Food peptides and the immune system: A review of their effects on macrophages, lymphocytes, and cytokine production.

Abstract

Food-derived bioactive peptides (FDBPs) are short amino acid sequences encrypted within dietary proteins that can be released during digestion, food processing or fermentation and exert immunomodulatory effects. This review critically examines recent evidence on the interactions between FDBPs and the immune system, with particular emphasis on macrophages, lymphocytes, and cytokine production. Peptides derived from dairy, egg, marine, and plant proteins have been shown to influence key immune functions. In macrophages, FDBPs may enhance phagocytosis and proliferation, and modulate M1/M2 polarization. Their effects on cytokine production are highly context-dependent: in resting cells, many peptides stimulate pro-inflammatory mediators such as TNF-α, IL-6, and nitric oxide, whereas in activated macrophages they may suppress these same mediators and promote IL-10 expression. In lymphocytes, FDBPs can stimulate proliferation and influence CD4⁺ T-helper cell differentiation, often shifting responses away from Th2-mediated allergy-associated pathways towards Th1 and regulatory T-cell-mediated tolerance. These effects are linked to interactions with cell surface receptors, including TLRs and to modulation of intracellular NF-κB and MAPK signaling pathways. This review also evaluates the methodological limitations in peptide generation, purification, and experimental modeling that contribute to inconsistent findings across studies. Finally, major knowledge gaps are identified, including the need for more human clinical trials, a deeper understanding of peptide bioavailability, and the role of the gut microbiota as a potential intermediary. Standardized, physiologically relevant models will be essential for translating the immunotherapeutic potential of FDBPs into practical applications.