Circulating Metabolite Signatures Linking Physical Activity to Inflammatory Bowel Disease Risk and Interactions With Genetic Susceptibility

BACKGROUND & AIMS: Recent studies have demonstrated the protective effect of physical activity on incident inflammatory bowel diseases (IBD), but the underlying mechanism remains unclear, and whether it interacts with genetic susceptibility is still unknown.

METHODS: The study was conducted leveraging large-scale circulating metabolomics data from 2 prospective cohorts, the UK Biobank study and the Whitehall II study. Moderate-to-vigorous physical activity (MVPA) in minutes per day was assessed by questionnaires, and the circulating metabolome was profiled using a high-throughput nuclear magnetic resonance (NMR)-based platform. Incident IBD cases were ascertained using linkage to nationwide primary care data, hospital inpatient records, and death registry data.

RESULTS: We identified a metabolic signature of 25 metabolites associated with MVPA, reflecting a favorable lipoprotein profile, a shift toward less saturated fatty acid composition, enhanced energy metabolism, and lower systemic inflammation. The signature was validated both internally and externally. During a mean follow-up of 13.3 years, 1182 incident IBD cases were documented among 183,370 UK Biobank participants. In multivariable Cox regressions, both MVPA and its metabolic signature were associated with reduced IBD risk, with a hazard ratio of 0.77 (95% confidence interval, 0.66-0.90) and 0.59 (95% confidence interval, 0.50-0.71) for the highest vs lowest quartile, respectively. The metabolic signature mediated approximately 13.9% of the MVPA-IBD association. Regarding IBD subtypes, MVPA and its metabolic signature were inversely associated with both Crohn's disease (MVPA: P trend < .001; metabolic signature: P trend < .001) and ulcerative colitis (MVPA: P trend = .026; metabolic signature: P trend = .001). We also observed interactions between MVPA, the metabolic signature, and genetic susceptibility to IBD (Pinteraction < .05).

CONCLUSIONS: Our findings indicate a potential role of MVPA in the prevention of IBD, particularly in individuals with a heightened genetic predisposition, and point to possible biological pathways through which physical activity may influence the incidence of IBD.