Microbial Metabolites and the Gut-Brain Axis in Neurological Disorders: Implications for Neuropharmacology and Therapy

Abstract

The bidirectional communication between the gut microbiota and the central nervous system through the gut-brain axis has become a new paradigm for understanding the pathological mechanisms of major neurological disorders and investigating their treatment. Accumulating experimental and clinical evidence indicates that microbial metabolites are key mediators of this microbiota-brain dialogue. Acting through neural, endocrine, and immune pathways, these metabolites modulate neuroinflammation, blood-brain barrier integrity, synaptic plasticity, and neuronal survival, and have been implicated in disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, autism spectrum disorder, and ischemic stroke. In contrast to previous reviews, which have typically focused on either specific diseases or single signaling routes, this review adopts a metabolite-centered framework integrating neural, endocrine, and immune mechanisms across disease contexts, and emphasizing cross-pathway convergence on shared targets. The review further synthesizes data from preclinical models and emerging clinical studies of microbiota- and metabolite-based interventions, and highlights their promise and current limitations. By describing common signaling modules and discussing methodological challenges, this review is aimed at clarifying the translational potential of microbial metabolites as druggable effectors within the gut-brain axis, and outlining their clinical relevance to early diagnosis, risk stratification, and mechanism-based neuropharmacological therapies.