Polyphenols as Systems Modulators of the Gut-Brain-Liver Axis: A Narrative Review of Neuro-Metabolic and Immunomodulatory Networks.

Dietary polyphenols are gaining attention as regulators of gut-brain-liver (GBL) signaling in metabolic disease. The objective of this narrative review is to examine how polyphenols affect neuro-metabolic and immune pathways across the gut-brain-liver axis in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease. The review covers literature from 2000 to 2025 indexed in PubMed, Scopus, and Web of Science, with emphasis on mechanistic, multi-omics, preclinical, and human studies. Most polyphenols show poor absorption in the gastrointestinal tract and depend on liver enzymes and intestinal microorganisms for conversion into active metabolites, including urolithins, phenyl-γ-valerolactones, equol, and other phenolic acids. These metabolites influence microbial composition, bile acid signaling, gut hormone secretion, and host processes related to oxidative stress, inflammation, energy balance, and mitochondrial function. In animal and cell models, polyphenols reduce hepatic fat accumulation, improve insulin sensitivity, strengthen gut barrier integrity, and lower endotoxemia. Human evidence remains limited, derived mainly from short-term trials with considerable inter-individual variability. This variability appears linked to metabotype, metabolic capacity, habitual diet, sex, and medication use. Overall, current evidence supports polyphenols as multi-target regulators of gut-brain-liver communication. Larger, well-designed clinical and translational studies are needed to confirm their therapeutic relevance.