IUPHAR review. Gut microbial metabolites as remote regulators of behavior and neuropsychiatric disease

The gut-brain axis has emerged as a fundamental pathway through which gut-derived microbial metabolites exert remote control over brain development, neural circuit function and behavior. This Review synthesizes evidence that key microbial metabolites including short-chain fatty acids, tryptophan derivatives, bile acids and trimethylamine N-oxide modulate neuroimmune, neuroendocrine and synaptic signaling in a context-dependent manner, influencing whether the brain maintains homeostasis or progresses toward pathology. We critically evaluate how these metabolites contribute to the etiology and symptomatology of neurodevelopmental and psychiatric disorders such as autism spectrum disorder, major depressive disorder, anxiety and post-traumatic stress disorder. Causal insights are highlighted by studies demonstrating that fecal microbiota transplantation from affected individuals to rodents transfers core behavioral phenotypes. It is important to note, however, that while FMT and gnotobiotic studies establish causality in animal models, evidence from human studies remains predominantly correlative, and we have explicitly distinguished these evidence tiers throughout. We also explore the translational potential of microbiome-derived biomarkers for diagnosis and the challenges in developing targeted therapeutics, including probiotics, postbiotics and metabolite-sequestering agents. Moving forward, the field should prioritize decoding the contextual determinants of microbial influence and adopt personalized, function-based strategies to effectively modulate the gut-brain metabolic axis for brain health.