An expert narrative review on the mechanisms and therapeutic potential of gut microbiota-derived metabolites in multi-organ crosstalk

Background: Gut microbiota-derived metabolites-short-chain fatty acids (SCFAs), tryptophan derivatives, and uremic toxins-translocate systemically and mediate multi-organ crosstalk along the gut-kidney-heart-brain-endocrine axis, influencing host physiology and disease. However, integrated mechanistic insights remain limited. Objective: We evaluated the effects of gut microbiota-derived metabolites (intervention) on inter-organ communication and disease outcomes in humans and model systems (population), compared to controls or standard care (comparison). Methods: We conducted a narrative review of studies from PubMed, Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov (2020-2025). We included randomized controlled trials, cohort studies, and mechanistic experiments. Two reviewers independently screened records using a standardized protocol; data synthesis employed narrative synthesis and random-effects meta-analysis where appropriate. Results: 41 included studies (n≈15,000 participants), SCFAs improved renal function (e.g., risk ratio [RR]=0.85 for composite outcomes, 95% CI: 0.72-0.98) with substantial heterogeneity (I²=68%). SCFAs conferred cardio protection and regulated neuroinflammation. Tryptophan metabolites showed dual roles in neuroprotection and metabolic dysfunction. Metabolites demonstrated diagnostic value (e.g., TMAO AUC = 0.87 for cardiovascular risk). Conclusion: Gut microbiota metabolites are pivotal in multi-organ crosstalk with moderate evidence certainty. They offer novel strategies for diagnosing and treating cardio-renal, metabolic, and neurological disorders, although individual variability and translational challenges persist.