title: DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH.
abstract: OBJECTIVE
  Intestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextran sulfate sodium (DSS) is a colitis model in mice characterized by damage of the intestinal barrier. This study was designed to investigate if application of DSS aggravates experimental NASH.
  
  
  METHODS
  Male C57bl/6 mice were allocated into four experimental groups receiving either (I) standard chow (SC), (II) a high fat (HF) diet, (III) SC+DSS (1% in the drinking water), and (IV) HF+DSS for 12 weeks.
  
  
  RESULTS
  DSS treatment caused inflammation and proinflammatory gene expression (IL-1β, IL-17, TNF) in the colon. Expression of colonic antimicrobial peptide Cramp was significantly induced in SC+DSS mice, whereas expression was blocked in the HF+DSS group. Endotoxin levels were elevated in SC+DSS and HF mice but further augmented in the HF+DSS group. In line with this, increased hepatic TLR4 and TLR9 mRNA levels were detected in HF+DSS mice. The histological analysis revealed hepatic steatosis in both HF groups. Hepatic inflammation was more severe in HF+DSS mice, reflected by histology and analysis of proinflammatory gene expression (TNF and MCP-1). HF+DSS mice showed increased hepatic fibrosis by sirius red staining, hepatic collagen I expression, and α-SMA positive cells accompanied by higher p47(phox), TIMP-1, TGF-β, Pai-1, and α-SMA mRNA expression.
  
  
  CONCLUSIONS
  Induction of an intestinal inflammation in experimental NASH promotes LPS translocation, hepatic inflammation, and fibrogenesis probably due to inhibition of intestinal antimicrobial peptides. These findings underscore the pathophysiological role of the gut-liver axis in the progression of NASH.
authors.affiliation: Department of Internal Medicine I, University Medical Center Regensburg, Germany. erwin.gaebele@klinik.uni-regensburg.de
authors.forename: Erwin
authors.initials: E
authors.lastname: Gäbele
authors.forename: Karin
authors.initials: K
authors.lastname: Dostert
authors.forename: Claudia
authors.initials: C
authors.lastname: Hofmann
authors.forename: Reiner
authors.initials: R
authors.lastname: Wiest
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Florian
authors.initials: F
authors.lastname: Obermeier
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001483:Base Sequence; D054804:Cathelicidins / Q000096:biosynthesis; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D008070:Lipopolysaccharides / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D017931:DNA Primers; D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate