Polyphenols as next-generation prebiotics targeting intestinal mucosal tolerance.

Polyphenols, long recognized for their antioxidant and anti-inflammatory properties, are widely consumed as dietary components or as constituents of functional foods and nutraceuticals. Emerging evidence, however, supports a paradigm shift beyond a purely redox-centered perspective, repositioning polyphenols as functionally relevant prebiotic phytochemicals with significant immunomodulatory capacity. This review frames polyphenols as next-generation prebiotics, emphasizing their capacity to act through coordinated, multi-layered mechanisms that extend beyond the stimulation of intestinal microbial growth. It examines how the gut ecosystem leverages their low systemic bioavailability and explores mechanisms linking their health benefits to microbiota-mediated intestinal mucosal tolerance as interconnected dimensions of prebiotic functionality. Emphasis is placed on the multimodal actions of polyphenol-derived microbial metabolites, increasingly recognized as bona fide postbiotics with therapeutic potential. These metabolites modulate key functional microbial outputs, including the secretion and cargo of bacterial extracellular vesicles, thereby regulating tolerogenic immune responses across the epithelial layer, lamina propria, Peyer's patches, and mesenteric lymph nodes. This integrated mode of action clearly distinguishes polyphenols from classical carbohydrate-based prebiotics, positioning them within a candidate functional category capable of targeting immune pathways in autoimmune and inflammatory diseases, including inflammatory bowel disease, diabetes and food allergies. The review further explores polyphenol-based prebiotic interventions driven by microbial functionality rather than taxonomic composition alone and highlights challenges and opportunities of polyphenols as tools in precision immunonutrition protocols where interventions are tailored to individual metabotypes, health status and metabolic variability.