Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis

Abstract

Background & Aims One important hypothesis in primary sclerosing cholangitis pathophysiology suggests that bacterial products from an inflamed leaky gut lead to biliary inflammation. We aimed to investigate whether circulating markers of bacterial translocation were associated with survival in a Norwegian primary sclerosing cholangitis cohort. Methods Serum levels of zonulin, intestinal fatty acid binding protein, soluble CD14, lipopolysaccharide and lipopolysaccharide‐binding protein were measured in 166 primary sclerosing cholangitis patients and 100 healthy controls. Results Lipopolysaccharide‐binding protein and soluble CD14 were elevated in primary sclerosing cholangitis compared with healthy controls (median 13 662 vs 12 339 ng/mL, P = 0.010 and 1657 vs 1196 ng/mL, P < 0.001, respectively). High soluble CD14 and lipopolysaccharide‐binding protein (values >optimal cut‐off using receiver operating characteristics) were associated with reduced liver transplantation–free survival (P < 0.001 and P = 0.005, respectively). The concentration of soluble CD14 was higher in patients with hepatobiliary cancer compared to other primary sclerosing cholangitis patients and healthy controls. Zonulin was lower in primary sclerosing cholangitis than controls, but when excluding primary sclerosing cholangitis patients with increased prothrombin time zonulin concentrations were similar in primary sclerosing cholangitis and healthy controls. Concomitant inflammatory bowel disease did not influence the results, while inflammatory bowel disease patients without primary sclerosing cholangitis (n = 40) had lower concentration of soluble CD14. In multivariable Cox regression, high soluble CD14 and high lipopolysaccharide‐binding protein were associated with transplantation‐free survival, independent from Mayo risk score (HR: 2.26 [95% CI: 1.15‐4.43], P = 0.018 and HR: 2.00 [95% CI: 1.17‐3.43], P = 0.011, respectively). Conclusions Primary sclerosing cholangitis patients show increased levels of circulating markers of bacterial translocation. High levels are associated with poor prognosis measured by transplantation‐free survival, indicating that ongoing gut leakage could have clinical impact in primary sclerosing cholangitis.

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

“…Antibiotic treatment has been recently confirmed to be effective in improving serological markers of cholestasis in PSC patients, with a possible indirect effect via modifications of the gut microbiome [61]. Moreover, a number of markers of bacterial translocation and gut barrier dysfunction (i.e., zonulin, intestinal fatty acid binding protein, soluble CD14, LPS and LPS-binding protein, antibodies against F-actin and gliadin, and various anti-microbial antibodies) have been found elevated in the sera of PSC patients, with a positive correlation with progressive disease [62,63]. Interestingly, genome-wide association studies have revealed a common risk factor for PSC and Crohn's disease in the fucosyltransferase 2 (FUT2) locus, which influences fecal and bile bacterial composition and has recently been linked to the development of hepatobiliary abnormalities in mice [64,65].…”

The gut microbial influence on cholestatic liver disease

“…The gut microbial metabolism involve a wide range of molecules ranging from short‐chain fatty acids and vitamins to secondary bile acids and neurotransmitters . Blood from the gut enters the systemic circulation through the liver via the portal vein, meaning that the liver is at the centre of gut microbiome‐host interaction . Microbiota‐derived molecules have the potential to activate the immune system and trigger inflammation, providing the liver with the challenging task of balancing tolerance to beneficial and unharmful molecules and metabolites with the need to act as a firewall against pathogens and harmful microbe‐derived molecules .…”

“…Blood from the gut enters the systemic circulation through the liver via the portal vein, meaning that the liver is at the centre of gut microbiome‐host interaction . Microbiota‐derived molecules have the potential to activate the immune system and trigger inflammation, providing the liver with the challenging task of balancing tolerance to beneficial and unharmful molecules and metabolites with the need to act as a firewall against pathogens and harmful microbe‐derived molecules . Disturbances of the gut‐liver axis are therefore potentially the key players in several liver diseases, and maybe biliary diseases especially as the gut microbiome is central to bile acid homeostasis.…”

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…Possibly, gut leakage of pro-inflammatory bacterial products (e.g. lipopolysaccharides, LPS) also contributes by involving innate immune responses [32][33][34][35]. Furthermore, a series of studies now strongly indicate that the gut microbiota may be involved in PSC pathogenesis [17,[36][37][38][39][40] giving rise to clinical trials involving fecal transplantation, non-absorbable antibiotics, and other means of manipulating the gut microbiome in patients [17,[41][42][43].…”

“…Novel and more specific biomarkers of liver fibrosis, discriminating collagen formation from degradation as opposed to just reflecting the more static fibrosis load, have also been associated with clinical outcome in PSC and may be suited to evaluate treatment effects, with PRO-C3 the currently most promising single marker [193]. Markers of inflammation, autoimmunity or gut barrier function including IL-8 [194], VAP-1 [177], autotaxin [195] or soluble CD14 [33] have also demonstrated association with clinical outcome and may represent relevant surrogate endpoints in trials targeting these pathways; however, independent validation and more knowledge about the natural history and fluctuations of theses markers, alone and in combination, are warranted.…”