Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis

// Chao Liu 1, 2, * , En-Dong Liu 2, * , Yun-Xiao Meng 3, * , Xiao-Ming Dong 4 , Ya-Lan Bi 3 , Huan-Wen Wu 3 , Yan-Chao Jin 2 , Ke Zhao 2 , Jian-Jie Li 5 , Miao Yu 2 , Yi-Qun Zhan 2 , Hui Chen 2 , Chang-Hui Ge 2 , Xiao-Ming Yang 1, 2, 4 and Chang-Yan Li 1, 2 1 An Hui Medical University, Hefei, 230032, China 2 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China 3 Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing, 100730, China 4 Tianjin University, School of Chemical Engineering and Technology, Department of Pharmaceutical Engineering, Tianjin, 300072, China 5 Key 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 Correspondence to: Xiao-Ming Yang, email: xiaomingyang@sina.com Chang-Yan Li, email: fmmli@163.com Keywords: CK8, colitis, colitis-associated colorectal cancer, gut microbiota, TLR4 Received: February 21, 2017      Accepted: May 13, 2017      Published: May 27, 2017 ABSTRACT 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.