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1. Stress-induced epinephrine promotes hepatocellular carcinoma progression via the USP10-PLAGL2 signaling loop

Author

Chen Wang, Jiaping Ni, Dongqing Zhai, Yanchao Xu, Zijie Wu, Yuyuan Chen, Ning Liu, Juan Du, Yumeng Shen, Guilai Liu, Yong Yang, Linjun You, and Weiwei Hu

Subjects
Medicine, Biochemistry, QD415-436
Abstract

Abstract Hepatocellular carcinoma (HCC) is associated with a poor prognosis. Our previous study demonstrated that Pleomorphic adenoma gene like-2 (PLAGL2) was a potential therapeutic target in HCC. However, the mechanisms that lead to the upregulation of PLAGL2 in HCC remain unclear. The present study revealed that stress-induced epinephrine increased the expression of PLAGL2, thereby promoting the progression of HCC. Furthermore, PLAGL2 knockdown inhibited epinephrine-induced HCC development. Mechanistically, epinephrine upregulated ubiquitin-specific protease 10 (USP10) to stabilize PLAGL2 via the adrenergic β-receptor-2-c-Myc (ADRB2-c-Myc) axis. Furthermore, PLAGL2 acted as a transcriptional regulator of USP10, forming a signaling loop. Taken together, these results reveal that stress-induced epinephrine activates the PLAGL2-USP10 signaling loop to enhance HCC progression. Furthermore, PLAGL2 plays a crucial role in psychological stress-mediated promotion of HCC progression.

Published
2024
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2. Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity

Author

Shuang Feng, Duowei Wang, Yanyan Jin, Shi Huang, Tong Liang, Wei Sun, Xiuli Du, Luoyi Zhuo, Chun Shan, Wenbo Zhang, Tian Jing, Sen Zhao, Ruisi Hong, Linjun You, Guilai Liu, Leilei Chen, Dan Ye, Xianjing Li, and Yong Yang

Subjects
CP: Metabolism, CP: Immunology, Biology (General), QH301-705.5
Abstract

Summary: The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.

Published
2024
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3. Bile duct ligation elevates 5-HT levels in cerebral cortex of rats partly due to impairment of brain UGT1A6 expression and activity via ammonia accumulation

Author

Hanyu Yang, Linjun You, Zhongyan Wang, Lu Yang, Xun Wang, Wenhan Wu, Hao Zhi, Guangmei Rong, Yun Sheng, Xiaodong Liu, and Li Liu

Subjects
Hepatic encephalopathy, Serotonin, UDP-Glucuronosyltransferase 1A6, Ammonia, Reactive oxygen species, Hepatocyte nuclear factor 4α, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Hepatic encephalopathy (HE) is often associated with endogenous serotonin (5-HT) disorders. However, the reason for elevated brain 5-HT levels due to liver failure remains unclear. This study aimed to investigate the mechanism by which liver failure increases brain 5-HT levels and the role in behavioral abnormalities in HE. Using bile duct ligation (BDL) rats as a HE model, we verified the elevated 5-HT levels in the cortex but not in the hippocampus and striatum, and found that this cortical 5-HT overload may be caused by BDL-mediated inhibition of UDP-glucuronosyltransferase 1A6 (UGT1A6) expression and activity in the cortex. The intraventricular injection of the UGT1A6 inhibitor diclofenac into rats demonstrated that the inhibition of brain UGT1A6 activity significantly increased cerebral 5-HT levels and induced HE-like behaviors. Co-immunofluorescence experiments demonstrated that UGT1A6 is primarily expressed in astrocytes. In vitro studies confirmed that NH4Cl activates the ROS-ERK pathway to downregulate UGT1A6 activity and expression in U251 cells, which can be reversed by the oxidative stress antagonist N-acetyl-l-cysteine and the ERK inhibitor U0126. Silencing Hepatocyte Nuclear Factor 4α (HNF4α) suppressed UGT1A6 expression whilst overexpressing HNF4α increased Ugt1a6 promotor activity. Meanwhile, both NH4Cl and the ERK activator TBHQ downregulated HNF4α and UGT1A6 expression. In the cortex of hyperammonemic rats, we also found activation of the ROS-ERK pathway, decreases in HNF4α and UGT1A6 expression, and increases in brain 5-HT content. These results prove that the ammonia-mediated ROS-ERK pathway activation inhibits HNF4α expression to downregulate UGT1A6 expression and activity, thereby increasing cerebral 5-HT content and inducing manic-like HE symptoms. This is the first study to reveal the mechanism of elevated cortical 5-HT concentration in a state of liver failure and elucidate its association with manic-like behaviors in HE.

Published
2024
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4. Identifying Immune-Specific Subtypes of Adrenocortical Carcinoma Based on Immunogenomic Profiling

Author

Qiqi Lu, Rongfang Nie, Jiangti Luo, Xiaosheng Wang, and Linjun You

Subjects
adrenocortical carcinoma, immunological classification, clustering analysis, steroid hormones, tumor immune microenvironment, Microbiology, QR1-502
Abstract

Background: The tumor immune microenvironment (TIME) of adrenocortical carcinoma (ACC) is heterogeneous. However, a classification of ACC based on the TIME remains unexplored. Methods: We hierarchically clustered ACC based on the enrichment levels of twenty-three immune signatures to identify its immune-specific subtypes. Furthermore, we comprehensively compared the clinical and molecular profiles between the subtypes. Results: We identified two immune-specific subtypes of ACC: Immunity-H and Immunity-L, which had high and low immune signature scores, respectively. We demonstrated that this subtyping method was stable and reproducible by analyzing five different ACC cohorts. Compared with Immunity-H, Immunity-L had lower levels of immune cell infiltration, worse overall and disease-free survival prognosis, and higher tumor stemness, genomic instability, proliferation potential, and intratumor heterogeneity. Furthermore, the ACC driver gene CTNNB1 was more frequently mutated in Immunity-L than in Immunity-H. Several proteins, such as mTOR, ERCC1, Akt, ACC1, Cyclin_E1, β-catenin, FASN, and GAPDH, were more highly expressed in Immunity-L than in Immunity-H. In contrast, p53, Syk, Lck, PREX1, and MAPK were more highly expressed in Immunity-H. Pathway and gene ontology analysis showed that the immune, stromal, and apoptosis pathways were highly enriched in Immunity-H, while the cell cycle, steroid biosynthesis, and DNA damage repair pathways were highly enriched in Immunity-L. Conclusions: ACC can be classified into two stable immune-related subtypes, which have significantly different antitumor responses, molecular characteristics, and clinical outcomes. This subtyping may provide clinical implications for prognostic and immunotherapeutic stratification of ACC.

Published
2023
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5. Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response

Author

Jin-Song Bian, Yue Wang, Dongdong Sun, Yong Yang, Xianjing Li, Lutz Birnbaumer, Yun Wang, Yan Cheng, Qiuhua Cao, Yanting Lin, Xinghua Gao, Hongbao Yang, Zhuo Wang, Lingyi Kong, Qijin Wu, Linjun You, and Dan-Dan Zhao

Subjects
Male, STAT3 Transcription Factor, 0301 basic medicine, MICROORGANISMOS, Mucin 2, Biology, Gut flora, Corrections, digestive system, Inflammatory bowel disease, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Stress, Physiological, medicine, Animals, Chronic stress, Colitis, Lymph node, Inflammation, Mice, Knockout, Mucin-2, Multidisciplinary, Interleukin-6, Dextran Sulfate, SISTEMA INMUNOLOGICO, biology.organism_classification, medicine.disease, ESTRES, Immunity, Innate, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Immunology, Muramidase, 030217 neurology & neurosurgery, COLITIS
Abstract

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.

Published
2018

6. Depression promotes prostate cancer invasion and metastasis via a sympathetic-cAMP-FAK signaling pathway

Author

Xianjing Li, Yun Wang, Jin-Song Bian, Qiuhua Cao, Lutz Birnbaumer, Xinghua Gao, Linjun You, Dan-Dan Zhao, Jin-Rong Zhou, Qingyi Zhu, Yong Yang, Yan Cheng, Yong-Ren Li, Hongbao Yang, Yun-Long He, and Hongxi Wu

Subjects
0301 basic medicine, Male, Cancer Research, Biology, DEPRESION, Article, Metastasis, Focal adhesion, Ciencias Biológicas, 03 medical and health sciences, Prostate cancer, Mice, Downregulation and upregulation, Biología Celular, Microbiología, Prostate, Cell Line, Tumor, Genetics, medicine, Cyclic AMP, metastasis via a sympathetic-cAMP-FAK, Animals, Humans, Neoplasm Invasiveness, prostate cancer invasion, Neoplasm Metastasis, Phosphorylation, Molecular Biology, Gene knockdown, Depression, Cancer, Prostatic Neoplasms, medicine.disease, CANCER, Up-Regulation, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Focal Adhesion Kinase 1, Gene Knockdown Techniques, METASTASIS, Cancer research, TRATAMIENTO MEDICO, Signal transduction, Neoplasm Grading, Neoplasm Transplantation, CIENCIAS NATURALES Y EXACTAS, Signal Transduction
Abstract

Fil: Cheng, Yan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Xing-Hua, Gao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Li, Xian-Jing. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Cao, Qiu-Hua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhao, Dan-Dan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Zhou, Jin-Rong. Harvard Medical School. Beth Israel Deaconess Medical Center. Department of Surgery. Nutrition/Metabolism Laboratory; Estados Unidos Fil: Wu, Hong-Xi. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Wang, Yun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: You, Lin-Jun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Yang, Hong-Bao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: He, Yun-Long. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Li, Yong-Ren. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Fil: Bian, Jin-Song. National University of Singapore. Yong Loo Lin School of Medicine. Department of Pharmacology; Singapur Fil: Zhu, Qing-Yi. Jiangsu Province Hospital of Traditional Chinese Medicine. Department of Urology; China Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Yang, Yong. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research. State Key Laboratory of Natural Medicines. Key Laboratory of Drug Discovery for Metabolic Disease; China Abstract: Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.

Published
2018

8. Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1

Author

Xianjing Li, Duowei Wang, Zhen Chen, Ermei Lu, Zhuo Wang, Jingjing Duan, Wei Tian, Yun Wang, Linjun You, Yulian Zou, Yan Cheng, Qingyi Zhu, Xiaojian Wan, Tao Xi, Meisheng Jiang, Yuyuan Han, Cong Cao, Lutz Birnbaumer, Wen-Ming Chu, and Yong Yang

Subjects
Multidisciplinary, ENDOSOME, CD14, Macrophage polarization, Biology, Bioquímica y Biología Molecular, Cell biology, Ciencias Biológicas, Growth factor receptor binding, Heterotrimeric G protein, TOLL-LIKE RECEPTOR 4, TLR4, biology.protein, GΑI1, GRB2, GundefinedI3, Receptor, Protein kinase B, MACROPHAGE POLARIZATION, CIENCIAS NATURALES Y EXACTAS
Abstract

Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gαi1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gαi1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gαi1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gαi1/3 knockdown in bone marrow-derived macrophage cells (Gαi1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincidedwith decreased Akt activation. Further, Gαi1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gαi1/3 were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gαi1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo. Fil: Li, Xiaolin. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Duowei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Chen, Zen. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Lu, Ermei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Zhuo. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Duan, Jingjing. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Tian, Wei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Yun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: You, Linjun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Zou, Yulian. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Cheng, Yan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Zhu, Qingyi. Jiangsu Province Hospital of Traditional Chinese Medicine. Departament of Urology; China Fil: Wan, Xiaojian. Second Military Medical University. Department of Anesthesiology and Intensive Care Medicine, Changhai Hospita; China Fil: Xia, Tao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute of Environmental Health Sciences. Laboratory of Neurobiology, ; Estados Unidos Fil: Yang, Yong. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China

Published
2015

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

Author

Xinghua Gao, Qiuhua Cao, Yan Cheng, Dandan Zhao, Zhuo Wang, Hongbao Yang, Qijin Wu, Linjun You, Yue Wang, Yanting Lin, Xianjing Li, Yun Wang, Jin-Song Bian, Dongdong Sun, Lingyi Kong, Lutz Birnbaumer, and Yong Yang

Subjects
COLITIS, IMMUNE system, INFLAMMATORY bowel diseases, MACROPHAGES, MUCINS
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. [ABSTRACT FROM AUTHOR]

Published
2018
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