title: DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model.
abstract: Nonalcoholic steatohepatitis (NASH) patients progress to liver cirrhosis and even hepatocellular carcinoma (HCC). Several lines of evidence indicate that accumulation of lipopolysaccharide (LPS) and disruption of gut microbiota play contributory roles in HCC. Moreover, in a dextran sodium sulfate (DSS)-induced colitis model in mice, a high-fat diet increases portal LPS level and promotes hepatic inflammation and fibrosis. However, this diet-induced NASH model requires at least 50 weeks for carcinogenesis. In this study, we sought to determine whether increased intestinal permeability would aggravate liver inflammation and fibrosis and accelerate tumorigenesis in a diet-induced NASH model. Mice were fed a choline-deficient high-fat (CDHF) diet for 4 or 12 weeks. The DSS group was fed CDHF and intermittently received 1% DSS in the drinking water. Exposure to DSS promoted mucosal changes such as crypt loss and increased the number of inflammatory cells in the colon. In the DSS group, portal LPS levels were elevated at 4 weeks, and the proportions of Clostridium cluster XI in the fecal microbiota were elevated. In addition, levels of serum transaminase, number of lobular inflammatory cells, F4/80 staining-positive area, and levels of inflammatory cytokines were all elevated in the DSS group. Liver histology in the DSS group revealed severe fibrosis at 12 weeks. Liver tumors were detected in the DSS group at 12 weeks, but not in the other groups. Thus, DSS administration promoted liver tumors in a CDHF diet-induced NASH mouse over the short term, suggesting that the induction of intestinal inflammation and gut disruption of microbiota in NASH promote hepatic tumorigenesis.
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Achiwa
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan. Electronic address: masaishi@med.nagoya-u.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ishizu
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Kuzuya
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Internal Medicine, Banbuntane Hotokukai Hospital, Fujita Health University, School of Medicine, Nagoya, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Katano
authors.affiliation: Department of Gastroenterology and Hepatology, Nagoya University Graduate, School of Medicine, Nagoya, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000473:pathology*; D002796:Choline Deficiency / Q000139:chemically induced / Q000473:pathology*; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D016264:Dextran Sulfate; D059305:Diet, High-Fat; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D007408:Intestinal Absorption / Q000187:drug effects; D008103:Liver Cirrhosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000473:pathology*
chemical_list: D016264:Dextran Sulfate
keywords: Choline-deficient high-fat; Colitis; Fibrosis; Nonalcoholic steatohepatitis; Tumorigenesis