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  3. Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment

Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment

  • Cell Metab. 2024 Jan 17:S1550-4131(23)00477-1. doi: 10.1016/j.cmet.2023.12.026.
Wei Wei 1,  Yali Liu 2,  Yuanlong Hou 3,  Shuqi Cao 1,  Zhuo Chen 1,  Youying Zhang 1,  Xiaoying Cai 1,  Qingyuan Yan 1,  Ziguang Li 1,  Yonggui Yuan 4,  Guangji Wang 5,  Xiao Zheng 6,  Haiping Hao 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong 999077, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacy, Shenzhen Luohu People's Hospital, Shenzhen 518005, China.
  • 4 Department of Psychosomatics and Psychiatry, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China. Electronic address: yygylh2000@sina.com.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: guangjiwang@cpu.edu.cn.
  • 6 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xzheng@cpu.edu.cn.
  • 7 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haipinghao@cpu.edu.cn.
PMID: 38266651 DOI: 10.1016/j.cmet.2023.12.026
Abstract

The 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, we describe a stress-responsive brain-to-gut metabolic axis that impairs intestinal stem cell (ISC) lineage commitment. Psychological stress-triggered sympathetic output enriches gut commensal Lactobacillus murinus, 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 α-ketoglutarate supplementation bolsters ISC differentiation and confers resilience to stress-triggered intestinal epithelial injury. We confirm that fecal IAA is higher in patients with mental distress and is correlated with gut dysfunction. These findings uncover a microbe-mediated brain-gut pathway that could be therapeutically targeted for stress-driven gut-brain comorbidities.

Keywords

Lactobacillus; brain-body communication; gut-brain axis; inflammatory bowel disease; intestinal stem cell; microbial metabolism; mitochondrial respiration; psychological stress; tryptophan metabolites.

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