Enhancement of gut barrier integrity by a <i>Bacillus subtilis</i> secreted metabolite through the GADD45A‐Wnt/β‐catenin pathway

Inflammatory bowel disease (IBD) represents a significant challenge to global health, characterized by intestinal inflammation, impaired barrier function, and dysbiosis, with limited therapeutic options. In this study, we isolated a novel strain of <i>Bacillus subtilis</i> (<i>B. subtilis</i>) and observed promising effects in protecting against disruption of the gut barrier. Our findings indicate that the enhancement of intestinal barrier function is primarily attributed to its metabolites. We identified a novel metabolite, 2-hydroxy-4-methylpentanoic acid (HMP), derived from <i>B. subtilis</i>, that significantly improved intestinal barrier function. We also show that growth arrest and DNA damage 45A (GADD45A) is a key regulator of mucosal barrier integrity, which is activated by HMP and subsequently activates the downstream Wnt/β-catenin pathway. Our findings potentially contribute to the development of probiotics-derived metabolites or targeted "postbiotics" as novel therapeutics for the treatment or prevention of IBD and other diseases associated with intestinal barrier dysfunction.