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

摘要

AIM To 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.METHODS Sera 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 Ig A/Ig G) and gliadin(AGA Ig A/Ig G)] 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 antimicrobial antibodies [anti-OMP Plus Ig A and endotoxin core Ig A antibody(Endo CAb)] 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. RESULTS A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA Ig A, AAA Ig G, AGA Ig A and AGA Ig G, respectively. Frequencies of AAA Ig A and AAA Ig G(P < 0.001, for both) and AGA Ig G(P = 0.01, for both) but not AGA Ig A were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA Ig A-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 Ig A-positivity was significantly associated with higher frequency of antimicrobial antibodies(P < 0.001 for Endo Cab Ig A and P = 0.012 for anti-OMP Plus Ig A) and higher level of the enterocyte damage marker(median I-FABP_(AAA Ig A pos vs neg): 365 vs 166 pg/m L, P = 0.011), but not with serum LBP level. CONCLUSION Presence of Ig A 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.