Modulating stress responses via the microbiota-gut-brain axis: a pathway-focused review of GABA, 5-HT, and kynurenine metabolites.

Stress is a major risk factor for human anxiety, depression, and other neuropsychiatric disorders, yet nutritional strategies that target upstream biological mechanisms remain insufficiently developed. Growing evidence indicates that host-microbiota co-regulated metabolites act as functional mediators within the microbiota-gut-brain axis, shaping individual vulnerability or resilience to stress. In this review, we synthesize current preclinical and human evidence with a focus on three metabolite systems of high mechanistic relevance-γ-aminobutyric acid, serotonin, and kynurenine-pathway metabolites. We discuss how microbial activity, host metabolism, and dietary inputs interact to modulate brain-relevant signaling under stress. We highlight neuroendocrine, neuroimmune, and neural pathways through which these systems may act, including stress-induced disruptions in intestinal and blood-brain barrier integrity and amplification of inflammatory signaling. Evidence across models suggests that stress-associated dysbiosis alters GABAergic and serotonergic signaling and shifts tryptophan metabolism toward neuroactive kynurenines, thereby biasing neural excitability, synaptic plasticity, and affect-related behaviors. We further evaluate food-based psychobiotic strategies-such as targeted whole-food matrices, fermented foods, and selected probiotic strains-that can reprogram microbial metabolism to restore neurotransmitter balance and attenuate inflammation. Finally, we propose a translational framework emphasizing strain- and pathway-specific mechanisms, standardized metabolite quantification, and biomarker-guided personalization to advance microbiome-metabolite interventions for stress-related brain dysfunction.