THE PHARMACOLOGY OF THE GUT–BRAIN AXIS: MICROBIAL METABOLITES AS EMERGING TARGETS FOR NEUROPSYCHIATRIC THERAPY

The gut–brain axis (GBA) is a bidirectional communication network linking the gastrointestinal tract and the central nervous system through neural, endocrine, immune and metabolic pathways. Increasing evidence indicates that gut microorganisms are not merely passive inhabitants of the intestine but active biochemical partners capable of producing, transforming and regulating neuroactive molecules. Microbial metabolites—including short-chain fatty acids (SCFAs), tryptophan-derived indoles and kynurenine-related metabolites, secondary bile acids, γ-aminobutyric acid (GABA), dopamine-related metabolites and other small molecules—can influence neuroinflammation, blood–brain barrier integrity, microglial activity, neurotransmission, synaptic plasticity and hypothalamic–pituitary–adrenal-axis signaling. These mechanisms have been associated with depression, anxiety, autism spectrum disorder, schizophrenia, stress-related disorders and neurodegenerative disease. From a pharmacological perspective, the most important emerging concept is that microbial metabolites and their host receptors may represent druggable targets rather than only biomarkers of disease. Potential strategies include receptor-directed agonism or antagonism, metabolite replacement, enzyme modulation, psychobiotics, next-generation probiotics, precision prebiotics, postbiotics, fecal microbiota-based approaches and targeted delivery systems. At the same time, the microbiome can modify the pharmacokinetics and pharmacodynamics of conventional CNS medicines, creating an additional source of interindividual variability. This review summarizes the principal microbial metabolites involved in GBA signaling, their pharmacological targets and mechanisms, links to neuropsychiatric disorders, therapeutic opportunities, safety issues and translational challenges. A metabolite-centered pharmacological framework may contribute to future precision neuropsychiatry, although causality, standardization, long-term safety and clinically validated biomarkers remain major barriers.