Microbial metabolism mediates the deteriorative effects of sedentary behaviour on insulin resistance

Abstract Background Prolonged sedentary time is a strong risk factor for insulin resistance. Recent evidence indicates that gut microbiota may influence the regulation of insulin sensitivity and demonstrates a distinct profile between sedentary and physically active individuals. However, whether and how microbial metabolism mediates the progression of insulin resistance induced by prolonged sedentary time remains unclear. Methods 560 male participants without hypoglycaemic therapy were included, and insulin resistance was evaluated using the Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR). The gut microbiota was identified through metagenomics, host genetic data were obtained using a genotyping array, and plasma metabolites were quantified by liquid chromatography mass spectrometry. Results A panel of 15 sedentary‐related species and 38 sedentary‐associated metabolic capacities accounted for 31.68% and 21.48% of the sedentary time‐related variation in HOMA‐IR, respectively. Specifically, decreased Roseburia sp. CAG:471 , Intestinibacter bartlettii , and Firmicutes bacterium CAG:83 , but increased Bacteroides xylanisolvens related to longer sedentary time, were causally linked to the development of insulin resistance. Furthermore, integrative analysis with metabolomics identified reduced L‐citrulline and L‐serine, resulting from a suppression of arginine biosynthesis as key microbial effectors linking longer sedentary time to enhanced insulin resistance. Conclusions In summary, our findings provide insights into the mediating role of gut microbiota on the progression of insulin resistance induced by excessive sedentary time, and highlight the possibility of counteracting the detrimental effect of prolonged sedentary time on insulin resistance by microbiota‐modifying interventions. Key points Prolonged sedentary time leads to a depletion of Roseburia sp. CAG:471 and Firmicutes bacterium CAG:83 , and suppresses arginine biosynthesis. Decreased L‐citrulline and L‐serine function as key microbial effectors mediating the adverse effect of sedentary time on insulin sensitivity. Targeting gut microbiota holds promise to combat insulin resistance induced by excessive sedentary time.