Gaebele, Erwin and Dostert, Karin and Hofmann, Claudia and Wiest, Reiner and Schoelmerich, Juergen and Hellerbrand, Claus and Obermeier, Florian (2011) DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. JOURNAL OF HEPATOLOGY, 55 (6). pp. 1391-1399. ISSN 0168-8278, 1600-0641
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Background & Aims: 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-1 beta, 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 alpha-SMA positive cells accompanied by higher p47(phox), TIMP-1, TGF-beta, Pai-1, and alpha-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. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FATTY LIVER-DISEASE; INCREASED INTESTINAL PERMEABILITY; INDUCED INSULIN-RESISTANCE; NECROSIS-FACTOR-ALPHA; NONALCOHOLIC STEATOHEPATITIS; CPG MOTIFS; STELLATE CELLS; KUPFFER CELLS; TNF-ALPHA; PATHOGENESIS; NASH; Colitis; Intestinal defensin; Liver fibrosis; LPS; Hepatic stellate cell; TLR |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 May 2020 09:29 |
| Last Modified: | 26 May 2020 09:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19748 |
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