1. Introduction

Impaired biliary formation or flow can lead to cholestasis [1]. Cholestatic liver diseases can be divided into acute (such as choledocholithiasis and malignancies) and chronic diseases. Chronic cholestatic liver diseases include inherit cholestatic diseases, primary sclerosing cholangitis (PSC), the generic term secondary sclerosing cholangitis (SSC) subsuming diseases caused by mechanical obstruction, ischemia, infections, immune-mediated diseases, or liver damage due to toxic substances, and primary biliary cholangitis (PBC) [2,3]. This review will focus on PSC, SSC in critically ill patients (SC-CIP) as a sub-entity of SSC and PBC because alterations of the gut-liver axis seem to play an important role in the pathogenesis of these diseases and knowledge about alterations of the gut-liver axis may influence future therapeutic strategies.

The occurrence of these diseases is rare, with an incidence between 0.3 and 5.8 per 100,000 people per year [4]. The pathogenesis is still not fully understood, but a multifactorial evolution seems likely. Clinical manifestations can happen in all ages, mainly in the form of elevated cholestasis parameters, jaundice and pruritus. Incidence is not equally distributed between women and men in all three disease types and prognosis without liver transplantation remains limited in many patients [2,4,5].

PSC can affect the intra- and extrahepatic biliary tree. Inflammation of bile ducts leads to progressive liver dysfunction and liver cirrhosis with the potential need for liver transplantation. This disease affects primary men (65–70%) and is associated with inflammatory bowel diseases (IBD) in the majority of patients (70–80%). The risk for hepatobiliary malignancies is increased [6,7,8]. Pharmaceutical treatment is currently not available and mean liver transplantation-free survival is 14.5 years [9,10]. SC-CIP occurs after long-term intensive care treatment with the need for catecholamine treatment and invasive ventilation. Male patients are affected more frequently than women [11]. Prognosis without liver transplantation is often poor and progression to liver cirrhosis can occur within a period of weeks [12,13,14]. PBC leads to progressive destruction of the intrahepatic biliary ducts and occurs most frequently in women of middle age with a sex ratio of 10:1. Clinical symptoms include fatigue, pruritus and jaundice. Due to improved pharmacological treatment options with ursodeoxycholic acid, bezafibrat, and obeticholic acid, liver transplantation is only necessary for 4% of affected patients [2,4,5,15].

The etiologies of these diseases remain widely enigmatic [2]. In PSC, genetic and environmental factors are proposed and associations with the human leukocyte antigen system and other gene loci could be shown, however, a clear causal relationship could not be proven [16,17]. Because recurrence of the disease is possible after liver transplantation, extrahepatic drivers are likely to play a significant role in the pathogenesis [7]. SC-CIP is most likely triggered by ischemic injury of the biliary system during critical illness with consecutive formation of biliary casts and recurrent biliary infections [18]. PBC is a multifactorial disease and environmental triggers like infections (urinary tract infections, infections with mycobacteria, Epstein-Barr virus, chlamydia, Helicobacter pylori) and smoking, as well as genetic predisposition and autoimmune factors have been described [5,19,20,21,22,23,24,25].

Recently, data has emerged highlighting the role of the microbiome and the gut barrier in liver diseases, leading to the concept of the gut-liver axis as a common pathogenetic principle and a potential therapeutic target [26].

2. The Gut-Liver Axis

The communication between the gut and the liver works bidirectionally [27,28,29] (Figure 1). The gut microbiome consists of a thousand species with trillions of microorganisms spanning from bacteria to fungi, protozoa, archaea, and viruses [30]. Composition of the gut microbiome is influenced in early life by mode of birth and breastfeeding, subsequently by age, genetics, food, and drug intake [31,32]. Disturbance of the gut microbiome leads to dysbiosis and further to increased gut permeability allowing translocation of microbes and microbial products named microbial or pathogen-associated molecular patterns (MAMPs/PAMPs) [28,33,34]. Immune receptors of liver cells can identify these patterns once they are in the blood circulation and they can lead to activation of inflammation cascades causing fibrosis and cirrhosis in the course of liver diseases [34]. Vice versa, the liver communicates with the gut through the biliary system and the systemic circulation by releasing bile acids and systemic inflammatory mediators like cytokines [35]. Primary bile acids are synthesized from cholesterol in the liver. Conjugation with taurine or glycine then happens in hepatocytes and the conjugated bile acids are released into the intestine, where they enable the uptake of lipids and fat-soluble vitamins. In the terminal ileum, the majority of bile acids is actively reabsorbed. The remaining 5% are transformed to secondary bile acids by microbial metabolisms in the colon and are passively reabsorbed or excreted. Transformation from primary to secondary bile acids (deconjugation and dihydroxylation) is facilitated by bile salt hydrolases (BSH) and 7α-dehydroxylase expressed by microbes of the gut microbiome including all major phyla (BSH) and the genera Bacteroides, Clostridium, Eubacterium, Lactobacillus, and Escherichia [34,36,37,38]. Bile acids do not act solely as agents involved in fat digestion, but they additionally work as signaling metabolites that can interact with luminal microbes and cellular receptors of the intestine [37,39,40].

Figure 1. The gut-liver axis in liver diseases. Dysbiosis of the microbiome leads to gut barrier damage enabling translocation of bacteria, toxins, pathogen associated molecular patterns (PAMPs), and metabolites of gut microbes. Via the portal vein, they reach the liver and trigger inflammation cascades leading to fibrosis and cirrhosis in disease courses. Bile acids are synthesized from cholesterol in hepatocytes. After conjugation, they are secreted into the bile ducts and reach the intestine as conjugated primary bile acids. In the gut, bile acids allow digestion of fat and they interact with gut microbes and cellular receptors. Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR) are the most important of these receptors. Binding of bile acids to FXR induces formation of fibroblast growth factor 19 (FGF-19) which serves as negative feed-back mechanism for bile acid synthesis in the liver. The majority of bile acids are reabsorbed in the terminal ileum, whereas a small proportion is secreted into the colon, metabolized to secondary bile acids and then also reabsorbed or excreted. Created with BioRender.com. CYP7A1 = Cytochrome P450, Family 7, Subfamily A, Polypeptide 1; NLRP3 = NOD-, LRR- and pyrin domain-containing protein 3. Created with Biorender.com

This entry is adapted from the peer-reviewed paper 10.3390/nu13031018