Abstract
Abstract Background Recent studies have demonstrated the protective effect of physical activity on incident IBD, but the underlying mechanism remain unclear. Here, large-scale circulating metabolomics data was used to identify a metabolic signature reflecting moderate-to-vigorous physical activity (MVPA). We then investigated whether this signature mediated the association between MVPA and inflammatory bowel diseases (IBD) risk and how genetic susceptibility to IBD played roles in the association. Methods The present study was conducted in two prospective cohorts: the UK Biobank (n=194,292 for prospective analysis, n=12,766 for identification of the metabolic signature) and the Whitehall II study (n=5,925 for validation of the metabolic signature). 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. Associations between MVPA and individual metabolites were assessed using multivariable linear models and the MVPA-related metabolic signature was identified using elastic net regression. The primary analyses evaluated the prospective associations between MVPA/metabolic signature and incident IBD using multivariable Cox proportional hazards regression, and further examined the mediation role of the metabolic signature and the interaction with genetic susceptibility to IBD. Results We identified 100 metabolites significantly associated with MVPA, with a combination of 25 metabolites selected comprising the metabolic signature. During a mean follow-up of 13.3 years, 1,259 incident IBD cases were documented. Both MVPA and metabolic signature were associated with reduced incident IBD, with hazard ratio [HR] of 0.77 (95%CI, 0.66-0.90) and 0.60 (95%CI, 0.51- 0.71) for highest quartile vs. lowest quartile, respectively. The MVPA-related metabolic signature mediated 15.2% of the inverse association between MVPA and IBD risk. Participants with low MVPA/ metabolic signature and high genetic risk showed the highest IBD incidence, with both additive and multiplicative interactions observed. Conclusion The identified metabolic signature reflecting MVPA was found to mediate the inverse association between MPVA and incident IBD. Measuring a specific set of metabolites representative of MVPA, together with genetic susceptibility, may identify individuals with higher risk of IBD.
Published Version
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