THE BIDIRECTIONAL CAUSAL ASSOCIATION BETWEEN IRRITABLE BOWEL SYNDROME AND MAJOR DEPRESSIVE DISORDER: MULTI-OMICS MENDELIAN RANDOMIZATION STUDY BASED ON MICROBIOTA-GUT-BRAIN AXIS

Background Irritable Bowel Syndrome (IBS) is often comorbid with major depressive disorder (MDD), and the causal relationship between them has not been elucidated. We aimed to explore the causal association and search for common risk exposures between IBS and MDD using a multi-omics Mendelian Randomization (MR) study based on the microbiota-gut-brain axis.
Methods Two-sample MR studies were used to analyze the following datasets. Genome-wide association studies (GWAS) of IBS were obtained from a meta-analysis of 53400 patients with IBS. Four studies were consulted for GWAS data on 131 genera of gut bacteria, 83 brain-wide regions, 486 blood metabolites, and 4782 serum proteins. GWAS data for eight psychiatric disorders were obtained from the Psychiatric Genomics Consortium and FinnGen database. We used inverse-variance weighted MR for the primary analysis.
Results A genetic predisposition to IBS tended to increase the risk of attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder, post-traumatic stress syndrome, and MDD (OR=1.44, p < 0.001). Genetically predicted ADAH, Bipolar Disorder, and MDD (OR=1.09, p = 0.005) may increase the risk of IBS. Hence, there is a bidirectional causal association between MDD and IBS. Subsequently, we searched for common risk factors for IBS and MDD from the dimensions of the gut microbiota, brain-wide regions, blood metabolomics, and serum proteomics. An increased abundance of bacteria (unknowngenus.id.1000001215) was associated with a higher risk of IBS (OR=1.10, p < 0.001) and MDD (OR=1.17, p=0.02). Genetic predisposition to high blood arginine concentrations may increase the risk of IBS (OR=1.42, p < 0.01) and MDD (OR=1.46, p < 0.02). MR showed that structural changes in the brain that could affect IBS did not overlap with those of MDD. In the MR of the plasma proteomic analysis, 215 serum proteins were associated with IBS and 221 with MDD. Increased levels of the seven serum proteins were associated with an increased risk of IBS and MDD (Table 2). Increased levels of the four serum proteins may reduce the risk of IBS and MDD.
Conclusion There was a bidirectional causal association between IBS and MDD. These two diseases share multiple risk exposures in gut microbiota, blood metabolomics, and serum proteomics. This work has important implications for the interpretation of IBS and MDD comorbidity.