Microbial biotherapeutic metabolite alleviates liver injury by restoring hepatic lipid metabolism through PPARα across the gut-liver axis

Infectious and non-infectious liver diseases are marked by disrupted liver metabolism and are frequently accompanied by gut epithelial barrier dysfunction and microbial dysbiosis, reflecting the compromised gut-liver axis. Despite the pivotal role of the gut-liver axis in health, transformative therapeutic interventions that simultaneously target both the liver and gut remain underexplored. Peroxisome proliferator-activated receptor alpha (PPARα) suppression drives both gut and liver metabolic diseases. In this study, we report on the therapeutic impact of microbial metabolite, 10-hydroxystearic acid (10-HSA), on restoring lipid metabolism and liver regeneration through PPARα activation, leading to a functional gut-liver axis in an <i>in vivo</i> liver injury model. We previously identified 10-HSA, a known PPARα agonist, in <i>Lactiplantibacillus plantarum-</i>treated intestine. Here, we report that oral administration of 10-HSA prevented AFB1-induced gut epithelial barrier disruption and preserved mucosal T cell populations. Prominent downstream effects of 10-HSA-activated PPARα signaling included significant upregulation of known PPARα-regulated gene expression in the gut and liver; prevention of fibrotic changes and reduction of TGF-β signaling-related gene expression in the gut and liver; and activation of toxicant clearance metabolic pathways in the liver through the PPARα-NRF2 pathway. Restoration of the functional gut microenvironment during 10-HSA treatment was evident by increased gut microbial diversity and circulating citrulline levels. Our findings unveil a novel therapeutic trajectory that harnesses a single microbial metabolite to activate PPARα-mediated tissue repair/renewal pathways across the gut-liver axis, offering a promising biologic therapeutic for treatment of metabolic and inflammatory liver diseases.IMPORTANCEChronic liver diseases, including liver steatosis and fibrosis, are driven in part by dysregulation of PPARα and lipid metabolism. These diseases also generate gut barrier disruption and microbiome dysbiosis, leading to dysfunction of the gut-liver axis. Therapeutic strategies that concurrently support liver regeneration and gut mucosal repair can be highly effective in resolving liver metabolic diseases but remain underexplored. Microbial biotherapeutic metabolite 10-HSA induced repair and regeneration of both liver and gut through the activation of PPARα and restored lipid metabolism. Our findings reveal the therapeutic potential of a single microbial bioactive lipid molecule to repair both hepatic and gut mucosal sites simultaneously with important ramifications for treatment of diseases that disrupt the gut-liver axis.