-c8e9-4f81-8480-8a0bf7835b3c","added_by":"auto","created_at":"2025-05-26 09:36:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4555106,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/674938f8-b33e-4801-ac87-4fa17a371d38.pdf"},{"id":83440046,"identity":"48f189ee-8fe6-49da-9cfb-5a85074cc198","added_by":"auto","created_at":"2025-05-26 09:20:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":43431,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEMRchecklistfillable.docx","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/59fe97057045bdda18b428b4.docx"},{"id":83440049,"identity":"5b6d381c-025a-4f87-becd-98faee7d28e6","added_by":"auto","created_at":"2025-05-26 09:20:51","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":199524,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.docx","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/bb71424dc630faaa64267e0b.docx"},{"id":83440047,"identity":"1382efb8-71f5-4012-81ea-e858551d5da5","added_by":"auto","created_at":"2025-05-26 09:20:51","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":796153,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6723420/v1/a8ac222498cdad513bb95e6c.xlsx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eDisentangling the Immune Cell-Mediated Causal Effects of Gut Microbiota on Inflammatory Bowel Disease via Mendelian Randomization\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eInflammatory Bowel Disease(IBD) is a type of chronic and relapsing intestinal inflammation disease including Crohn's Disease and Ulcerative Colitis[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence and prevalence rate of IBD continue to increasingly become common diseases that affect severely patients' quality of life and social economy[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The pathogenesis of IBD is not entirely definite[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Various pieces of research indicate that the interaction between genetic susceptibility and environmental factors may play a role in the pathogenesis. Common environmental hazardous factors include smoking, dietary habits, infections, and other factors[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, impaired immune system function and intestinal barrier function are essential for the progression of IBD[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The gut microbiota consists of trillions of microbes living in the body's intestine, mainly including bacteria, viruses, fungi, archaea, and other microorganisms, which are vital components in maintaining human health[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recently, the increasing number of studies shows that the gut microbiota plays a crucial role in the pathogenic mechanism of IBD[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The composition of gut microbiota in patients with IBD shows significant differences compared to healthy individuals, not only in terms of microbial species but also in their abundance and function[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Various metabolites produced by gut microbiota play a key role in regulating intestinal inflammation and immune responses[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Short-chain fatty acids, such as butyrate, promote the generation of regulatory T cells while inhibiting the release of pro-inflammatory cytokines, effectively suppressing inflammation[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Additionally, microbial metabolites provide energy to intestinal epithelial cells, promoting their differentiation and helping to maintain the integrity of the gut barrier[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In recent years, studies have shown a bidirectional interaction between gut microbiota and the host immune system[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Gut microbes can interact with host immunity, in which immune cells maintain gut microbiota homeostasis and gut microbiota supports host immune function[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Human Leukocyte Antigen D region(HLA-DR) is a major histocompatibility complex class II molecule expressed on antigen-presenting cells (APCs) such as monocytes, macrophages, dendritic cells, and B cells. It plays a crucial role in delivering processed antigens to T cells and activating adaptive immune responses. HLA-DR on monocytes is used as a marker to assess the status of the immune system, which reflects its functional status[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. When patients are infected with acute inflammatory diseases (such as injury and sepsis), the expression of HLA-DR on monocytes is reduced. This reduces the innate immune system's responsiveness to pathogens, thereby increasing the risk of secondary infection and poor prognosis in patients[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In addition, some scholars have proposed that the immune response of patients can be restored by improving the expression of HLA-DR[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Gut microbiota can directly interact with intestinal immune cells to modulate the host's immune response[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This complex interaction mechanism plays a crucial role in maintaining intestinal immune homeostasis and regulating inflammation. Previous studies, which were mostly observational, had certain inherent limitations. Their results were influenced by confounding factors and reverse causality. However, compared with previous observational studies, Mendelian randomization (MR) analysis better removes the effect of potential confounding factors such as environmental factors, dietary habits, and lifestyle[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, MR can better reveal the complex causal relationship between gut microbiota, immune cells, and IBD, which not only deepens our understanding of gut microbiota and immune cells in the pathogenesis of IBD, but also provides important guidance for clinical individualized intervention. MR analysis is a type of analysis that utilizes genetic variation as instrumental variables (IVs), which assesses the causal relationship between hazardous factors and the clinical outcome of observational data[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In addition, compared to traditional observational studies, MR effectively reduces bias caused by confounding factors or reverse causality, ensuring higher reliability and validity of the experimental results[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Recently, researchers have discussed the causal relationship between gut microbiota and IBD by MR analysis[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, previous studies were limited in the types of gut microbiota exposure data they collected. In this study, exposure data of 473 types of gut microbiota are used, covering a much wider range of gut microbiota. On this basis, we also add immune cells as mediators to help us more comprehensively understand the complex mechanism of gut microbiota and immune cells in inflammatory bowel disease (IBD).\u003c/p\u003e"},{"header":"2. MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design\u003c/h2\u003e \u003cp\u003eAll data are from published sources with prior ethical approval; no additional review is needed. Methods followed the STROBE-MR checklist. IBD was the outcome, using FinnGen as the exploration dataset (ED) and European data as validation (VD). We analyzed 473 gut microbiota (exposures) and 731 immune cells (mediators), using SNPs as IVs to assess causality. Cross-population validation was applied to reduce bias and enhance result reliability (In Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data sources\u003c/h2\u003e \u003cp\u003eOur gut microbiota data comes from GWAS of 5959 individuals in the FINRISK 2002 cohort, a Finnish population study conducted every five years since 1972. Participants aged 25\u0026ndash;74 were sampled from six regions, and fecal samples were frozen at \u0026minus;\u0026thinsp;20\u0026deg;C and later sequenced. Summary statistics for 473 microbiota traits (GCST90032172\u0026ndash;GCST90032644) are available at EBI GWAS[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe used IBD GWAS data from Finnish (FinnGen R11: 322 cases, 438,277 controls) and European (IIBDGC meta-analysis: 12,882 cases, 21,770 controls) cohorts. The FinnGen project provides detailed participant info[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e],while European data (12.7\u0026nbsp;million SNPs) are available at IEU GWAS[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe obtained GWAS data on 731 immune cell types from 3,757 Europeans (GCST90001391\u0026ndash;GCST90002121). These include absolute counts, surface antigen levels, relative counts, and morphological traits, classified into seven immune cell groups[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Instrumental variable selection and data harmonization\u003c/h2\u003e \u003cp\u003eWe involve SNPs(P\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10^-8)as IVs at the genome-wide significance level. If SNPs do not reach the genome-wide significance level, SNPs with P\u0026thinsp;\u0026lt;\u0026thinsp;1 \u0026times; 10^-5 are used as candidate IVs[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Then, these SNPs are clustered based on linkage disequilibrium (window size\u0026thinsp;=\u0026thinsp;10,000kb and r2\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Linkage disequilibrium levels are estimated from the 1000 Genomes Project based on European samples[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. We assess the robustness of the selected SNPs as instrumental variables (IVs) by analyzing the F-statistic to mitigate the risk of instrumental variable bias. The F-statistic is calculated using the formula [(N \u0026ndash; K \u0026ndash; 1)/K]/[R\u0026sup2;/(1 \u0026ndash; R\u0026sup2;)], where K is the number of genetic variants and N is the sample size. We exclude weak instrumental variables (F-statistic\u0026thinsp;\u0026lt;\u0026thinsp;10)[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eIn our MR Study, we analyze the data using R software (version 4.3.1) and the \"Two-Sample MR \"package the \"foreach\" package and\" ggplot2 \"package, and inverse variance weighted (IVW) method, MR Egger, Weighted Median, Weighted Mode, and Simple Mode are used to evaluate the causal relationship between gut microbiota and IBD.Because the IVW method produces consistent causal effects without heterogeneity, we chose it as our primary method[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].If the IVW result is significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), this confirms the existence of a causal relationship. The direction of causality can be determined by the direction of the estimated effect[\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Mediation analysis\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the frame diagram of the analysis. Firstly, we discover a significant causal relationship between Alistipes shahii and IBD through two-sample Mendelian randomization, which is referred to as the direct effect. Then, we conduct a two-sample bidirectional MR analysis to explore the causal relationship between 731 immune cells and ED and VD. Finally, we analyze the causal relationship between Alistipes shahii and immune cells to explore whether HLA DR on monocyte mediates a causal pathway from Alistipes shahii to IBD. Overall effects can be divided into indirect effects (through mediators) and direct effects (without mediators)[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The total effect of Alistipes shahii on IBD can be divided into the direct effect of Alistipes shahii on IBD and the indirect effect of Alistipes shahii mediated through immune cells. We calculate the percentage of the mediation effects by dividing the indirect effect by the total effect[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Sensitivity analysis\u003c/h2\u003e \u003cp\u003eWe estimate heterogeneity among IVs by using Cochran\u0026rsquo;s Q statistic. A P value less than 0.05 indicates statistically significant heterogeneity among IVs[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. We test level pleiotropy by using the MR-Egger intercept method and the MR-PRESSO global test. Horizontal pleiotropy is not considered present if the P value is greater than 0.05[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Finally, leave-one-out analysis is used to validate the effect of each SNP on the overall causal estimates. After detecting outliers, we re-evaluate the causal effect after removing these outliers.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. RRSULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Association of 473 Gut Microbiota with IBD\u003c/h2\u003e \u003cp\u003eAfter removing palindromic and ambiguous SNPs, firstly, the causal relationship between 473 gut microbiota and ED and VD is analyzed at the genome-wide significance level (P\u0026thinsp;\u0026lt;\u0026thinsp;1 x 10\u0026thinsp;\u0026minus;\u0026thinsp;5).19 types of gut microbiota are significantly associated with VD and 23 with ED by IVW (In Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). We use 10\u0026ndash;39 SNPs to generate IVs, in which all gut microbiota have F values greater than 10 in gut microbiota associated with VD (In Supplementary Table S1); we also use 9\u0026ndash;29 SNPs to generate IVs, in which all gut microbiota have F values greater than 10 in gut microbiota associated with ED.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThen we identify overlapping gut microbiota in ED and VD (In Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). To be specific, we discover that Alistipes shahii shows consistent associations in ED and VD. Alistipes shahii significantly reduces the risk of developing IBD (IVW odds ratio [OR] per SD increase in VD\u0026thinsp;=\u0026thinsp;0.8917 [95% CI, 0.8006\u0026thinsp;\u0026minus;\u0026thinsp;0.9933], P\u0026thinsp;=\u0026thinsp;0.0373);(IVW odds ratio [OR] per SD increase in ED\u0026thinsp;=\u0026thinsp;0.5944 [95% CI, 0.3628\u0026thinsp;\u0026minus;\u0026thinsp;0.9738], P\u0026thinsp;=\u0026thinsp;0.0389). Additionally, We conduct reverse Mendelian randomization with IBD patients as exposure and Alistipes shahii as outcome, and the results show that there is no reverse causality between genetically predicted IBD and Alistipes shahii(In Supplementary Table S3༉.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Association of 731 immune cells with IBD\u003c/h2\u003e \u003cp\u003eWe analyze a causal relationship between 731 immune cells and ED and VD at genome-wide significance level (P\u0026thinsp;\u0026lt;\u0026thinsp;1 x 10\u0026thinsp;\u0026minus;\u0026thinsp;5). We obtain 54 types of immune cells associated with VD and 37 types of immune cells associated with ED (In Supplementary Table S5). Then, we identify that HLA DR on monocytes is associated with both ED and VD. (In Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The genetic instrument for HLA DR on monocyte explained 1.5% and 1.6% of the variance for the ED and VD, respectively, with F-statistic of 57 and 61 (Supplementary Table S5).The IVW method shows that the genetically predicted HLA DR on monocyte has a positive correlation with VD [OR\u0026thinsp;=\u0026thinsp;1.0759,95% CI, 1.0038\u0026thinsp;\u0026minus;\u0026thinsp;1.1533; P\u0026thinsp;=\u0026thinsp;0.0388]; and a negative correlation with ED [OR\u0026thinsp;=\u0026thinsp;0.6538,95% CI, 0.4545\u0026thinsp;\u0026minus;\u0026thinsp;0.9404; P\u0026thinsp;=\u0026thinsp;0.0220](In Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Additionally, we use data from patients with IBD as exposure and HLA DR on monocyte as the outcome to conduct reverse Mendelian randomization, showing no reverse causality between genetically predicted IBD and Alistipes shahii (In Supplementary Table S3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Association of Alistipes shahii with HLA DR on monocyte\u003c/h2\u003e \u003cp\u003eWe analyze HLA DR on monocyte as the medium from the Alistipes shahii to the IBD pathway.We find that Alistipes shahii is associated with increased HLA DR on monocyte(In Supplementary Table S4), but HLA DR on monocyte is associated with increased risk of VD (associated with decreased risk of ED ). Based on the beta_all and beta_direct, HLA DR on monocyte weakens part of the protective effect of Alistipes shahii on IBD. (beta_direct=-0.12,beta_all=-0.11,beta1*2: 1.2%; Mediating Effect:NA in the VD ; beta_direct=-0.44,beta_all=-0.52,beta1*2: -0.07%; Mediating Effect:13.9% in the ED).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Sensitivity analyses\u003c/h2\u003e \u003cp\u003eWe examine heterogeneity in the results using Cochran's Q-test and funnel plot. Thus it can be seen that there is no heterogeneity or asymmetry in the causal relationship between these SNPs (In Supplementary Table S2 and Supplementary Fig.\u0026nbsp;1). We also examine horizontal pleiotropy using the MR-Egger intercept and MR-PRESSO global test, showing no horizontal pleiotropy (In Supplementary Table S2 ). The effect of each SNP on the overall causal estimate is verified by a leave-one-out analysis (supplementary Figure S2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Results after FDR correction\u003c/h2\u003e \u003cp\u003eThe aforementioned results did not demonstrate statistical significance after the implementation of FDR correction for multiple comparisons.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThis research discusses the causal relationship between gut microbiota and IBD using a two-sample bidirectional Mendelian randomization method, which using ED and VD confirmed that Alistipes shahii may reduce the risk of IBD. These findings suggest that gut microbiota may have a protective effect against IBD. In recent years, it has been confirmed that the gut microbiota composition of IBD patients differs from that of healthy subjects[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Li \u003cem\u003eet al\u003c/em\u003e. suggested that the main manifestation of gut microbiota imbalance in IBD patients was the decrease of Firmicutes and Bacteroidetes, while the bacterial species of Enterobacteriaceae are relatively increased[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Sha \u003cem\u003eet al\u003c/em\u003e.also found that the most common pattern of gut microbiota imbalance is the decrease in diversity of symbiotic bacteria, especially in the species of Bacteroidetes[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Alistipes shahii is a bacterial species within the genus Alistipes of the Bacteroidetes phylum.Currently the known Alistipes genus includes the following 13 species: Alistipes finegoldii, Alistipes putredinis, Alistipes onderdonkii, Alistipes shahii, Alistipes indistinctus, Alistipes senegalensis, Alistipes timonensis, Alistipes obesi, Alistipes ihumii, Alistipes inops, Alistipes megaguti, Alistipes provencensis and Alistipes massiliensis[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Interestingly, several studies have investigated changes in the abundance of Alistipes bacteria in human patients and mouse models during the disease. Studies showed that the gut microbiota imbalance of Alistipes is a double-edged sword. Moschen et al. further demonstrated that in WT, LCN 2 KO, and IL-10 KO C57BL/6J mice, oral administration of Alistipes finegoldii for one week induced intestinal inflammation[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e].However, other researchers have observed contradictory findings, where the intervention of Alistipes finegoldii significantly reduced the severity of colitis in mice induced by oral DSS[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. In addition, previous studies have shown that the abundance of Alistipes shows an increasing trend in the microbial community spectrum of NOD2 knockout mice. This was confirmed by Butera \u003cem\u003eet al\u003c/em\u003e., who reported that NOD2 knockout mice that were given trinitrobenzene sulfonic acid (TNBS) through the rectum to induce colitis showed milder symptoms of colitis than wild-type mice. It was further found that NOD2 knockout mice showed an increase in Alistipes flora and anti-inflammatory cytokines[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].This suggests that the imbalance of Alistipes is an important marker of intestinal inflammation; however, the role Alistipes plays in the metabolic mechanisms of the gut microbiota remains unclear.The above studies are consistent with our results obtained through Mendelian randomization, suggesting that Alistipes may play a vital role in IBD. However, most studies are largely concentrated on other species of the genus Alistipes, and less research on Alistipes shahii. A study on mice with hepatocellular carcinoma (HCC) showed that treatment with a probiotic called Prohep resulted in reduced tumor growth and a decrease in Th17 cells, while the anti-inflammatory cell subsets Treg/Tr1 increased. Notably, the abundance of Alistipes in the mice also increased[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e].Collectively, these studies suggest that Alistipes shahii may influence IBD through immune cell-mediated mechanisms.\u003c/p\u003e \u003cp\u003eSeveral studies have shown that monocytes are potential targets for conventional IBD therapies[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. HLA-DR is an important immune molecule that is widely expressed on the surface of various immune cells, particularly monocytes[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. It belongs to the major histocompatibility complex (MHC) class II molecules, which are primarily responsible for presenting exogenous antigens to CD4\u0026thinsp;+\u0026thinsp;T cells and subsequently initiating and regulating the immune response[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Macrophages and dendritic cells are transformed from monocytes and are an important part of the innate immune system. High expression of HLA-DR usually marks the activation of monocytes. Monocyte levels are significantly increased in IBD patients[\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Additionally, previous studies also have observed that elevated levels of functionally suppressed HLA-DR-myeloid-derived cells are found in IBD patients, reflecting the need for immunosuppression in the disease state. L et al. report that CD14(+)HLA-DR(hi) monocytes show a significant increase in the blood of patients with active IBD.\u0026rdquo; Monocyte subsets not only produce pro-inflammatory cytokines that may trigger or exacerbate an inflammatory response but also guide the migration of monocytes to the inflammatory sites in the colon. This guidance is achieved through the expression of the C-C chemokine receptor 9[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. This is consistent with our study. In addition, Joshi et al. highlight that monocyte HLA-DR has advantages in analytical validity and a direct biological link to mononuclear phagocyte function, making it a potential gold standard for identifying sepsis immune paralysis. They also confirm that Granulocyte-Macrophage Colony-Stimulating Factor therapy can restore immune function and improve patient outcomes by upregulating monocyte HLA-DR expression[\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Given that IBD is also an immune system dysfunction-related disease, the regulatory role of HLA-DR⁺ monocytes in the protective effect against Alistipes shahii in this study suggests that they may also have value in \"immune status monitoring\" or \"therapeutic response prediction\" in IBD. In the future, we can further explore whether it can be used as a key biomarker in the individualized decision-making of IBD treatment and even become one of the evaluation indicators of immune intervention.\u003c/p\u003e \u003cp\u003eSpecific Alistipes strains (such as Alistipes onderdonkii) may participate in the occurrence of postoperative poor anastomotic healing by up-regulating the expression of pro-inflammatory factors (such as TNF-α and IL-1β) in the intestinal mucosa. This proinflammatory phenotype is detected preoperatively and could be transferred to mouse models via fecal bacterial transplantation, suggesting that its inflammatory regulation depends on microflora composition[\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. In addition, the abundance of Alistipes is positively correlated with circulating IL-17 levels in the population, further supporting its possible proinflammatory potential. However, it is worth noting that Alistipes is not a whole proinflammatory, and different strains of Alistipes may play completely different roles in inflammatory response[\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. In a recent study on coronary atherosclerotic disease (CAD), researchers not only focus on the correlation between Alistipes and the disease but also introduce immune cells and inflammatory factors as mediating mechanisms. Studies have found that Alistipes is significantly reduced in CAD patients, and with the increase of circulating LPS level, it further activates monocytes or macrophages, induces the production of pro-inflammatory factors such as MCP-1, and promotes the adhesion and migration of monocytes to vascular endothelia[\u003cspan additionalcitationids=\"CR70\" citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]. This study provides a new perspective for understanding Alistipes' mechanism of disease mediated by immune cells and also suggests that many biological pathways involved in immune regulation may have commonalities among different tissues and systems. Therefore, the findings in the CAD model can also provide references for the study of other disease mechanisms. Notably, another study using a breast cancer mouse model found that amino acid\u0026ndash;optimized nutritional supplements significantly increased the abundance of Alistipes in the gut, thereby maintaining muscle function during chemotherapy[\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. Studies have shown that Alistipes can produce short-chain fatty acids(SCFAs), such as butyric acid, propionic acid, and acetic acid, which are not only important sources of energy for intestinal epithelial cells but also regulate immune and inflammatory states through various mechanisms[\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e]. Butyric acid and propionic acid have been shown to exert anti-inflammatory effects by acting on monocytes and their downstream signaling pathways. Butyric acid can inhibit histone deacetylase(HDAC)activity in monocytes, and then inhibit NF-κB mediated inflammatory pathway, and reduce the expression of TNF-α, IL-6 and IL-12[\u003cspan additionalcitationids=\"CR76\" citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. In addition, SCFAs can also induce the polarization of monocytes and macrophages towards the anti-inflammatory M2 phenotype by activating G protein-coupled receptors such as free fatty acid receptor 2 and niacin receptor, promote immune tolerance and alleviate inflammation[\u003cspan additionalcitationids=\"CR79 CR80\" citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]. In patients with IBD, downregulation of FFAR2 expression has been linked to persistent inflammation, and SCFA-mediated FFAR2 activation reduces lamina propria monocytes' overresponse to symbiotic bacteria. At the same time, butyrate can activate GPR109A, induce the secretion of anti-inflammatory factor IL-10, promote the differentiation of regulatory T cells (Tregs), and inhibit the activation of inflammatory dendritic cells[\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e]. Therefore, we speculate that Alistipes shahii may be involved in the immune regulation of IBD through two different but interrelated mechanisms in IBD. On the one hand, Alistipes shahii may directly interact with gut innate immune cells (such as monocytes) to influence their activation status or differentiation direction. For example, it may bind to pattern recognition receptors (such as TLR4) via specific bacterial components, like cell wall components or low-toxicity lipopolysaccharides, to induce anti-inflammatory immune cells and thereby reduce mucosal inflammation. On the other hand, A. shahii may also indirectly act on monocytes through its metabolites (such as short-chain fatty acids or indole tryptophan metabolites) to regulate key IBD pathways, including NF-κB, HDAC, FFAR2, GPR109A, and AHR.\u003c/p\u003e \u003cp\u003eInterestingly, we find that in Finnish IBD patients, HLA-DR enhances the protective effect of Alistipes shahii on monocytes. However, in the European population, HLA-DR expression weakens this protective effect. In Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Mendelian randomization analysis with HLA-DR expression on monocytes as the exposure variable and IBD as the outcome shows that in the European population: [OR\u0026thinsp;=\u0026thinsp;1.0759, 95% CI: 1.0038\u0026ndash;1.1533, P\u0026thinsp;=\u0026thinsp;0.0388]. In the Finnish population: [OR\u0026thinsp;=\u0026thinsp;0.6538, 95% CI: 0.4545\u0026ndash;0.9404, P\u0026thinsp;=\u0026thinsp;0.0220], the effect direction is opposite, and the difference is statistically significant. This difference between populations may be due to the combined effect of multiple factors. First, the HLA-DRB1 allele frequency varies significantly between Finland and other European populations. For example, the Finnish-specific A03-B35-DRB101:01 haplotype is rare elsewhere in Europe, while DRB103:01 (AH 8.1) is more common. These differences may impact the antigen-presenting ability and immunoregulatory mechanisms of HLA-DR molecules in monocytes[\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]. Secondly, the composition of the gut microbiota also varies significantly among different populations. The interactions between microbial communities may indirectly modulate HLA-DR-mediated immune effects, thereby influencing the function of Alistipes shahii. In the early stage of the disease, the immune response is relatively mild, and HLA-DR may play an anti-inflammatory role by regulating the function of monocytes, enhancing the protective effect of Alistipes shahii. In advanced stages, the continuously activated immune system and upregulated HLA-DR may amplify inflammation, weaken Alistipes shahii\u0026rsquo;s benefits, and exacerbate mucosal damage [\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e, \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]. Notably, studies in Asian populations have shown that the abundance of Alistipes shahii is significantly increased in healthy elderly individuals and may exert potential protective effects in energy metabolism and immune homeostasis through alternative butyrate-producing pathways (such as lysine \u0026rarr; butyrate). Aarthi Ravikrishnan et al. not only emphasized the population specificity of gut microbiota functions across different ethnic groups but also provided indirect support for our observation in European populations that Alistipes shahii may reduce the risk of IBD[\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]. Although Alistipes shahii may influence host health through distinct mechanisms in different populations, its consistent association with \u0026ldquo;anti-inflammatory\u0026rdquo; or \u0026ldquo;metabolic health\u0026rdquo; traits across multiple cohorts suggests that it may possess a relatively conserved beneficial function. This provides both theoretical rationale and population-based support for future investigations into the relationship between Alistipes shahii and IBD, as well as for microbiota-based intervention studies in broader populations.\u003c/p\u003e \u003cp\u003eFurthermore, fecal microbiota transplantation (FMT) is an emerging technology to treat disease by transplanting normal fecal microbiota obtained from healthy donors[\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e]. Many animal studies have explored FMT as a potential tool for the treatment of various intestinal diseases and other metabolic disorders[\u003cspan additionalcitationids=\"CR91\" citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e]. However, the number of randomized controlled trials of FMT for IBD is still limited, and the efficacy is affected by many factors, such as the composition of the flora, donor selection and host differences. Although it is unclear whether transplantation of A. shahii can alleviate IBD, previous studies suggest Alistipes may play an important role in maintaining intestinal homeostasis and immune balance. Therefore, further study of the specific mechanisms of Alistipes in IBD, and exploration of its potential protective role via metabolites (such as short-chain fatty acids, tryptophan metabolites, etc.) or immunomodulatory pathways, could provide a theoretical basis for its use as a potential \"next-generation probiotic\" or FMT target in IBD treatment. Of course, there are still many challenges in translating Alistipes's basic research findings into clinical applications. For example, there is a lack of systematic safety assessment of the bacteria in humans, and its colonization ability and long-term effects are unclear. In addition, how to achieve large-scale cultivation, accurate delivery, and maintain stable ecological functions in different populations is also a problem that must be solved in the future. In the future, it can be combined with metabolomics, single-cell transcriptome and spatial omics technology to screen its key regulatory pathways and action targets, to promote its clinical transformation and provide new ideas for individualized treatment of IBD.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, our study is mainly based on the analysis of the European and Finnish populations, so the universality of the results may be limited to other populations. As Chinese scholars, we should further collect the sequencing data of gut microbiota and IBD patients in the Asian population to explore whether Alistipes shahii has a causal relationship with IBD patients in the Asian population. Second, in this study, although the results did not reach the strict threshold for FDR correction, we believe they may be biologically significant. For example, these results are consistent with existing literature and experimental observations, suggesting a potentially important association. In fact, in many practical biomedical studies, extremely strict statistical thresholds can sometimes reduce sensitivity to potential discoveries, especially in areas of research with complex mechanisms and multiple potentially interfering factors. Finally, this study reveals a potential causal relationship between Alistipes shahii and HLA-DR on monocyte in the development of IBD. However, HLA-DR on monocyte, as the intermediary factor in the protective effect of Alistipes shahii against IBD, only accounted for 13.9% of the mediating effect. This indicates that this pathway could only explain part of the role of Alistipes shahii in the occurrence and development of IBD. However, its specific mechanism remains to be further explored. This indicates that there are still other more important immune regulatory or metabolic pathways in the protective effect of Alistipes shahii on IBD, which need to be further explored and verified. Future studies can use the combination of single-cell transcriptome sequencing and spatial omics to screen possible related immune regulatory factors, to determine which immune cells play a more important role in the process of Alistipes shahii's influence on IBD. In addition, Alistipes shahii may also regulate HLA-DR on monocyte through its metabolites (such as short-chain fatty acids SCFAs, secondary bile acids, tryptophan metabolites, etc.), and possible metabolites can be explored through metabolomics and transcriptomics in the future. Despite these limitations, our study also shows significant advantages. First, in addition to being based on a single dataset, our findings are repeatedly verified by analyzing two different ethnic GWAS datasets. The use of GWAS data with the largest number of participants ensures strong statistical power and minimizes confounding effects common in observational studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eInflammatory Bowel Disease（IBD)\u003c/p\u003e\n\u003cp\u003eMendelian randomization (MR)\u003c/p\u003e\n\u003cp\u003esingle nucleotide polymorphism（SNPs）\u003c/p\u003e\n\u003cp\u003eExploration Database(ED)\u003c/p\u003e\n\u003cp\u003eRadiation Database(VD)\u003c/p\u003e\n\u003cp\u003einstrumental variables（IVs）\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used in this study are accessible through online repositories. The article's Table 1 include the repository names and accession numbers. We are deeply appreciative of all participants and researchers who shared these valuable datasets.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLintao Dong,Jingping Hu:Writing original draft,Methodology,Formal analysis, Conceptualization.\u003c/p\u003e\n\u003cp\u003eFang Wang*:Writing – review \u0026amp; editing, Conceptualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Grant No. 82460563, project title: The mechanism of PFKFB4 inhibition of SIRT2-mediated ketone body degradation regulating Rela/ZZ modification in promoting chemoresistance in colorectal cancer).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data for the exposure and outcome in this study were obtained from the GWAS database, and both have received ethical approval and participant informed consent. We appreciate all the participants and investigators for sharing these data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSartor RB. Mechanisms of disease: pathogenesis of crohn\u0026apos;s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006 2006 Jul;3(7):390-407. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\u0026amp;db=pubmed\u0026amp;dopt=Abstract\u0026amp;list_uids=16819502\u0026amp;query_hl=1 doi: 10.1038/ncpgasthep0528\u003c/li\u003e\n\u003cli\u003eKaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015 2015 Dec;12(12):720-27. 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Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\u0026amp;db=pubmed\u0026amp;dopt=Abstract\u0026amp;list_uids=38444807\u0026amp;query_hl=1 doi: 10.3389/fmicb.2024.1352555\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable1\u0026nbsp;\u003c/strong\u003eDetails of the genome-wide association studies and datasets used in this study.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExposure or outcome\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample\u0026nbsp;size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 314px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLinks for datadownload\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePMID\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e473 Gut microbiota\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5959\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 314px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehttps://www.ebi.ac.uk/gwas/GCST90032172-GCST90032644\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e35115689\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEuropean IBD population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e34652\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 314px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehttps://gwas.mrcieu.ac.uk/datasets/ieu-a-31/\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26192919\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFinnish IBD population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e438599\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 314px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehttps://storage.googleapis.com/finngen-public-data-r11/summary_stats/finngen_R11_K11_IBD_STRICT_PSC.gz\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e36653562\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e731immune cells\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3757\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 314px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehttps://www.ebi.ac.uk/gwas/GCST90001391-90002121\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e37582716\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"ce91087a-bc78-4325-8a9a-ad8b99b8156a","identifier":"10.13039/501100001809","name":"National Natural Science Foundation of China","awardNumber":"82460563","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"causal relationship, Alistipes shahii, HLA DR on monocyte, mendelian randomization, inflammatory bowel disease","lastPublishedDoi":"10.21203/rs.3.rs-6723420/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6723420/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Inflammatory Bowel Disease (IBD), including Crohn's Disease and Ulcerative Colitis, is a chronic intestinal inflammation that significantly impacts patients' quality of life. Recently, studies have highlighted that the gut microbiota can influence the pathogenesis of IBD by mediating immune cells.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e:We used a two-sample bidirectional Mendelian Randomization (MR) analysis on genetically predicted gut microbiota and IBD. Additionally, a two-step MR approach was applied to quantify the mediating effect of HLA DR on monocytes on the influence of gut microbiota on IBD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e:The results indicate that Alistipes shahii significantly reduces the risk of developing IBD (IVW odds ratio [OR] per SD increase in IBD =0.8917/ 0.5944 P =0.0373/0.0389），HLA-DR on monocyte, as the intermediary factor between Alistipes shahii and IBD, can strengthen the protective effect of Alistipes shahii on IBD, and the proportion of mediation effect accounted for 13.9%\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e:In summary, our study found that the protective effect of HLA DR On monocytes enhanced the protective effect of Alistipes shahii on IBD in Finland. However, most of the mechanisms by which Alistipes shahii affects IBD on monocytes via HLA DR are unknown.Further research is needed to explore other risk factors as potential mediators.\u003c/p\u003e","manuscriptTitle":"Disentangling the Immune Cell-Mediated Causal Effects of Gut Microbiota on Inflammatory Bowel Disease via Mendelian Randomization","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-26 09:20:46","doi":"10.21203/rs.3.rs-6723420/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"22110a30-60c3-45ae-9883-9ec09a82d256","owner":[],"postedDate":"May 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48898482,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2025-05-26T09:20:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-26 09:20:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6723420","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6723420","identity":"rs-6723420","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}