Philipp Solbach1,2,3,4, Patrick Chhatwal2,3, Sabrina Woltemate2,3, Evelina Tacconelli5,6, Michael Buhl6,7, Ingo B Autenrieth6,7, Maria J G T Vehreschild8,9,10, Nathalie Jazmati9,11, Markus Gerhard12,13, Christoph K Stein-Thoeringer13,14, Jan Rupp15,16, Kurt Ulm17, Armin Ott17, Florian Lasch18, Armin Koch18, Michael P Manns1,2, Sebastian Suerbaum2,3,13,19, Oliver Bachmann1,2. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 2. German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. 3. Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. 4. Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany. 5. Division of Infectious Diseases, Department of Internal Medicine 1, Tübingen University Hospital, Tübingen, Germany and Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Italy. 6. German Center for Infection Research (DZIF), partner site Tübingen, Germany. 7. Institute of Medical Microbiology and Hygiene, Tübingen University Hospital, Tübingen, Germany. 8. 1st Department of Internal Medicine, University Hospital Cologne, Cologne, Germany. 9. German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany. 10. Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany. 11. Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany; currently: Laboratory Dr. Wisplinghoff, Cologne, Germany. 12. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany. 13. German Center for Infection Research (DZIF), partner site Munich, Germany. 14. Microbiome and Cancer Research Division, German Center for Cancer Research (DKFZ), Heidelberg, Germany. 15. Department of Infectious Diseases and Microbiology, University Hospital Schleswig-Holstein, Lübeck, Germany. 16. German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, Germany. 17. Institute of Medical Informatics, Statistics and Epidemiology, Technische Universität München, Munich, Germany. 18. Institute for Biometry, Hannover Medical School, Hannover, Germany. 19. Chair of Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, Munich, Germany.
Abstract
BACKGROUND: Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficile infection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable. METHODS: C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity. RESULTS: 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp.. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization. CONCLUSIONS: Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition.
BACKGROUND: Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficileinfection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable. METHODS:C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity. RESULTS: 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp.. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization. CONCLUSIONS: Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition.