Urolithin A: a multi-target therapeutic candidate derived from the gut microbiota for obesity and metabolic...

This review comprehensively examines the role and mechanisms of Urolithin A (UroA), a gut microbial metabolite derived from dietary ellagitannins (ETs), in ameliorating obesity and related metabolic disorders. The in vivo production of UroA is strictly dependent on specific gut microbiota, and the substantial inter-individual variation in this metabolic capacity (UM phenotype) directly influences population responsiveness to ETs-rich dietary interventions. Mechanistically, UroA acts through multiple coordinated pathways: it activates thermogenesis in brown and beige adipose tissue to promote energy expenditure; bidirectionally regulates lipid metabolism by enhancing fatty acid oxidation while suppressing lipogenesis; remodels the immune microenvironment by polarizing macrophages toward the anti-inflammatory M2-like phenotype to alleviate chronic inflammation; and modulates gut microbiota composition at multiple taxonomic levels and regulates microbial tryptophan metabolism, alongside enhancing intestinal barrier integrity. These integrated effects collectively improve systemic insulin sensitivity, glucose homeostasis, and reduce lipid accumulation. Although preclinical evidence is robust, its efficacy in humans requires further validation through large-scale clinical trials. In summary, UroA represents a pivotal active molecule within the "diet-microbiota-host" interaction axis, offering a novel scientific rationale and a potential target for developing personalized nutritional strategies against obesity and other metabolic diseases.