Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: An input for novel therapies

Abstract

Non-alcoholic fatty liver disease is a multifactorial condition, ranging from simple steatosis to non-alcoholic steatohepatitis with or without fibrosis. In non-alcoholic fatty liver disease, alteration of gut microbiota and increased intestinal permeability increase exposure of the liver to gut-derived bacterial products: lipopolysaccharides and unmethylated CpG DNA. These products stimulate innate immune receptors, namely Toll-like receptors, which activate signalling pathways involved in liver inflammation and fibrogenesis. Currently, there are several studies on the involvement of lipopolysaccharide-activated Toll-like receptor 4 signalling in non-alcoholic fatty liver disease pathogenesis. There has been widespread interest in the study of the involvement of resident hepatic stellate cells and Kupffer cells activation in liver fibrogenesis upon TLR4 stimulation. Although the best evidence to support a role for gut microbiota in non-alcoholic fatty liver disease-induced fibrosis comes largely from animal models, data from human studies are accumulating and could lead to new therapeutic approaches. Therapeutic modulation of gut microflora may be an alternative strategy to develop an anti-fibrotic therapy.

In this review, we discuss the relevant role of gut-liver axis in non-alcoholic liver disease-associated liver fibrosis and discuss the evidence on novel anti-fibrotic therapeutic approaches.

Introduction

During the last decades non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease [1]. It includes a wide spectrum of pathological liver conditions, ranging from simple hepatic fat accumulation to non-alcoholic steatohepatitis (NASH) with or without fibrosis, which can eventually progress to cirrhosis and hepatocellular carcinoma [2].

Although the complexity and timing of the pathophysiological events in NAFLD remain unclear, the “multiple-hit hypothesis” is currently the most recognized theory to explain disease development and progression. According to this theory, various genetic and environmental factors play crucial roles in the multifactorial pathogenesis of NAFLD [3]. Several factors such as genetic background, epigenetic mechanisms, environmental factors, high caloric intake and low levels of physical activity, seem to promote lipid accumulation in the liver and insulin resistance, which may lead to simple steatosis [4]. In this early stage, other triggers (i.e. lipotoxicity and gut-liver axis) may contribute to the systemic and metabolic profile that characterizes patients with steatosis. Furthermore, either adipocytokines or inflammatory signals released by adipose tissue in response to an increased intestinal permeability and consequent endotoxemia may promote oxidative stress in the liver, inducing progression to NASH [5]. During NASH progression, the described compound setting activates molecular mechanisms involved in fibrogenesis. Fibrogenesis is a wound healing response to liver injury in which liver resident specialized cells, the hepatic stellate cells (HSCs), after a pro-proliferative induction and an epithelial–mesenchymal transition (EMT), become activated and induce an excessive extracellular matrix (ECM) deposition that characterizes fibrosis [6]. In particular, HSCs acquire a myofibroblastic phenotype and produce collagens that represent the main scaffold of a fibrotic lesion [7].

So far, a number of studies have shown that the gut-liver axis is involved, not only in the pathogenesis of NAFLD, but also in the development of liver fibrosis in various ways, some unexpected [8], [9], [10]. Knowledge of interaction networks, metabolic or molecular, that link gut-liver axis to fibrosis may represent a launch platform for novel therapeutic approaches.

This review focuses on the role of gut-liver axis in NAFLD-associated liver fibrosis and on its potential as an input for new, targeted therapies.