The impairment of intestinal barrier function is implicated in primary sclerosing cholangitis, but the clinical evidence is scarce. Therefore, we performed a cross-sectional study to evaluate serological markers of inflammation and intestinal permeability (Reg3a, iFABP, Zonulin, Calprotectin) in patients after liver transplantation (LT) for PSC. The cohort included 26 subjects with PSC recurrence (rPSC), 87 subjects without PSC recurrence (non-rPSC), and a unique control group consisting of post-LT patients (n = 113) transplanted due to alcohol cirrhosis. Generalized Linear Models were calculated to assess the association between serological markers of intestinal barrier function or inflammation (IP_Models) and PSC diagnosis per se (IP_Model_1), non-rPSC (IP_Model_2) or rPSC incidence (IP_Model_3) and compared with models (ST_Models) based on validated PSC markers (ALP, GGT, bilirubin). The increased probability of PSC occurrence (IP_Model_1, p < 0.001, AIC = 182) was associated with higher serum Reg3a concentration, while a negative association was found for iFABP, BMI, and age. The probability of non-recurrence (IP_Model_2, p < 0.001, AIC = 167) was associated with lower Reg3a concentration, older age, and BMI. The performance of IP_Models_1,2 and ST_models_1,2 was comparable. rPSC prediction was less precise by both models (IP_Model_3 p = 0.063, AIC = 92; ST_Model_3 p < 0.001, AIC = 108). rPSC incidence was positively associated with fecal calprotectin and serum zonulin concentrations, while it was independent of Reg3a, iFABP, age or BMI. In conclusion, this pilot study suggests that impaired intestinal permeability is associated with the pathophysiology of rPSC. Our data could serve as a basis for testing in a larger independent validation cohort and, if confirmed, help to explain the mechanisms underlying the pathophysiology of PSC and the recurrence of this disease after transplantation.

Center of Experimental Medicine Institute for Clinical and Experimental Medicine Videnska Prague 1958 Czech Republic

Clinical and Transplant Pathology Centre Institute for Clinical and Experimental Medicine Prague 14021 Czech Republic

Department of Data Science Institute for Clinical and Experimental Medicine Videnska Prague 1958 Czech Republic

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Videnska Prague 1958 Czech Republic

Department of Internal Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University and Thomayer Hospital Prague 14059 Czech Republic

Institute of Pathology of the 1st Faculty of Medicine and General Teaching Hospital Prague 12800 Czech Republic

Zobrazit více v PubMed

Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. PubMed DOI

Boonstra K, Weersma RK, van Erpecum KJ, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. PubMed DOI

Visseren T, Erler NS, Polak WG, et al. Recurrence of primary sclerosing cholangitis after liver transplantation – analysing the European liver transplant registry and beyond. PubMed DOI PMC

Bajer L, Kverka M, Kostovcik M, et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. PubMed DOI PMC

Hole MJ, Jørgensen KK, Holm K, et al. A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation. PubMed DOI PMC

Steenstraten IC, Sebib Korkmaz K, Trivedi PJ, et al. Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation. PubMed DOI PMC

Dean G, Hanauer S, Levitsky J. The role of the intestine in the pathogenesis of primary sclerosing cholangitis: evidence and therapeutic implications. PubMed DOI

Coufal S, Galanova N, Bajer L, et al. Inflammatory bowel disease types differ in markers of inflammation, gut barrier and in specific anti-bacterial response. PubMed DOI PMC

Dhillon AK, Kummen M, Trøseid M, et al. Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis. PubMed DOI

Chen Z, Downing S, Tzanakakis ES. Four decades after the discovery of regenerating islet-derived (Reg) proteins: current understanding and challenges. PubMed DOI PMC

Yang J, Syed F, Xia Y, et al. Blood biomarkers of intestinal epithelium damage regenerating islet-derived protein 3α and trefoil factor 3 are persistently elevated in patients with alcoholic hepatitis. PubMed DOI PMC

Pelsers MMAL, Hermens WT, Glatz JFC. Fatty acid-binding proteins as plasma markers of tissue injury. PubMed DOI

Linsalata M, Riezzo G, Clemente C, D’Attoma B, Russo F. Noninvasive biomarkers of gut barrier function in patients suffering from diarrhea predominant-IBS: an update. PubMed DOI PMC

Zheng D, Liao H, Chen S, et al. Elevated levels of circulating biomarkers related to leaky gut syndrome and bacterial translocation are associated with Graves’ disease. PubMed DOI PMC

Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. In: Fromm M, Schulzke JD, editors. PubMed PMC

Wang X, Memon AA, Palmér K, Hedelius A, Sundquist J, Sundquist K. The association of zonulin-related proteins with prevalent and incident inflammatory bowel disease. PubMed DOI PMC

Graziadei IW, Wiesner RH, Marotta PJ, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. PubMed DOI

Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calculation for linear and logistic regression. PubMed DOI

Lacombe LAC, Matiollo C, Rosa JSD, Felisberto M, Dalmarco EM, Schiavon LL. Factors associated with circulating zonulin in inflammatory bowel disease. PubMed DOI

Camilleri M. Is intestinal permeability increased in obesity? A review including the effects of dietary, pharmacological and surgical interventions on permeability and the microbiome. PubMed DOI PMC

Li ZJ, Gou HZ, Zhang YL, Song XJ, Zhang L. Role of intestinal flora in primary sclerosing cholangitis and its potential therapeutic value. PubMed DOI PMC

Kim YS, Hurley EH, Park Y, Ko S. Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut–liver axis. PubMed DOI PMC

Maccauro V, Fianchi F, Gasbarrini A, Ponziani FR. Gut microbiota in primary sclerosing cholangitis: from prognostic role to therapeutic implications. PubMed DOI