Gut microbial metabolism via hippocampal indole-AhR signaling regulates emotional symptoms.

Abstract

Gut microbiota modulate emotion, yet mechanistic insight and therapeutic targets remain limited. Here, we identify reduced gut microbiota-derived indole causally modulating emotion through hippocampal aryl hydrocarbon receptor (AhR). We found that decreased abundance of Alistipes shahii reduced intestinal indole levels via loss of tryptophanase, the rate-limiting step for indole production in microbial tryptophan metabolism, in irritable bowel syndrome (IBS) patients and model mice. In the brain, indole acts via AhR, which is enriched in the ventral dentate gyrus (vDG), a hub in regulating emotion. Reduced indole diminished nuclear AhR expression and vDG granule cell activity, leading to affective symptoms. Tryptophanase-producing microbiota transplantation, indole/tryptophanase supplementation, chemogenetic activation of vDG neurons, or diosmin, a clinically approved AhR agonist, rescued emotional symptoms in IBS mice. Together, these findings define an Alistipes shahii-tryptophanase-indole-AhR-vDG pathway as a mechanistic and translationally tractable gut-brain axis underlying affective disturbances.