Assessment of Causal Direction Between Gut Microbiota and Inflammatory Bowel Disease: A Mendelian Randomization Analysis

Zhang, Zijia; Qu, Huan; Zhao, Na; Wang, Jing; Wang, Xiuyan; Hai, Rong; Li, Bin

doi:10.3389/fgene.2021.631061

Cited by 32 publications

(32 citation statements)

References 38 publications

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“…In previous studies, Zhang et al. ( 14 ) and Xiang et al. ( 15 ) performed MR analyses to investigate the effects of gut microbiota on IBD and SLE, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The above two studies fall short in that they treat gut microbiota composition as a whole without distinguishing specific taxa, while different microbial taxa may have distinct effects on human health. During the preparation of this article, Zhang et al (14) and Xiang et al (15) investigated the causal effects of specific microbial taxa on two ADs, inflammatory bowel disease (IBD) and SLE. However, studies on other ADs are still sparse.…”

Section: Introductionmentioning

confidence: 99%

“…During the preparation of this article, Zhang et al. ( 14 ) and Xiang et al. ( 15 ) investigated the causal effects of specific microbial taxa on two ADs, inflammatory bowel disease (IBD) and SLE.…”

Section: Introductionmentioning

confidence: 99%

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Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

et al. 2022

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BackgroundGrowing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship.ObjectiveTo reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis.Materials and MethodsWe assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation.ResultsCombining the results from the discovery and replication stages, we identified one causal bacterial genus, Bifidobacterium. A higher relative abundance of the Bifidobacterium genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339–1.922; PFDR = 4.19 × 10−7] and CeD (OR: 1.401; 95% CI, 1.139–1.722; PFDR = 2.03 × 10−3), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the Bifidobacterium genus.ConclusionThis study implied a causal relationship between the Bifidobacterium genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.

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“…In previous studies, Zhang et al. ( 14 ) and Xiang et al. ( 15 ) performed MR analyses to investigate the effects of gut microbiota on IBD and SLE, respectively.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

et al. 2022

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“…45 The specific microbes most affected by HBOT, which allowed for this proportional increase in Firmicutes, included known mucinophiles with an association between Akkermansia muciniphila and HBOT response status. Akkermansia is associated with risk of IBD development, 46 but data is conflicting on whether A. muciniphila is pathogenic or protective against colitis. [47][48][49] Strain specific anti-or pro-inflammatory properties exist for A. muciniphila.…”

Section: Discussionmentioning

confidence: 99%

Ulcerative Colitis Host-Microbiome Response to Hyperbaric Oxygen Therapy

González

Mills

Kordahi

et al. 2022

Preprint

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Objective: This study examined the host-microbe changes underpinning treatment response to hyperbaric oxygen therapy (HBOT) in ulcerative colitis. Design: Pre- and post-intervention mucosal tissue and fecal samples from two clinical trials, along with fecal samples from healthy controls and fecal and mucosal tissue from disease severity matched UC controls. Mucosal tissue bulk-RNA sequencing, digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed, in addition to 16S rRNA, shotgun metagenomics, metabolomics, and metaproteomics of fecal samples. Fecal colonization experiments in IL10-/- germ-free mice were performed to confirm observations. Results: Proteomics identified associations between HBOT response status and neutrophil degranulation, with specificity of effect for azurophilic granules. DSP identified a specific HBOT effect on reducing neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with an accompanying proportional increase in Firmicutes and a secondary bile acid lithocholic acid. The reduction in diversity was due to reductions in mucinophiles, with differences in Akkermansia muciniphila strains being associated with HBOT response status. Proteomics observed an accompanying effect for HBOT on MUC2. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared to stool obtained from HBOT non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses. Conclusion: HBOT reduces host neutrophil STAT3 and azurophilic granule activity in UC patients, and changes in microbial composition and metabolism in ways that improve colitis activity. Intestinal microbiota, especially strain level variations in A. muciniphila, may contribute to HBOT non-response.

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“…The prevailing view in IBD pathogenesis is focused on a predisposition due to a barrier defect concerning mucus [5] and epithelial energy metabolism in ulcerative colitis [6] and antibacterial peptides in CD [7]. Although the role of the microbiome triggering immune response is not in doubt, it is still not settled whether changes in microbiome diversity and composition are hen or egg in this confrontation [5, 8].…”

Section: Introductionmentioning

confidence: 99%

Twenty‐five years of biologicals in IBD: What´s all the hype about?

Herrlinger

Stange

2021

J Intern Med

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Twenty‐five years ago the field was revolutionized by the introduction of infliximab as the first hybrid anti‐TNF‐antibody. Subsequently, other humanized anti‐TNFs were developed and marketed, followed by antibodies to new targets including integrins (vedolizumab) and interleukin 12/23 (ustekinumab). All these so‐called biologicals were shown in registrational trials to induce remission superior to placebo but consistently were effective in only a minority of patients. Even though in most trials only the responders were selected to continue on the respective medication for maintenance, many experienced a secondary loss of response and only a minority of usually <25% of the initial cohort achieved long‐term (1 year) remission. In 'real life studies', the outcome was somewhat better, probably due to proper selection of patients and open, mostly retrospective study designs. A clear benefit of biologicals is apparent in otherwise treatment refractory patients, in extraintestinal manifestations and in Crohn´s disease (CD) with fistulizing complications. Biologicals achieve mucosal healing (MH) more often than corticosteroids or thiopurines, and MH is associated with improved prognosis. However, this does not justify escalating treatment until MH is reached since controlled trials proving this point of 'treat to target' are lacking both in ulcerative colitis and CD. Surgical rates have decreased with increasing use of biologicals, but disease progression has not been proven to improve. With the exception of opportunistic infections, serious adverse events are rare. In conclusion, biologicals have changed the scene considerably and expanded our armamentarium, but there is also a marketing hype fostering expectations without evidence.

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Assessment of Causal Direction Between Gut Microbiota and Inflammatory Bowel Disease: A Mendelian Randomization Analysis

Cited by 32 publications

References 38 publications

Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study

Ulcerative Colitis Host-Microbiome Response to Hyperbaric Oxygen Therapy

Twenty‐five years of biologicals in IBD: What´s all the hype about?

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