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

BackgroundRecent studies have shown that the gut microbiota is closely related to the pathogenesis of Inflammatory Bowel Disease (IBD), but the causal nature is largely unknown. The purpose of this study was to assess the causal relationship between intestinal bacteria and IBD and to identify specific pathogenic bacterial taxa via the Mendelian randomization (MR) analysis.Materials and MethodsMR analysis was performed on genome-wide association study (GWAS) summary statistics of gut microbiota and IBD. Specifically, the TwinsUK microbiota GWAS (N = 1,126 twin pairs) was used as exposure. The UK inflammatory bowel disease (UKIBD) and the Understanding Social Program (USP) study GWAS (N = 48,328) was used as discovery outcome, and the British IBD study (N = 35,289) was used as replication outcome. SNPs associated with bacteria abundance at the suggestive significance level (α = 1.0 × 10–5) were used as instrumental variables. Bacteria were grouped into families and genera.ResultsIn the discovery sample, a total of 30 features were available for analysis, including 15 families and 15 genera. Three features were nominally significant, including one family (Verrucomicrobiaceae, 2 IVs, beta = −0.04, p = 0.05) and two genera (Akkermansia, 2 IVs, beta = 0.04, p = 0.05; Dorea, 2 IVs, beta = −0.07, p = 0.04). All of them were successfully replicated in the replication sample (Verrucomicrobiaceae and Akkermansia Preplication = 0.02, Dorea Preplication = 0.01) with consistent effect direction.ConclusionWe identified specific pathogenic bacteria features that were causally associated with the risk of IBD, thus offering new insights into the prevention and diagnosis of IBD.

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Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab329 ◽

2021 ◽

Author(s):

Christa Meisinger ◽

Dennis Freuer

Keyword(s):

Inflammatory Bowel Disease ◽

Atopic Dermatitis ◽

Bowel Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

The Other ◽

Uk Biobank ◽

Inflammatory Bowel ◽

The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

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Gut Microbiota-driven Drug Metabolism in Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa143 ◽

2020 ◽

Author(s):

Femke Crouwel ◽

Hans J C Buiter ◽

Nanne K de Boer

Keyword(s):

Inflammatory Bowel Disease ◽

Drug Metabolism ◽

Gut Microbiota ◽

Bowel Disease ◽

Intestinal Bacteria ◽

Bacterial Degradation ◽

Aminosalicylic Acid ◽

Text Reading ◽

Inflammatory Bowel ◽

Pharmacologically Active

Abstract Background and Aims The gut microbiota plays an important role in the metabolization and modulation of several types of drugs. With this study we aimed to review the literature relating to microbial drug metabolism of medication prescribed in inflammatory bowel disease [IBD] practice. Methods A systematic literature search was performed in Embase and PubMed from inception to October 2019. The search was conducted with predefined MeSH/Emtree and text terms. All studies regarding drug metabolism by microbiota of medication prescribed in IBD practice were eligible. A total of 1018 records were encountered and 89 articles were selected for full text reading. Results Intestinal bacterial metabolism or modulation is of influence in four specific drugs used in IBD (mesalazines, methotrexate, glucocorticoids and thioguanine). The gut microbiota cleaves the azo-bond of sulfasalazine, balsalazide and olsalazine and releases the active moiety 5-aminosalicylic acid. It has an impact on the metabolization and potentially on the response of methotrexate therapy. In particular, thioguanine can be converted by intestinal bacteria into the pharmacologically active 6-thioguanine nucleotides without the requirement of host metabolism. Glucocorticoid compounds can be prone to bacterial degradation. Conclusion The human intestinal microbiota can have a major impact on drug metabolism and efficacy of medication prescribed in IBD practice. A better understanding of these interactions between microbiota and drugs is needed and should be an integral part of the drug development pathway of new IBD medication.

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