Emerging Roles of Postbiotics in Gut-Brain-Microbiome Axis Modulation and Neurobiological Pathways of Chronic Stress-Related Brain Dysfunction.

Chronic psychological stress disrupts the gut-brain-microbiome axis (GBMA) through gut dysbiosis, intestinal and blood-brain barrier disruption, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and neuroinflammation, collectively impairing neurotransmitter signaling and neuroplasticity. Addressing these interconnected pathological processes requires therapeutic strategies capable of acting across multiple nodes of the GBMA simultaneously. Postbiotics, defined as preparations of inanimate microorganisms and/or their components that confer a health benefit on the host, have emerged as promising candidates for restoring GBMA homeostasis under chronic stress. Key postbiotic classes, including short-chain fatty acids, tryptophan metabolites, GABA-related compounds, heat-killed bacteria, and bacterial extracellular vesicles, attenuate neuroinflammation, reinforce barrier integrity, normalize neurotransmitter balance, and promote brain-derived neurotrophic factor (BDNF)-dependent neuroplasticity. Preclinical evidence has consistently demonstrated behavioral and neurochemical improvements following postbiotic administration, and limited clinical data suggest preliminary reductions in cortisol, inflammatory biomarkers, and stress-related symptom severity. However, clinical translation remains constrained by the absence of standardized postbiotic characterization and limited mechanistic data from human trials. This review provides an integrated account of the neurobiological pathways by which chronic stress disrupts the GBMA and examines the emerging roles of postbiotics in modulating these pathways, with the goal of informing future postbiotic-based strategies for chronic stress-related brain dysfunction.