ABSTRACT 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. IMPORTANCE Voluntary 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.
Bellar et al. (Wed,) studied this question.