Attenuated fibrosis in specific pathogen-free microbiota in experimental cholestasis- and toxin-induced liver injury

摘要

In advanced chronic liver disease (CLD), the translocation of intestinal bacteria and the resultant increase of proinflammatory cytokines in the splanchnic and systemic circulation may contribute to the progression of fibrosis. We therefore speculated that fibrosis and portal hypertension (PHT) would be attenuated in a mouse model of limited intestinal colonization with altered Schaedler flora (ASF) compared to a more complex colonization with specific pathogen-free (SPF) flora. We induced liver fibrosis in ASF and SPF mice by common bile duct ligation (BDL) or by carbon tetrachloride (CCl4) treatment. We then measured portal pressure (PP), portosystemic shunts (PSSs), and harvested tissues for further analyses. There were no differences in PP between sham-treated ASF or SPF mice. After BDL or CCl4 treatment, PP, PSSs, and hepatic collagen deposition increased in both groups. However, the increase in PP and the degree of fibrosis was significantly higher in ASF than SPF mice. Expression of fibrotic markers alpha-smooth muscle actin, desmin, and platelet-derived growth factor receptor beta were significantly higher in ASF than SPF mice. This was associated with higher activation of hepatic immune cells (macrophages, neutrophils) and decreased expression of the intestinal epithelial tight junction proteins (claudin-1, occludin-1). In 2 models of advanced CLD, SPF mice presented significantly attenuated liver injury, fibrosis, and PHT compared to ASF mice. In contrast to our hypothesis, these findings suggest that a complex intestinal microbiota may play a "hepato-protective" role.