Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response

Fil: Gao, Xinghua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Gao, Xinghua. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Gao, Xinghua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Cao, Qiuhua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Cao, Qiuhua. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Cao, Qiuhua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Cheng, Yan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Cheng, Yan. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Cheng, Yan. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhao, Dandan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Zhao, Dandan. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhao, Dandan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Zhuo. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Zhuo. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Zhuo. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Zhuo. Nanjing University of Chinese Medicine. Translational Medicine Center; China Fil: Yang, Hongbao. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Hongbao. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Yang, Hongbao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wu, Qijin. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wu, Qijin. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wu, Qijin. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: You, Linjun. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: You, Linjun. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: You, Linjun. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lin, Yanting. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lin, Yanting. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Lin, Yanting. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Li, Xianjing. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Bian, Jin-Song. National University of Singapore. Yong Loo Lin School of Medicine. Department of Pharmacology; Singapur Fil: Sun, Dongdong. Nanjing University of Chinese Medicine. Translational Medicine Center; China Fil: Kong, Lingyi. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Kong, Lingyi. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Kong, Lingyi. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Yong. China Pharmaceutical University. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Abstract: Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6-/- mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.