Gut epithelial barriers as regulators of metabolite-driven immune responses

Immunometabolism provides a framework for understanding how metabolic cues shape immune cell fate and function. While traditionally centered on cell-intrinsic pathways, emerging evidence highlights a critical role for epithelial barrier regulation in shaping immune responses by controlling exposure to microbiome derived metabolites. Microbial metabolites including short-chain fatty acids, bile acid derivatives, tryptophan catabolites, and polyamines engage conserved metabolic checkpoints such as mTOR, AMPK, PPARs, SIRT1, and HIF-1α to influence immune activation, tolerance, and inflammatory tone. Critically, epithelial barriers regulate immune exposure to these signals, positioning barrier integrity as an upstream determinant of immunometabolic reprogramming. Altered epithelial metabolism compromises tight junction stability and metabolite flux, contributing to dysregulated immune activation and chronic inflammation. In this review, we synthesize current evidence supporting the concept that epithelial barriers act as metabolic gatekeepers of immunity, integrating microbial signals with host metabolic pathways to regulate immune function and disease susceptibility.