Causal relationship between gut microbiota and gastrointestinal diseases: a mendelian randomization study

Abstract

Background: Recent research increasingly highlights a strong correlation between gut microbiota and the risk of gastrointestinal diseases. However, whether this relationship is causal or merely coincidental remains uncertain. To address this, a Mendelian randomization (MR) analysis was undertaken to explore the connections between gut microbiota and prevalent gastrointestinal diseases.

Methods: Genome-wide association study (GWAS) summary statistics for gut microbiota, encompassing a diverse range of 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla), were sourced from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were gathered from the UK Biobank, FinnGen study, and various extensive GWAS studies. MR analysis was meticulously conducted to assess the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. To validate the reliability of our findings, sensitivity analyses and tests for heterogeneity were systematically performed.

Results: The MR analysis yielded significant evidence for 251 causal relationships between genetically predicted gut microbiota and the risk of gastrointestinal diseases. This included 98 associations with upper gastrointestinal diseases, 81 with lower gastrointestinal diseases, 54 with hepatobiliary diseases, and 18 with pancreatic diseases. Notably, these associations were particularly evident in taxa belonging to the genera Ruminococcus and Eubacterium. Further sensitivity analyses reinforced the robustness of these results.

Conclusions: The findings of this study indicate a potential genetic predisposition linking gut microbiota to gastrointestinal diseases. These insights pave the way for designing future clinical trials focusing on microbiome-related interventions, including the use of microbiome-dependent metabolites, to potentially treat or manage gastrointestinal diseases and their associated risk factors.

Keywords: Gastrointestinal disease; Gut microbiota; Mendelian randomization; SNPs.

Fig. 1

The design and flowchart of MR analysis in our study. This schematic representation emphasizes the research question that we attempted to answer, the analysis workflow and the data used. Based on large-scale publicly available genome-wide association study (GWAS) summary statistics data, we conducted Mendelian randomization (MR) analysis to explore the causal relationship between the gut microbiota and 22 gastrointestinal diseases, including upper gastrointestinal diseases, lower gastrointestinal diseases, liver and gallbladder diseases, and pancreatic diseases. Sensitivity analysis was used to verify the robustness of the MR results. SNP, single nucleotide polymorphism; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; MR, Mendelian randomization; IVW, inverse variance weighted

Fig. 2

Heatmap of correlation coefficients between gut microbiota abundance and gastrointestinal diseases. Pink blocks represent an increase in the abundance of gut microbiota, which may be associated with an increased risk of developing outcome diseases. Blue blocks demonstrate gut microbiota abundance was negatively correlated with outcome diseases (P value < 0.05). Other blocks represent that there is no causal relationship between gut microbiota and gastrointestinal diseases (P value > 0.05)

Fig. 3

Forest plots of Mendelian randomization (MR) estimates between gut microbiota and gastrointestinal diseases according to P value corrected. MR results suggested 12 causal relationships in upper gastrointestinal diseases, 17 in lower gastrointestinal diseases, 15 in hepatobiliary diseases and 6 in pancreatic diseases according to P value corrected. NAFLD, nonalcoholic fatty liver disease; IVW, inverse variance weighted; CI, Confidence interval; OR, Odds ratios