Influence of DSS induced colitis in a model of experimental NASH

Aims: Intestinal bacterial overgrowth and increased intestinal permeability are pathophysiological features of non alcoholic steatohepatitis (NASH). Further, bacterial endotoxins have been shown to promote NASH progression. Application of dextran sulphate sodium (DSS) is an established model to induce acute colitis in mice characterized by damage of the intestinal barrier and elevated serum endotoxin levels.

The aim of this study was to investigate if application of DSS aggravates experimental NASH.

Methods and Results: Male C57bl/6 mice (n=6) were randomly allocated into four experimental groups receiving ether (i) standard chow (SC), (ii) a high fat (HF) diet (17% fat, supplemented with 1.25% cholesterol and 0.5% cholate, according to Matsuzawa et al. Hepatology 2007), (iii) SC + DSS (1% in the drinking water), and (iv) HF+DSS for 12 weeks.

As expected, chronic DSS treatment caused intestinal inflammation, which was absent in SC mice and HF treated mice. Histological analysis showed microvesicular hepatic steatosis in both HF and HF+DSS groups. Further, HF lead to hepatic inflammation that was more severe in HF+DSS mice as reflected by liver histology and analysis of proinflammatory gene expression (TNF, IL-6 and MCP-1). Moreover, HF+DSS mice had significantly higher hepatic CYP2E1, p47^phox as well as TIMP-1, TGFβ and α-SMA expression, indicating a more pronounced oxidative and profibrogenic response.

Summary and Conclusions: Simultaneous induction of chronic intestinal inflammation promotes inflammation and fibogenesis in an experimental NASH model. These findings further underscore the pathophysiological role of the gut-liver axis in the progression of NASH. The here presented model of addition of DSS to a dietary NASH model provides a new experimental setting to investigate the pathogenesis of NASH.

NASH - colitis - fibrogenesis - gut liver axis - inflammation