Gastrointestinal fate of bioactive peptides: A mechanistic review of stability, transport, and bioavailability.

Bioactive peptides (BAPs), encrypted within food proteins, offer significant potential for health promotion and disease prevention. However, their practical application as nutraceuticals or therapeutics is hampered by low and variable oral bioavailability. The discrepancy that often exists between potent in vitro activity and diminished in vivo efficacy is largely attributable to the formidable challenges encountered during gastrointestinal (GI) transit. This review provides a critical and mechanistic examination of the GI fate of BAPs, focusing on the interplay between their stability, transport, and ultimate bioavailability. The enzymatic barriers of the stomach and intestine are dissected, analyzing the structural and physicochemical properties that dictate peptide survival. The complex mechanisms of transepithelial transport, including carrier-mediated (PEPT1), paracellular, and transcytotic routes, are evaluated, while discussing the controversy surrounding intact oligopeptide absorption. Methodologies for assessing GI fate, from the standardized INFOGEST digestion model to in vitro (Caco-2) and ex vivo (Ussing chamber) permeability assays, are compared, highlighting their inherent limitations and the sources of conflicting data. The profound modulatory influences of the food matrix and the gut microbiota are explored, emphasizing microbial metabolites beyond short-chain fatty acids. Finally, advanced strategies are critically assessed for applicability, industrial feasibility, and safety. Priority research directions are proposed, including AI-assisted peptide design, dynamic biomimetic digestion models, and microbiota-targeted clinical trials, to translate the promise of BAPs into tangible health benefits.