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Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):E2960-E2969. doi: 10.1073/pnas.1720696115. Epub 2018 Mar 12.

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

Gao X1,2,3, Cao Q1,2,3, Cheng Y1,2,3, Zhao D1,2,3, Wang Z1,2,3,4, Yang H1,2,3, Wu Q1,2,3, You L1,2,3, Wang Y1,2,3, Lin Y1,2,3, Li X1,2,3, Wang Y1,2,3, Bian JS5, Sun D4, Kong L1,2,3, Birnbaumer L6,7, Yang Y8,2,3.

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State Key Laboratory of Natural Medicines, China Pharmaceutical University, 211198 Nanjing, China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 211198 Nanjing, China.
Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, 211198 Nanjing, China.
Translational Medicine Center, Nanjing University of Chinese Medicine, 210023 Nanjing, China.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
Biomedical Research Institute, Catholic University of Argentina, C1107AAZ Buenos Aires, Argentina.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 211198 Nanjing, China;


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.


DSS-induced colitis; chronic stress; gut microbiota; immune reaction; mucin-2

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