Restoration of A Healthy Intestinal Microbiota Normalizes Portal Hypertension In A Rat Model of Nonalcoholic Steatohepatitis

ABSTRACT

Portal hypertension (PH) drives most of the clinical complications in chronic liver diseases. However, its progression in nonalcoholic steatohepatitis (NASH) and its association with the intestinal microbiota (IM) has been scarcely studied. Our aim was to investigate the role of IM in the mechanisms leading to PH in early NASH. The experimental design was divided in two stages: Stage 1: Sprague-Dawley rats were fed for 8 weeks with high-fat diet and high-glucose/fructose syrup (HFGFD) or control diet/water (CD). Representative rats were selected as IM donors for Stage 2. Stage 2: additional HFGFD and CD rats underwent intestinal decontamination followed by IM transplantation with faeces from opposite diet donors (heterologous transplant, Tr) or autologous faecal transplant (Atr) ((as controls)), generating four groups: CD-Atr, CD-Tr, HFGFD-Atr, HFGFD-Tr. After IM transplantation, the original diet was maintained for 12-14 days until euthanasia.HFGFD rats developed obesity, insulin resistance, NASH without fibrosis but with PH, intrahepatic endothelial dysfunction and IM dysbiosis. In HFGFD rats, transplantation with faeces from CD donors caused a significant reduction of PH to levels comparable to CD without significant changes in NASH histology. The reduction in PH was due to a 31% decrease of intrahepatic vascular resistance compared to HFGFD-Atr (p<0.05). This effect occurs via the restoration of the sensitivity to insulin of the hepatic Akt-dependent eNOS signaling pathway. Conclusions The intestinal microbiota exerts a direct influence in the development of PH in rats with diet-induced NASH and dysbiosis. Portal hypertension, insulin resistance and endothelial dysfunction revert when a healthy intestinal microbiota is restored. This article is protected by copyright. All rights reserved.

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