Evolving insights in the pathophysiology of complications of cirrhosis: The farnesoid X receptor (FXR) to the rescue?

Acute clinical deterioration of a patient with chronic liver disease remains a decisive time point, both in terms of medical management and prognosis. The emergence of ascites, jaundice, variceal hemorrhage, hepatic encephalopathy, and/or acute bacterial infections defines acute decompensation and initiates a new chapter in the natural history of a patient with cirrhosis irrespective of its etiology. More specifically, each of these individual complications, either related to liver insufficiency, portal hypertension (PHT), or a combination of both, impacts significantly on morbidity and mortality and potentially forms the prelude to a rapidly evolving multiorgan dysfunction characterized by high short-termmortality, currently referred to as acute-on-chronic liver failure. The impaired gut-liver axis is considered pivotal in this transition, with bacterial translocation (BT) as the ultimate embodiment of (hepatic) evil. This latter not only acts as a pacemaker to hepatic decompensation, but might also relentlessly propagate further liver injury and even extend to remote organ injury. The exact mechanism by which BT emerges, however, remains far from clear, as are the pathways through which this drives liver deterioration. What is sure is that intestinal barrier dysfunction parallels cirrhosis progression, and thus an increasing degree of PHT and hepatocellular failure, leading not only to impaired innate defense mechanisms, but also to impaired bile production. As such, the bacteriostatic impact of bile acids, both directly and indirectly, is compromised, which heralds decay of the gut-liver axis with intestinal dysbiosis and a dysfunctional intestinal barrier as a result. In recent years, the farnesoid X receptor (FXR), a bileacid–responsive transcription regulator, has emerged as a promising target for numerous hepatobiliary and gastrointestinal disorders. In addition to its involvement in numerous key intrahepatic processes (such as bile production, lipid metabolism, regeneration, inflammation, etc.), its expression and functionality have recently also been documented in intestine (especially ileum), immune cells, and endothelial tissue. Not surprisingly, FXRknockout mice conversely display pronounced hepatic inflammation and fibrosis as well as an inflammatory bowel disease–like phenotype with increased intestinal inflammation and permeability and, eventually, BT. A recent translational study by Ubeda et al. using a rodent model of decompensated cirrhosis has boosted the contemporary growing body of literature substantiating a central role for FXR in the impaired gut-liver axis and moreover opened the door to therapeutic intervention. The Spanish group used rats with CCl4-induced cirrhosis with ascites as a model for decompensated cirrhosis with BT (present in 80% of the animals). Once ascites was obtained, rats were gavaged for 2 consecutive weeks with either vehicle or obeticholic acid (OCA), a first-in-class semisynthetic FXR agonist that has received considerable attention in recent phase 3 trials for primary biliary cirrhosis and nonalcoholic steatohepatitis. The investigators not only showed a marked reduction in clinically relevant BT in the OCA-treated group compared to vehicle, but they also identified several complementary beneficial mechanisms trying to close the different breaches in the intestinal barrier. More specifically, these involve the restoration of antimicrobial defense and structural integrity of the intestinal barrier (the so-called “leaky” gut), reduction of intestinal inflammation, and induction of changes in the number (reduced fecal bacterial load) and composition of gut microbiota (recovery of dysbiosis with a fall in Proteobacteria) conjoined by reduced liver fibrogenesis. In more detail, mechanistically, the investigators were able to demonstrate dysfunction of the FXRsignaling pathway in the ileum and could reactivate it by oral administration of OCA, as shown by the increased expression of its downstream effector, small heterodimer partner. This reactivation was found to be associated with restored levels of different antimicrobial peptides, such as angiogenin-1 and alpha-5defensin, and ileal gene-expression of epithelial tightjunction proteins, such as zonulin-1 and occludin. Notably, these results largely confirm and strengthen earlier findings in a cholestatic model of chronic liver disease using bile duct ligation. Similarly to Ubeda