A stress-responsive brain-gut metabolic axis instructs intestinal cell lineage commitment

The brain and gut are intricately connected in response to various stressful stimuli. Here we describe a brain-to-gut pathway in mice that instructs intestinal stem cells (ISCs) lineage commitment via bacterial metabolic signals. Psychological stress signals from the brain trigger a sympathetic pathway to enrich gut commensal Lactobacillus, which contributes to a transferrable loss of intestinal secretory cell subtypes. Indole-3-acetate (IAA) production by Lactobacillus murinus disrupts mitochondrial bioenergetics of ISCs and blocks secretory lineage commitment. In patients with mental stress, we observe similar enrichment of IAA and Lactobacillus species associated with gut dysfunction. These findings uncover a stress-responsive brain-gut signalling mechanism that skews ISCs fate decision and could be targeted for stress-driven gut-brain comorbidities.