• B. breve AMR101 alleviates depression via AHR-AHN signaling. • IPA activates hippocampal AHR signaling to promote adult neurogenesis. • A novel microbiota-IPA-AHR-neurogenesis axis is defined for depression therapy. • Probiotic-derived IPA restores stress-induced behavioral and metabolic deficits. Major depressive disorder (MDD) is a chronic and debilitating condition for which probiotics are emerging as a promising microbiota-based therapeutic avenue. While food-derived probiotics hold considerable potential, their specific bioactive molecules and corresponding central nervous system mechanisms remain largely undefined. In this study, we isolated Bifidobacterium breve strains from dairy sources and identified AMR101 as a high-yield producer of indole-3-propionic acid (IPA), a neuroprotective gut metabolite. We demonstrate that Bifidobacterium breve AMR101 functions as a potent antidepressant probiotic in a chronic stress model, exerting its effects in a dose-dependent manner. Administration of AMR101 or exogenous IPA reversed stress-induced physiological and behavioral deficits, alleviating both anxiety-like and depressive-like phenotypes. Quantification of indole metabolites revealed that IPA, indole-3-lactic acid (ILA), and indole-3-acetic acid (IAA) were significantly elevated in mice receiving high-dose AMR101, and their levels correlated negatively with depressive-like behaviors. Furthermore, AMR101 treatment reduced circulating proinflammatory cytokines and increased hippocampal serotonin levels. At the neural circuit level, AMR101 enhanced brain plasticity by promoting adult hippocampal neurogenesis (AHN) and synaptogenesis, effects that were faithfully recapitulated by IPA administration. Mechanistically, we demonstrated that the antidepressant benefits of AMR101 are mediated through activation of the aryl hydrocarbon receptor (AHR) signaling pathway in the hippocampus, as pharmacological inhibition of AHR completely abolished the behavioral, neurogenic, and anti-inflammatory effects. Collectively, our findings delineate a gut–brain axis pathway in which B. breve AMR101 activates hippocampal AHR signaling via IPA, thereby enhancing neurogenesis and ultimately alleviating depressive-like phenotypes. This work positions microbiome-derived IPA as a critical effector molecule and proposes that targeting the food microbe–AHR–neurogenesis axis could offer a novel therapeutic strategy for major depressive disorder.
Li et al. (Sun,) studied this question.