Pro-inflammatory signalling and gut-liver axis in non-alcoholic and alcoholic steatohepatitis: Differences and similarities along the path

Abstract

Non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) represent a spectrum of injury, ranging from simple steatosis to steatohepatitis and cirrhosis. In humans, in fact, fatty changes in the liver, possibly leading to end-stage disease, were observed after chronic alcohol intake or in conditions of metabolic impairment. In this article, we examined the features and the pro-inflammatory pathways leading to non-alcoholic and alcoholic steatohepatitis. The involvement of several events (hits) and multiple inter-related pathways in the pathogenesis of these diseases suggest that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination treatment towards multiple pro-inflammatory targets would eventually be required. Gut-liver crosstalk is involved not only in the impairment of lipid and glucose homoeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis in both NAFLD and ALD. Modulation of the gut-liver axis has been suggested as a possible therapeutic approach since gut-derived components are likely to be involved in both the onset and the progression of liver damage. This review summarizes the translational mechanisms underlying pro-inflammatory signalling and gut-liver axis in non-alcoholic and alcoholic steatohepatitis. With a multitude of people being affected by liver diseases, identification of possible treatments and the elucidation of pathogenic mechanisms are elements of paramount importance.

Keywords: ASH; NASH; gut-liver axis; inflammation; microRNA; steatohepatitis.

Figure 1

Spectrum of liver diseases associated with NAFLD or ALD with the corresponding prevalence. Different pathologic affections encountered in NAFLD and ALD are reported in figure for comparison. Circle area is proportional to the prevalence of any specific condition. In the legend, prevalence is reported in percentage with the corresponding disease. Data were obtained from references. ⁶ , ⁷ ALD, alcoholic liver disease; ASH, alcoholic steatohepatitis; HCC, hepatocellular carcinoma; NAFLD, non‐alcoholic fatty liver disease; NASH, non‐alcoholic steatohepatitis

Figure 2

Schematic representation of TLR‐4 activation in the course of NASH or ASH. TLR‐4 activation, upon LPS stimulation, requires LBP and CD‐14 cooperation to facilitate LPS binding with TLR4/MD‐2 complex. The following intracellular processes are then different comparing NASH and ASH. In NASH, TLR4 oligomerizes and reacts with TIRAP and its protein adaptor Myd‐88 giving origin to a pro‐inflammatory cytokines response. On the other hand, during ASH, TLR4 reacts with TRAM coupling with its adaptor TRIF. Inflammatory response is then mainly represented by type 1 interferon, and interferon inducible genes. ASH, alcoholic steatohepatitis; LBP, LPS‐binding protein; LPS, lipopolysaccharide; Myd88, myeloid differentiation primary response 88; NASH, non‐alcoholic steatohepatitis; TLR4, Toll‐like receptor 4; TRAM, TRIF‐related adaptor molecule; TRIF, TIR domain‐containing adapter–inducing interferon‐β

Figure 3

Schematic representation of gut‐liver axis role in NASH and ASH liver inflammation. (1) These diseases determine a condition of leaky gut as a consequence of the alteration of the normal bowel wall; (2) increased levels of PAMPS (LPS) are released in blood; (3) these in turn stimulate TLR4 pathway and liver inflammation. ASH, alcoholic steatohepatitis; LBP, LPS binding protein; LPS, lipopolysaccharide; NASH, non‐alcoholic steatohepatitis; PAMPs, pathogen‐associated molecular patterns; TLR4, Toll‐like receptor 4