Urolithins in clinical translation: from gut microbial metabolites to precision interventions.

Urolithins are gut microbiota-derived metabolites generated from ellagitannins and ellagic acid, and have emerged as promising mediators at the diet-microbiota-host interface. Interest in this metabolite family has increased substantially owing to growing evidence that urolithins, particularly urolithin A, influence mitochondrial quality control, autophagy, inflammatory signaling, and metabolic homeostasis across multiple tissues. These mechanistic properties have positioned urolithins as candidate interventions for aging-related functional decline, cardiometabolic disorders, neuroinflammatory conditions, and other chronic diseases characterized by impaired cellular resilience. However, their path to clinical application remains incompletely defined. In this Review, we synthesize current knowledge on the origin, microbial biotransformation, metabotypes, pharmacokinetics, and exposure biology of urolithins, with particular attention to the determinants of interindividual variability and the unresolved question of which molecular species are truly active in vivo. We then examine the core mechanisms of urolithin action and evaluate evidence across major disease contexts, integrating pre-clinical findings with available human data. Particular emphasis is placed on the current clinical literature on urolithin A, including safety, tolerability, dosing, target-engagement biomarkers, and functional endpoints. We further analyze the major factors underlying the translational gap between experimental promise and clinical outcomes, including differences in microbial production capacity, free vs. conjugated molecular forms, exposure-response uncertainty, responder heterogeneity, and limitations in trial design. Finally, we discuss how metabotype-guided stratification, microbiome-targeted strategies, improved formulations, and standardized biomarkers may support the development of urolithins within precision nutrition and translational medicine. Collectively, urolithins represent a compelling yet still evolving class of diet-derived microbial metabolites whose clinical utility will depend on resolving key mechanistic, pharmacological, and methodological uncertainties.