Causal Relationship Between Gut Microbiota, Serum Metabolites and Inflammatory Bowel Disease: A Mendelian Randomization Study

Abstract

Background: Inflammatory bowel disease (IBD) encompasses a range of chronic conditions that cause inflammation of the digestive tract, including ulcerative colitis (UC) and Crohn’s disease (CD). Current treatments for IBD primarily involve drugs such as salicylic acid, glucocorticoids, immunosuppressants, and biological agents, which aim to induce or maintain symptom relief, as a complete cure remains elusive. Objectives: The present study aimed to investigate the potential causal relationship between gut microbiota (GM), serum metabolites, and IBD. Methods: All datasets were sourced from the genome-wide association study (GWAS) database. A bidirectional Mendelian randomization (MR) analysis was conducted to evaluate the causal relationship between GM and IBD. The sensitivity and stability of the results were assessed. The GWAS data for 1,091 metabolites and 309 metabolite ratios were obtained from 8,299 individuals. Potential mediating metabolites were identified. Results: The MR results indicated a causal relationship between 14 taxa and IBD among 207 GM, with Bacteroides uniformis having the most pronounced effect on IBD risk. Among the 15 taxa with a reverse causal relationship to IBD, Parabacteroides johnsonii was the most affected. Fourteen metabolites and three metabolite ratios were ultimately identified as being associated with IBD. Mediated MR revealed five potential metabolites that could mediate causal effects between seven taxa and IBD. Multivariable Mendelian randomization (MVMR) showed that the associations between Bacteroides caccae and IBD were mediated by 1-arachidonoyl-GPE, and the associations between Coprobacter fastidiosus and IBD were mediated by epiandrosterone sulfate. Even after adjusting the GM with MVMR, glycine, glycosyl ceramide, and linoleoyl-arachidonoyl-glycerol showed a negative correlation with IBD. Conclusions: This study provides genetic evidence for the causal relationship between GM and IBD and identifies potential intermediate metabolites.