Recently, the journal Cell Metabolism published the latest research results of Prof. Hao Haiping'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 the susceptibility of intestinal epithelial cell damage induced by chronic mental stress, and identified microbial metabolic markers with clinical monitoring value. PhD student Wei Wei, master's graduate Liu Yali and postdoctoral researcher Hou Yuanlong from China Pharmaceutical University (CPU), are the co-first authors of the paper, while Prof. Hao Haiping, Academician Wang Guangji, Prof. Zheng Xiao from CPU and Prof. Yuan Yonggui from Southeast University are the co-corresponding authors, and China Pharmaceutical University is the first corresponding unit for the paper. The paper was selected as the cover article of the March issue of Cell Metabolism, and the progress of this research was reported in the form of NEWs on the Nature homepage.
Epidemiological studies have shown that chronic exposure to psychosomatic stress drives the development of a wide range of 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, there is rarely reported 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, could effectively rescue IAA-induced damage in vitro and in vivo. Finally, the research team demonstrated that the IAA-producing capacity of the gut 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 their mechanisms of abnormal intestinal stem cell differentiation driven by microbial dysregulation under mental stress through multidisciplinary techniques, which provides new ideas and potential targets for subsequent research on brain-intestinal axis signaling, target discovery, and precise drug intervention. This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, National High-Level Talents Special Support Program, and China Pharmaceutical University Xingyao Scholar Program.
Original link: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00477-1
Link to report of the research on Nature official website: https://www.nature.com/articles/d41586-024-00188-4
