Evolving insights in the pathophysiology of complications of cirrhosis: The farnesoid X receptor (FXR) to the rescue?
Authors: Wim Laleman, Jonel Trebicka, Len Verbeke
Journal: Hepatology (2016)

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-term mortality, currently referred to as acute-on-chronic liver failure.1 The impaired gut-liver axis is considered pivotal in this transition, with bacterial translocation (BT) as the ultimate embodiment of (hepatic) evil.1, 2 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 bile-acid–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.2-4 Not surprisingly, FXR-knockout 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.3, 4 A recent translational study by Ubeda et al.5 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 FXR-signaling 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-5-defensin, and ileal gene-expression of epithelial tight-junction 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.2 Similarly to Ubeda et al.,5 an up-regulation of occludin and zonulin-1 was observed, but, additionally, the earlier study also documented an abundant ileal expression of the pore-forming claudin-2, which was countered by overexpression of the pore-closing claudin-1 after treatment with OCA.2 In conjunction to these structural changes, evidence was not only provided for a functional restoration of the intestinal barrier (by measuring transepithial resistance and dextran permeability in full-thickness intestinal tissue), but the study also confined the effect of FXR agonism to the ileum. More specifically, reactivation of the FXR pathway was observed only in the ileum and not the jejunum of bile-duct–ligated rats, which paralleled selective functional restoration of intestinal integrity and coincided with a marked reduction in BT. Taken together, these findings propose the ileum as a primary source for BT. The finding that FXR is mainly expressed in the ileum is not surprising, given its pivotal role in the regulation of enterohepatic reabsorption of bile acids and the ileal clustering of gut immunity (through, among others, Peyer's patches). This latter brings us to the second beneficial effect in the study of Ubeda et al.5 and relates to a significant reduction in cirrhosis-associated intestinal infiltration of activated immune cells as well as ileal expression of inflammatory cytokines (such as tumor necrosis factor [TNF-α], interferon-gamma [IFN-γ], interleukin-10, etc.) after OCA treatment. This effect was shown to be mediated through normalization of nuclear factor kappa B activation, a protein complex that controls proinflammatory cytokine production. Moreover, these anti-inflammatory effects, albeit direct or indirect, were found to extend to mesenteric lymph nodes and the systemic circulation, as shown by reduced expansion of activated proinflammatory monocytes and effector T lymphocytes. Interestingly and most consistently, we also found similar anti-inflammatory effects in this regard after OCA treatment. In light of the earlier-mentioned impact on intestinal barrier dysfunction, the effect of OCA on ileal overexpression IFN-γ is most interesting for various reasons. First, IFN-γ was shown to induce increased permeability in cultured intestinal epithelial monolayers, allowing the passage of Escherichia coli–derived lipopolysaccharide in vitro. Second, recent data suggest that IFN-γ also enhances the increased permeability induced by other cytokines, such as TNF-α.6 Third, IFN-γ promotes the internalization of epithelial tight junction proteins and, fourth, IFN-γ also appears to promote passage of bacteria, such as E. coli, through a transcellular route, which was not assessed neither in the study of Ubeda et al.5 nor in ours.2 In this way, the anti-inflammatory effects of OCA seem to indirectly rectify dysregulation of paracellullar intestinal permeability. The third favorable effect observed by Ubeda et al.5 points toward an effect on gut microbiota and dysbiosis in particular. In response to OCA, the investigators found the enteric bacterial load to be reduced in number and rebalanced in its composition with a correction of relative abundance of Proteobacteriacea and relative reduction of Firmicutes. Again, this effect does not seem to be direct, but rather indirect, and was ascribed to improved intestinal barrier function. The exact mechanism on how OCA drives this mutual beneficial interaction between restoration of intestinal barrier and gut microbiota remains to be elucidated, but, from a clinical perspective, this particular observation raises opportunities. In the last decade, we have turned more and more to the use of oral antibiotics, such as rifaximin, to attenuate complications of cirrhosis. However, these beneficial hepatological effects are largely set off by major remaining concerns for induction of multiresistant supermicroorganisms fueling the quest for alternatives. Finally, FXR agonism was also shown to reduce liver fibrogenesis and PHT, which might add to the overall favorable impact.5, 7, 8 However, this endpoint might be achieved directly through effects on the hepatic cells8 and indirectly through beneficial modulation of the gut-liver axis.2, 5 Taken together, the article by Ubeda et al.5 not only substantiates the growing body of consistent literature pointing out FXR as a unifying molecular master switch in what is considered the nec sum ultra in cirrhosis progression (i.e. BT), but it also opens the door for clinical use of FXR-agonistic drugs, such as OCA. Therefore, FXR agonists truly harbor the potential to become the hepatologist's aspirin. The hepatological society should urgently invest efforts to explore this further in randomized, clinical trials in patients with cirrhosis. Wim Laleman, M.D., Ph.D.1 Jonel Trebicka, M.D., Ph.D.2,3 Len Verbeke, M.D., Ph.D.1 1Department of Gastroenterology & Hepatology University Hospitals Leuven KU Leuven Leuven, Belgium 2Department of Internal Medicine I University of Bonn Bonn, Germany 3Department of Hepatology Faculty of Health Sciences University of Southern Denmark Odense, Denmark