Amandeep K Dhillon1,2,3, Martin Kummen1,2,3, Marius Trøseid2,3,4, Sissel Åkra5, Evaggelia Liaskou6, Bjørn Moum2,7, Mette Vesterhus1,8,9, Tom H Karlsen1,2,3,10, Ingebjørg Seljeflot2,5, Johannes R Hov1,2,3,10. 1. Norwegian PSC Center, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. 2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 3. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway. 5. Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway. 6. Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Centre, Institute of Immunology & Immunotherapy, University of Birmingham, Birmingham, UK. 7. Department of Gastroenterology, Division of Medicine, Oslo University Hospital Ullevål, Oslo, Norway. 8. Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway. 9. Department of Clinical Science, University of Bergen, Bergen, Norway. 10. Section of Gastroenterology, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
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.
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 cholangitispatients 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 cholangitispatients and healthy controls. Zonulin was lower in primary sclerosing cholangitis than controls, but when excluding primary sclerosing cholangitispatients 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 diseasepatients 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 cholangitispatients 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.
Authors: Lars Bossen; Mette Vesterhus; Johannes R Hov; Martti Färkkilä; William M Rosenberg; Holger J Møller; Kirsten M Boberg; Tom H Karlsen; Henning Grønbæk Journal: Clin Transl Gastroenterol Date: 2021-03-01 Impact factor: 4.396
Authors: Diana E Matei; Madhvi Menon; Dagmar G Alber; Andrew M Smith; Bahman Nedjat-Shokouhi; Alessio Fasano; Laura Magill; Amanda Duhlin; Samuel Bitoun; Aude Gleizes; Salima Hacein-Bey-Abina; Jessica J Manson; Elizabeth C Rosser; Nigel Klein; Paul A Blair; Claudia Mauri Journal: Med (N Y) Date: 2021-07-09