The role of gut microbiota and plasma metabolites in ulcerative colitis: Insights from Mendelian randomization analysis

Emerging research suggests that alterations in gut microbiota composition may play a significant role in the pathogenesis of ulcerative colitis (UC). Plasma metabolites, which are influenced by gut microbiota, have also been implicated, but their role in UC remains unclear. This study aims to determine whether specific plasma metabolites mediate the causal relationship between gut microbiota and UC using Mendelian randomization (MR) analysis. This study employed publicly available summary-level data from genome-wide association studies and metagenomic datasets. Gut microbiota data were derived from the FINRISK cohort (5959 participants), plasma metabolite data from the Canadian Longitudinal Study on Aging (8299 individuals), and UC data from multiple consortia (17,030 cases and 883,787 controls). Forward and reverse MR analyses, supplemented by linkage disequilibrium score regression (LDSC), were conducted to assess causal relationships. Mediation effects of plasma metabolites between gut microbiota and UC were analyzed using the product of coefficients method. Various sensitivity analyses, including MR-Egger and MR-PRESSO, were applied to detect pleiotropy and ensure robust results. The study identified 20 bacterial taxa and 93 plasma metabolites linked to UC. Forward MR analysis showed that Clostridium S felsineum increased UC risk via reduced carnitine levels, with a mediation proportion of 39.77%. Eubacterium callanderi was associated with decreased UC risk through the tryptophan to pyruvate ratio (16.02% mediation). Additionally, species CAG-590 sp000431135 increased UC risk through elevated mannitol/sorbitol levels, mediating 28.38% of the effect. Sensitivity analyses confirmed the robustness of these findings, with minimal heterogeneity and pleiotropy detected. This study highlights the significant role of gut microbiota and their associated plasma metabolites in the pathogenesis of UC. Specific microbial species influence UC through metabolites, suggesting potential therapeutic targets. Modulating carnitine, tryptophan metabolism, or sugar alcohols could offer promising avenues for UC management.