Abstract
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
Highlights
The strategic anatomical localization and blood supply from the portal vein links the liver and the gut tightly both anatomically and functionally
The gut microbiome has recently been found to be an active part in the complex relationship between the liver and the gut [4]. It is composed of a wide collection of microorganisms, and the dominant phyla are Firmicutes, Actinobacteria, Bacteroidetes, Proteobacteria, Fusobacteria, and Verrucomicrobia, with the Firmicutes and Bacteroidetes representing over 90% of the flora [5]
Primary biliary cholangitis (PBC) biliary acids (BAs) pool was associated with a decreased conversion of conjugated and unconjugated, and primary to secondary BAs. These results suggest an impaired microbial BA metabolism
Summary
The strategic anatomical localization and blood supply from the portal vein links the liver and the gut tightly both anatomically and functionally. A small proportion of the primary BAs, after reaching the colon, are deconjugated by the microflora into the secondary BAs, lithocholic acid and deoxycholic acid. The former is reabsorbed and after being conjugated in the liver is secreted in the bile [16]. An abundance of the deoxycholic-acid affects the microbiota composition and has been related to obesity in non-alcoholic fatty liver disease [17] New treatment such as obeticholic acid has been shown to be hopeful for NAFLD therapy. The activation of FXR has been shown to improve glucose tolerance and insulin resistance in murine models [18, 19] Upon their action on FXR, bile acids can
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