Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

Abstract

AIMTo assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients.METHODSSera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various anti-microbial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls.RESULTSA total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG (P < 0.001, for both) and AGA IgG (P = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), P = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), P = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies (P < 0.001 for EndoCab IgA and P = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABPAAA IgA pos vs neg: 365 vs 166 pg/mL, P = 0.011), but not with serum LBP level.CONCLUSIONPresence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC.

Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis

“…We performed an observational cohort study among adult and pediatric PSC patients recruited in Hungarian referral hepatology centers (Hungarian Autoimmune Liver Disease Study Group). This study population is equal with the patient cohort published previously 34 , with exception that 4 patients were excluded due to prior liver transplantation in this study. In total 65 well-characterized PSC patients with a complete clinical follow-up (adult: 55 [male/female: 39/16], median age at presentation: 28 years [IQR: 19–37], median disease duration: 6 years [2–10] and children: 10 [male/female: 7/3], median age at presentation: 10 years [IQR: 6–11], disease duration: 5 [1.5–7.5]) were included between January, 2006 and December, 2007.…”

“…Phenotypical characterization of this patient cohort was performed previously and is provided similarly as the publication 34 . PSC patients were enrolled into a prospective follow-up study, where treating physicians registered laboratory data, imaging and endoscopic findings, medical treatment, date and type of complications (cirrhosis, colorectal cancer, biliary tract cancer: cholangiocarcinoma [CCA] gallbladder cancer [GBC] or cholangitis) during regular outpatient follow-up visits and inpatient stays.…”

Functional polymorphisms of innate immunity receptors are not risk factors for the non‐SBP type bacterial infections in cirrhosis

“…EndoCAb directs against a mixture of incomplete endotoxins of four different species ( Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli and Klebsiella aerogenes ), while anti‐OMP Plus antibody does to a mixture of multiple bacterial proteins derived from two species of intestinal bacteria (one Gram‐positive and one Gram‐negative). Cut‐off positivity was 195 AU/mL for EndoCAb IgA, defined by our group previously as a value exceeding the 95th percentile level of the healthy control group, and 25 U for anti‐OMP Plus IgA as recommended by the manufacturer.…”

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].…”