Chronic stress and sustained glucocorticoid exposure disrupt intracellular signaling networks that regulate mitochondrial function and neurotrophic support, thereby increasing vulnerability to depressive disorders. Among these alterations, redox imbalance and mitochondrial dysfunction contribute to impairment of neuronal survival pathways, including TrkB–ERK–CREB–BDNF signaling. However, upstream biological modulators of these stress-responsive processes remain incompletely understood. Here, we investigated whether gut-derived commensal bacteria function as modulators of neuronal signaling under chronic stress conditions. Using a fecal microbiota transplantation (FMT)-based behavioral stratification approach, we identified Intestinimonas butyriciproducens and Parabacteroides merdae as species depleted in mice with increased depressive-like immobility. Functional validation showed that both strains attenuated oxidative stress, reduced intracellular reactive oxygen species, and suppressed mitochondrial apoptotic signaling in neuronal cells, accompanied by restoration of TrkB–ERK–CREB signaling and increased brain-derived neurotrophic factor expression. In a chronic corticosterone model, oral administration of these strains reduced depressive-like behavior and restored hippocampal BDNF levels. Collectively, these findings demonstrate that defined commensal bacteria act as biological modulators of intracellular signaling pathways, including redox balance and mitochondrial function, thereby preserving neurotrophic signaling. This study provides evidence linking specific commensal taxa to modulation of neuronal signaling under chronic stress conditions.
Chung et al. (Fri,) studied this question.