Microbial metabolites at the front line: Orchestrating gastrointestinal and systemic barrier immunity across the lifespan

Microbiota-derived metabolites are central mediators between commensal microbes and host immune system at mucosal barrier surfaces. Insights from mouse models have revealed precise molecular mechanisms by which numerous metabolites, including short-chain fatty acids, tryptophan catabolites and bile acid derivatives, regulate epithelial integrity, innate immune tone, and adaptive immunity and tolerance. Parallel studies in humans increasingly confirm these pathways and link metabolite dysregulation to diseases, such as inflammatory bowel disease, asthma, and atopic dermatitis. This review synthesizes current understanding of how microbial metabolites orchestrate gastrointestinal barrier immunity, while also integrating emerging insights into the gut-lung and gut-skin axes. Crucially, we examine these interactions through a developmental lens, highlighting how metabolite exposure during critical early-life "windows of opportunity" shapes long-term immune trajectories. We integrate evidence from experimental models and human data to highlight conserved mechanisms, species-specific divergences, and the therapeutic potential of targeting these metabolic pathways as strategies to promote barrier health and durable immune homeostasis.