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

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.