Gut microbial and human genetic signatures of inflammatory bowel disease increase risk of comorbid mental disorders

The high prevalence of comorbid mental disorders (CMDs), such as anxiety and depression, in patients with inflammatory bowel disease (IBD) is well documented. The reported bidirectional relationship between the two conditions suggests a crucial role of a gut-brain axis in CMD development in patients with IBD. This study aimed to investigate a complex interplay between gut microbiota and host genetic variants relevant to the development of CMDs in IBD. Genome-wide variant data, gut metagenomic data, and/or anxiety/depression estimates were obtained from 507 patients with IBD and 75 healthy controls. A series of integrative analyses were performed, profiling gut microbial diversity, microbial abundance, polygenic risk score, microbial quantitative trait locus (mbQTL), and microbial IBD-risk score. Patients with IBD had significantly lower gut microbial alpha diversity than controls, particularly those with CMD. Beta diversity revealed that a large fraction of IBD-associated taxa contributing to the top principal component were potentially associated with CMD risk. We identified 146 significantly differentially abundant taxa (DATs) between IBD patients and controls, and 48 DATs between CMD-free and CMD-affected IBD patients, with the majority showing consistent changes in abundance between IBD and CMD. Microbial IBD-risk scores, developed to estimate the degree of microbial IBD-specific burden in each individual, supported a significant enrichment of IBD-risk signatures in CMD-affected patients. Additionally, we found an IBD-risk mbQTL for an IBD/CMD-associated DAT, implicating an interplay between IBD-risk variants and gut dysbiosis in the development of both IBD and CMD. Collectively, IBD-associated gut dysbiosis predominantly confers risk of CMD in IBD patients partially through genetic variant-mediated regulation.