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

  • Cell Metab. 2026 Apr 1:S1550-4131(26)00097-5. doi: 10.1016/j.cmet.2026.03.003.
Ting-Ting Wang  1 ,  Yan-Jia Luo  2 ,  Wen Feng  3 ,  Lian-Xiang Jiang  3 ,  Qing-Song Yu  3 ,  Yu-Ting He  3 ,  Lizhi Guan  4 ,  Bing-Qian Zhu  5 ,  Hong Jiang  2 ,  Min Li  5 ,  Ruixin Liu  6 ,  Jing Wang  7 ,  Ya-Dong Li  8
Affiliations
  • 1. Department of Gastroenterology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; School of Nursing, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 2. Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 3. Department of Gastroenterology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China.
  • 4. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China.
  • 5. School of Nursing, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 6. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China. Electronic address: [email protected].
  • 7. Department of Gastroenterology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China. Electronic address: [email protected].
  • 8. Department of Gastroenterology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, State Key Laboratory of Eye Health, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; School of Nursing, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address: [email protected].
PMID: 41928504 DOI: 10.1016/j.cmet.2026.03.003
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.

Keywords
emotion; indole, hippocampus, irritable bowel syndrome, gut-brain axis; microbial metabolism.
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