The intestinal microbiota and microenvironment in liver

Abstract

The intestinal microbiome plays a significant role in the development of autoimmune diseases, in particular, inflammatory bowel diseases. But the interplay between the intestinal tract and the liver may explain the increased association with autoimmune liver diseases and inflammatory bowel diseases. The gut–liver axis involves multiple inflammatory cell types and cytokines, chemokines and other molecules which lead to the destruction of normal liver architecture. Triggers for the initiation of these events are unclear, but appear to include multiple environmental factors, including pathogenic or even commensal microbial agents. The variation in the gut microbiome has been cited as a major factor in the pathogenesis of autoimmune liver disease and even other autoimmune diseases. The unique positioning of the liver at the juncture of the peripheral circulation and the portal circulation augments the interaction between naïve T cells and other hepatic cells and leads to the disruption in the development of tolerance to commensal bacteria and other environmental agents. Finally, the innate immune system and in particular toll-like receptors play a significant role in the pathogenesis of autoimmune liver disease.

Introduction

The liver and the gastrointestinal tract are intimately connected in the context of metabolic activity and immune responses, primarily resulting from their close anatomical and physiological relationship [1]. The liver has a dual blood supply. A quarter of the blood supply is derived from the systemic circulation which reaches the liver through the hepatic artery. The other three quarters are gut derived nutrient-rich blood that enters the liver through the portal vein. The term “gut–liver axis” has been coined to reflect the immunological phenomenon linking the two in health and disease [2].

Microbes exist in the gut environment and play a significant role in digestion, and are a part of the mucosal immune system that helps shape our ability to distinguish safe and danger signals [3], [4]. Since the liver receives blood from both systemic circulation and the intestines, microbes in the intestines may also affect the immune environment in the liver. Portal venous blood returning from the intestines contains the products of digestion, along with antigens and microbial products that originate from the bacteria in the small and large intestines [5]. The exposure of liver cells to antigens, and to microbial products derived from the intestinal bacteria, results in a distinctive local immune environment that modulates immune tolerance in the liver [6], [7], [8].

To establish this tolerogenic environment, hepatic immune cells including Kupffer cells, natural killer cells, dendritic cells and lymphocytes, together with other nonparenchymal cells including endothelial cells and stellate cells orchestrate a controlled and organized response to these potentially highly inflammatory factors from the intestines [9], [10]. However, this tolerance is quite metastable and can be reversed by the right combination of signals, resulting in active local immunity [5]. For example, changes in the composition of the microbiome or alterations in gut permeability can promote translocation of microbes into the portal circulation that delivers blood directly to the liver [2]. These gut-derived microbial components represent danger signals for the host cells in liver, activate the inflammatory cascade in immune cells and modulate the function of liver parenchymal cells [9].

There is a growing body of evidence showing that the intestinal microbiome possesses critical functions in liver physiology and metabolic homeostasis [11]. Gut-derived bacterial products aggravate hepatic fibrosis [12], [13], whereas, gut sterilization helps prevent hepatic fibrosis after bile-duct ligation [12]. Moreover, disruption of the intestinal mucosal barrier facilitates bacterial translocation and promotes the progression of liver fibrosis [13]. Prior studies also suggested that the gut microbiota may affect the progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) [14], [15]. This dysbiosis in the digestive tract results in the exacerbation of hepatic steatosis and obesity [16].

The relationship between intestinal homeostasis and autoimmune liver diseases is summarized in this review by discussing the potential involvement of intestinal homeostasis in the pathogenesis of autoimmune liver diseases [17], [18], [19], the understanding of which will ultimately steer the development of novel clinical treatments.