Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis
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Chao Liu1,2,*, En-Dong Liu2,*, Yun-Xiao Meng3,*, Xiao-Ming Dong4, Ya-Lan Bi3, Huan-Wen Wu3, Yan-Chao Jin2, Ke Zhao2, Jian-Jie Li5, Miao Yu2, Yi-Qun Zhan2, Hui Chen2, Chang-Hui Ge2, Xiao-Ming Yang1,2,4 and Chang-Yan Li1,2
1An Hui Medical University, Hefei, 230032, China
2State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China
3Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing, 100730, China
4Tianjin University, School of Chemical Engineering and Technology, Department of Pharmaceutical Engineering, Tianjin, 300072, China
5Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Thoracic Oncology, Peking University Cancer Hospital Institute, Beijing, 100871, China
*These authors contributed equally to this work
Xiao-Ming Yang, email: [email protected]
Chang-Yan Li, email: [email protected]
Keywords: CK8, colitis, colitis-associated colorectal cancer, gut microbiota, TLR4
Received: February 21, 2017 Accepted: May 13, 2017 Published: May 27, 2017
Keratin 8 (CK8) is the major component of the intermediate filaments of simple or single-layered epithelia. Gene targeting mice model suggest that CK8 is involved in colonic active ion transport, colorectal hyperplasia and inflammation. In the present study, we found that CK8 is downregulated in the colon during DSS-induced colitis and AOM/DSS-induced colitis-associated colorectal cancer (CAC) development. In human patients with colon cancer, CK8 is downregulated. Using CK8 heterozygous knockout mice (CK8+/−), we found that CK8+/− mice are highly susceptible to DSS-induced colitis and more prone to AOM/DSS-induced CAC than wild type (WT) mice. The colonic permeability is increased with DSS or AOM/DSS treatment, leading to alteration of gut microbiota in CK8+/− mice with CAC. Metagenomic analysis of fecal microbiota suggests Firmicutes and Proteobacteria are increased in CK8+/− mice with CAC, while Bacteroidetes and Verrucomicrobia are decreased. Antibiotic treatment decreases the incidence of colorectal cancer tumorigenesis and TLR4 inhibitor attenuates the susceptibility of CK8+/− mice to DSS-induced colitis. These data suggest CK8 protects mice from colitis and colitis-associated colorectal cancer by modulating colonic permeability and gut microbiota composition homeostasis.
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