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0 reviewsSUMMARYThe brain and gut are intricately connected and respond to various stimuli. Stress-induced brain-gut communication is implicated in the pathogenesis and relapse of gut disorders. The mechanism that relays psychological stress to the intestinal epithelium, resulting in maladaptation, remains poorly understood. Here, wedescribe a stress-responsive brain-to-gut metabolic axis that impairs intestinal stem cell (ISC) lineagecommitment. Psychological stress-triggered sympathetic output enriches gut commensal Lactobacillusmurinus, increasing the production of indole-3-acetate (IAA), which contributes to a transferrable loss of intestinal secretory cells. Bacterial IAA disrupts ISC mitochondrial bioenergetics and thereby prevents secretory lineage commitment in a cell-intrinsic manner. Oral a-ketoglutarate supplementation bolsters ISC differentiation and confers resilience to stress-triggered intestinal epithelial injury. We confirm that fecal IAAis higher in patients with mental distress and is correlated with gut dysfunction. These findings uncovera microbe-mediated brain-gut pathway that could be therapeutically targeted for stress-driven gut-braincomorbidities.