Supplementary Material for: Gut Microbiome Mediates the Effect of Inflammatory Bowel Disease on Sarcopenia: A Bidirectional Mendelian Randomization Study

Background: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), imposes a global health burden. Observational studies suggest links between IBD and sarcopenia as well as obesity, but establishing causality is challenging due to confounding factors. Method: This study utilized two-sample Mendelian randomization (MR) analyses to explore bidirectional causality between obesity, sarcopenia, and IBD, using genetic instruments from summary-level data. The primary causal estimates were derived using the inverse-variance weighted (IVW) method. To ensure robustness, we performed a range of sensitivity analyses, including MR-Egger regression and the weighted median method to detect and adjust for horizontal pleiotropy, and MR-PRESSO to identify and remove potential outliers. Result: MR analysis revealed significant associations between obesity, sarcopenia, and IBD, especially CD. Trunk fat percentage, body fat percentage and abdominal subcutaneous adipose tissue volume were positively associated with an increased risk of CD, whereas hand grip strength showed a negative association, highlighting the role of obesity and sarcopenia in CD risk. Conversely, CD was causally linked to lower abdominal fat, muscle mass, and strength. For UC, only visceral adipose tissue volume showed an association with disease risk. Mediation analysis indicated the gut microbiome might mediate the causal effect of CD on sarcopenia-related traits. Conclusion: This MR study confirms bidirectional causality between sarcopenia, obesity, and IBD, particularly CD. It highlights the complex interplay between body composition and IBD pathogenesis. Moreover, the gut microbiome may mediate the relationship between CD and sarcopenia. These findings underscore the importance of managing obesity and sarcopenia in IBD treatment and suggest potential therapeutic targets related to the gut-muscle axis.