Polyphenols-mediated immune regulation: Metabolite-driven epigenetic regulatory mechanisms

Dietary polyphenols are recognized modulators of immune function. Although metabolic and epigenetic effects have been examined separately, relationships and implications for immune regulation remain unclear. Addressing the gap is critical to understanding how diet shapes immune homeostasis and disease risk. Previous studies examined metabolic and epigenetic effects separately, leaving their interconnections-and implications for immune regulation-unclear.

This review aims to elucidate, from a novel perspective, the polyphenols-metabolic-epigenetic modification-immunity regulatory axis that underlies polyphenols-mediated immunoregulation. By emphasizing this framework, we highlight mechanistic insights into the interplay among diet, metabolism, and immune homeostasis, providing potential strategies for preventing and treating chronic inflammatory and metabolic diseases.

A comprehensive search of peer-reviewed publications was performed from core collections of electronic databases such as PubMed, Web of Science, Google Scholar, and Science Direct.

Polyphenols regulate immunity by reprogramming metabolic pathways and modulating epigenetic mechanisms. Metabolite-driven crosstalk between metabolism and epigenetics offers insights into immune phenotype stability, particularly across generations. These mechanisms are relevant to clinical phenotypes highlighted in the manuscript, including obesity, features of metabolic syndrome, and autoimmune conditions. Challenges remain in translation, including bioavailability, dose-response variability, and limited evidence on transgenerational effects. Future studies should explore how polyphenols-mediated metabolic shifts affect epigenetic regulators during early development and immune inheritance. Integrating polyphenols into immunometabolism and epigenetic regulation offers novel strategies for disease prevention and precision nutrition.

This review provides a new perspective on polyphenols-mediated immune regulation, offering a theoretical basis for understanding how small molecules influence immunity through metabolism and epigenetics. This framework, rarely highlighted in current studies, may also guide future research in epigenetics.