Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine

Annette Brandt,Anja Baumann,Angélica Hernández-Arriaga,Anika Nier,Ina Bergheim,Cheng Jun Jin,Victor Sánchez,Amélia Camarinha-Silva,Richard Kehm

doi:10.1038/s41598-019-43228-0

Abstract

The antidiabetic drug metformin has been proposed to affect non-alcoholic fatty liver disease (NAFLD) through its effects on intestinal microbiota and barrier function. However, so far most studies focused on long-term effects and more progressed disease stages. The aim of this study was to assess in two experimental settings, if the onset of NAFLD is associated with changes of intestinal microbiota and barrier function and to determine effects of metformin herein. C57Bl/6J mice were fed a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) for four days or six weeks ±300 mg/kg BW/day metformin (Met). Markers of liver health, intestinal barrier function and microbiota composition were assessed. Metformin treatment markedly attenuated FFC-induced NAFLD in both experiments with markers of inflammation and lipidperoxidation in livers of FFC + Met-fed mice being almost at the level of controls. Metformin treatment attenuated the loss of tight junction proteins in small intestine and the increase of bacterial endotoxin levels in portal plasma. Changes of intestinal microbiota found in FFC-fed mice were also significantly blunted in FFC + Met-fed mice. Taken together, protective effects of metformin on the onset of NAFLD are associated with changes of intestinal microbiota composition and lower translocation of bacterial endotoxins.

Highlights

With a prevalence of approximately 25% worldwide[1], non-alcoholic fatty liver disease (NAFLD) is thought to be the most common liver disease in the world
Liver to body weight ratio and triglyceride concentration in liver tissue were similar between FFC− and FFC + metformin (FFC + Met)-fed mice, NAFLD activity score (NAS) was significantly lower in FFC + Met-fed mice when compared with FFC-fed animals
Expression of interleukin 10 (Il10) mRNA in liver was significantly higher in FFC + Met-fed mice than in all other groups (P < 0.05, Supplementary Table S1), whereas Il10 mRNA expression was almost at the level of controls in FFC-fed mice

Summary

Introduction

With a prevalence of approximately 25% worldwide[1], non-alcoholic fatty liver disease (NAFLD) is thought to be the most common liver disease in the world . Results of several more recent studies suggest that the development of NAFLD is associated with marked changes of fecal microbiota composition and increased bacterial endotoxin levels[3,4,5,6]. Results of animal studies and some human studies suggest that targeting intestinal microbiota and/or barrier function may have protective effects on the development of NAFLD7–9. Mechanisms involved as well as if the effects of metformin on intestinal microbiota composition and barrier function are only found after an extended intake of the drug, remains to be determined. We determined if effects on NAFLD are associated with changes of intestinal microbiota composition and altered translocation of bacterial endotoxin

Objectives

Methods

Results