Circadian rhythm disruption (CRD)-related intestinal inflammation is a significant cause of gastrointestinal disorders. Although the benefits of physical exercise have been investigated, its preventive and therapeutic roles in CRD-related intestinal inflammation remain ambiguous. Given the critical role of gut microbiota in regulating intestinal homeostasis and the inflammatory response to external stimuli, we hypothesized that gut microbiota could mediate the anti-inflammatory efficacy of physical exercise on intestinal inflammation. Initially, a two-sample bidirectional Mendelian randomization (MR) was conducted on the causality between physical exercise, intestinal inflammation, and gut microbiota. Subsequently, the preventive efficacy was evaluated in a CRD mouse model. Next, a potential anti-inflammatory mechanism was explored through transcriptomic sequencing, 16S rRNA sequencing, and fecal metabolome analysis. The results of the MR suggested alleviated intestinal inflammation from gut microbiota modulated by physical exercise. Ameliorated intestinal injury and inflammation were observed in exercising CRD mice, which was dampened by oral chenodeoxycholic acid (CDCA) administration. Then, comprehensive analysis indicated that the benefit of physical exercise may be associated with enhanced intestinal clock gene expression and the genus Prevotella. Our findings indicate the potential for the effects of physical exercise to be relevant to reduced CDCA; they also emphasize the benefits of undertaking adequate physical activity in maintaining a healthy condition within a modern lifestyle that involves various risk factors.
