Bacterial exopolysaccharides and live biotherapeutics: Orchestrating immune modulation and therapeutic potential in...

Microbial exopolysaccharides (EPS) are emerging as critical effector molecules orchestrating host immunity. Their remarkable structural diversity, driven by variations in monosaccharide composition, charge, and glycosidic linkages, dictates potent immunomodulatory functions through specific interactions with host pattern recognition receptors (CLRs, TLRs), triggering defined cellular responses and cytokine profiles, often with minimal toxicity. Beyond direct immune effects, EPS shape the gut environment by fortifying barrier integrity and acting as prebiotics. This therapeutic potential can be harnessed via Live Biotherapeutics (LBs) as natural producers, or through purified or rationally engineered EPS for targeted intervention. Cutting-edge synthetic biology and production strategies aim to unlock this potential, though significant structure-function knowledge gaps and scalability challenges in linking specific structural motifs to predictable immune outcomes and in developing scalable, reproducible production methods remain. This review synthesizes and critically evaluates current understanding, focusing specifically on the immunomodulatory EPS produced by gut-commensal and probiotic bacteria. We highlight the promise of these molecules as therapeutics and provide a roadmap for the rational design of next-generation immunotherapies, including engineered LBs that produce tailored EPS in situ to target the gut ecosystem.