Martin Kummen1, Louise B Thingholm2, Malte C Rühlemann2, Kristian Holm3, Simen H Hansen3, Lucas Moitinho-Silva4, Timur Liwinski5, Roman Zenouzi6, Christopher Storm-Larsen3, Øyvind Midttun7, Adrian McCann7, Per M Ueland7, Marte L Høivik8, Mette Vesterhus9, Marius Trøseid10, Matthias Laudes11, Wolfgang Lieb12, Tom H Karlsen13, Corinna Bang2, Christoph Schramm14, Andre Franke2, Johannes R Hov15. 1. Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway. 2. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. 3. Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany. 5. Institute of Medical Systems Biology, Center for Molecular Neurobiology, Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 7. Bevital, Bergen, Norway. 8. Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo, Norway. 9. Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway. 10. Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway. 11. Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine 1, University of Kiel, Kiel, Germany. 12. Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany. 13. Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 14. I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 15. Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address: j.e.r.hov@medisin.uio.no.
Abstract
BACKGROUND & AIMS: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). METHODS: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. RESULTS: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. CONCLUSIONS: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
BACKGROUND & AIMS: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). METHODS: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. RESULTS: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. CONCLUSIONS: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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