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The objective of this narrative review is to examine how polyphenols affect neuro\u2010metabolic and immune pathways across the gut\u2010brain\u2010liver axis in obesity, type 2 diabetes, and metabolic dysfunction\u2010associated steatotic liver disease. The review covers literature from 2000 to 2025 indexed in PubMed, Scopus, and Web of Science, with emphasis on mechanistic, multi\u2010omics, 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\u2010\u03b3\u2010valerolactones, 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\u2010term trials with considerable inter\u2010individual variability. This variability appears linked to metabotype, metabolic capacity, habitual diet, sex, and medication use. Overall, current evidence supports polyphenols as multi\u2010target regulators of gut\u2010brain\u2010liver communication. Larger, well\u2010designed clinical and translational studies are needed to confirm their therapeutic relevance.<\/jats:p>","DOI":"10.1002\/mnfr.70560","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:21:06Z","timestamp":1786342866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Polyphenols as Systems Modulators of the Gut\u2010Brain\u2010Liver Axis: A Narrative Review of Neuro\u2010Metabolic and Immunomodulatory Networks"],"prefix":"10.1002","volume":"70","author":[{"given":"Aftab","family":"Alam","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy Prince Sattam Bin Abdulaziz University  Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talha","family":"Jawaid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine Imam Mohammad Ibn Saud Islamic 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