Recently, Cell Metabolism, a leading consensus journal, published online the latest research results of Prof. Hai-Ping Hao's team entitled Psychological Stress-induced Microbial Metabolite Indole-3-acetate Disrupts Intestinal Cell Lineage Commitment. The study reveals a new mechanism of brain-gut signaling and metabolic regulation of chronic mental stress-induced susceptibility to intestinal epithelial cell injury, and discovers metabolic markers of bacterial flora with clinical monitoring value. Wei Wei, a doctoral student, Liu Yali, a master's degree graduate, and Hou Yuanlong, a postdoctoral fellow of the School of Pharmaceutical Sciences of the University of China, are the co-first authors of this paper, while Prof. Hao Haiping, Academician Wang Guangji, and Prof. Zheng Xiao are the co-corresponding authors, and Prof. Yuan Yonggui of Southeast University, and the University of Pharmaceutical Sciences of China is the first corresponding organization. The paper was selected as the cover article of the March issue of Cell Metabolism, and at the same time, the progress of the study was reported in the form of NEWs on the Nature homepage.
Epidemiologic studies have shown that chronic exposure to psychosocial stress drives the development of many diseases. For example, chronic psychosocial stress in modern society is closely related to the high prevalence of intestinal diseases such as inflammatory bowel disease and irritable bowel syndrome. However, little is known about the brain-gut signaling mechanism under mental stress, especially how mental stress transmits and perturbs intestinal homeostasis. Focusing on the above issues, Prof. Hao Haiping's team found that chronic psychological stress exposure triggers irreversible small intestinal epithelial cell dysfunction based on the mouse model of chronic restraint stress and plantar electric shock model established in the previous period. Through organoid culture, intestinal stem cell differentiation profiling and multi-omics approaches, the team found that the above phenotypes are associated with the disruption of mitochondrial bioenergetics and functional homeostasis of small intestinal stem cells (ISCs) under mental stress. The team further found that L. murinus and its metabolite indole-3-acetic acid (IAA) play a key role in the stress-induced ISC differentiation abnormalities through chemical intervention, sterile mice, metabolomics and engineered bacteria construction. Subsequent mechanistic studies showed that IAA acts as a metabolic signal to inhibit ISC mitochondrial bioenergetics, thereby disrupting its lineage differentiation and aggravating intestinal epithelial cell damage in a cell-intrinsic manner, while supplementation of the tricarboxylic acid cycle intermediate, α-ketoglutaric acid, effectively rescued IAA-induced damage in vitro and in vivo. Finally, the research team demonstrated that the IAA-producing capacity of the intestinal flora under psychiatric stress is consistently increased and associated with intestinal dysfunction in clinical patients suffering from different psychiatric disturbances.
This study reveals the signaling molecules and mechanisms of microbial dysregulation driving the abnormal differentiation of intestinal stem cells under mental stress through multidisciplinary techniques, which provides new ideas and potential targets for subsequent research on brain-gut axis signaling, target discovery and precise drug intervention. This research work was funded by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the National High-level Young Talent Program, and the Xingdao Scholar Program of China Pharmaceutical University, and supported by the National Key Laboratory of Multi-target Natural Drugs and the Jiangsu Key Laboratory of Pharmacokinetics.
Original link: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00477-1
