Causal associations between human gut microbiota and cholelithiasis: a mendelian randomization study

Abstract

Background: There was some evidence that gut microbiota was closely related to cholelithiasis, but the causal relationship between them remained unclear. In this study, we try to use Two-sample Mendelian randomization (MR) to clarify the potential causal relationship between gut microbiota and cholelithiasis.

Methods: Summary Genome-Wide Association Studies (GWAS) statistical data for gut microbiota was obtained from MiBioGen, and the data of cholelithiasis was obtained from UK Biobank (UKB). Two-sample MR analyses were performed to assess causalities between gut microbiota and cholelithiasis mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were used to determine the robustness of the MR results. Reverse MR analyses were performed to examine the reverse causal association.

Results: Our research results, based primarily on the IVW method, support the existence of a causal relationship between nine gut microbial taxa and cholelithiasis. We observed a positive association between Genus Butyrivibrio (p=0.032), Genus Lachnospiraceae_UCG_001 (p=0.015), Genus Ruminococcaceae_NK4A214_group (p=0.003), Genus Ruminococcaceae_UCG_011 (p=0.010) and cholelithiasis, while Order Rhodospirillales (p=0.031), Genus Actinomyces (p=0.010), Genus Phascolarctobacterium (p=0.036), Genus Rikenellaceae_RC9_gutgroup (p=0.023), Genus Ruminococcaceae_UCG_013 (p=0.022) may be associated with a reduced risk of cholelithiasis. We did not find a reverse causal relationship between cholelithiasis and 9 specific gut microbial taxa.

Conclusions: This is the first mendelian randomization study to explore the causalities between specific gut microbiota taxa and cholelithiasis, which may provide new ideas and a theoretical basis for the prevention and treatment of cholelithiasis in the future.

Keywords: gut microbiota; causality; cholelithiasis; genetic association; mendelian randomization.

Figure 1

(A) Three assumptions of Mendelian randomization. (B) Flowchart of this Mendelian randomization study. GWAS, Genome Wide Association Studies; IV, Instrumental variable; SNP, single nucleotide polymorphism; MR, Mendelian randomization; IVW, Inverse-variance weighted; WM, Weighted median; UKB, UK Biobank.

Figure 2

Forest plot of the associations between genetically determined 9 gut microbial genera with the risks of cholelithiasis in UKB. Abbreviations: OR, odds ratio; SNP, single-nucleotide polymorphism; SE, Standard Error.