Voluntary wheel running modulates murine gut microbiome during hyperammonemic stress

Exercise modulates multiple physiological systems, including skeletal muscle and the gut microbiome (GMB). Ammonia, a microbiome-derived cytotoxic metabolite, causes cellular hyperammonemic stress (HAS) in chronic diseases. We investigated the impact of voluntary wheel running (VWR) on GMB during HAS in a mouse model. Male C57BL/6J mice were randomized to treatment with either ammonium acetate (AmAc) (2.5 mmol/kg/day) or vehicle for 6 weeks. Stool 16S rRNA sequencing was performed at baseline, pre-intervention, and post-intervention. GMB diversity, taxa-level abundance, and correlation analyses were performed. Overall GMB composition remained stable between baseline and pre-intervention across groups (r > 0.57; P < 0.001). Following interventions, VWR or usual activity (UA), alpha-diversity was highest in AmAc-treated, specifically AmAc-VWR, mice. Eubacterium xylanophilum was reduced in AmAc-UA vs other groups (P < 0.05). Akkermansia abundance declined over time in UA mice, but in AmAc-VWR mice, this depletion was reversed (P = 0.002). Clostridium sensu stricto 1 and Eubacterium ventriosum were increased in AmAc-VWR mice (P < 0.05). Correlation analysis revealed high stability in PBS-UA (r = 0.667; P < 0.001), moderate restructuring in AmAc-VWR (r = 0.566; P < 0.001), and PBS-VWR (r = 0.385; P = 0.0099). HAS-induced GMB instability, with loss of beneficial taxa, including short-chain fatty acid-producing bacteria, was partially ameliorated by VWR. Exercise-mediated GMB modulation may be a strategy to mitigate HAS-induced complications in chronic diseases.IMPORTANCEVoluntary exercise is recommended in chronic diseases to improve outcomes, but biological responses in disease are not well characterized. Perturbations in the metabolism of ammonia, a microbiome-generated toxin, occur in chronic diseases that can be compounded by muscle-generated ammonia during exercise. Exercise-induced molecular responses are adversely affected by hyperammonemic stress of chronic diseases, including liver cirrhosis. We investigated gut microbiome changes during voluntary wheel running, which replicates human endurance exercise in a preclinical mouse model of hyperammonemia. Adverse impacts of Hyperammonemic stress included a reduction in short-chain fatty acid producers that were reversed by voluntary wheel running. Our data lay the foundation for future studies on how endurance-type exercise promotes a favorable gut microbial composition and strategies to use exercise as a regulator of hyperammonemic stress via targeting the gut microbiome.