title: Functional Intestinal Bile Acid 7α-Dehydroxylation byClostridium scindensAssociated with Protection fromClostridium difficileInfection in a Gnotobiotic Mouse Model.
abstract: Bile acids, important mediators of lipid absorption, also act as hormone-like regulators and as antimicrobial molecules. In all these functions their potency is modulated by a variety of chemical modifications catalyzed by bacteria of the healthy gut microbiota, generating a complex variety of secondary bile acids. Intestinal commensal organisms are well-adapted to normal concentrations of bile acids in the gut. In contrast, physiological concentrations of the various intestinal bile acid species play an important role in the resistance to intestinal colonization by pathogens such asClostridium difficile. Antibiotic therapy can perturb the gut microbiota and thereby impair the production of protective secondary bile acids. The most important bile acid transformation is 7α-dehydroxylation, producing deoxycholic acid (DCA) and lithocholic acid (LCA). The enzymatic pathway carrying out 7α-dehydroxylation is restricted to a narrow phylogenetic group of commensal bacteria, the best-characterized of which isClostridium scindens. Like many other intestinal commensal species, 7-dehydroxylating bacteria are understudiedin vivo. Conventional animals contain variable and uncharacterized indigenous 7α-dehydroxylating organisms that cannot be selectively removed, making controlled colonization with a specific strain in the context of an undisturbed microbiota unfeasible. In the present study, we used a recently established, standardized gnotobiotic mouse model that is stably associated with a simplified murine 12-species "oligo-mouse microbiota" (Oligo-MM12). It is representative of the major murine intestinal bacterial phyla, but is deficient for 7α-dehydroxylation. We find that the Oligo-MM12consortium carries out bile acid deconjugation, a prerequisite for 7α-dehydroxylation, and confers no resistance toC. difficileinfection (CDI). Amendment of Oligo-MM12withC. scindensnormalized the large intestinal bile acid composition by reconstituting 7α-dehydroxylation. These changes had only minor effects on the composition of the native Oligo-MM12, but significantly decreased early large intestinalC. difficilecolonization and pathogenesis. The delayed pathogenesis ofC. difficileinC. scindens-colonized mice was associated with breakdown of cecal microbial bile acid transformation.
authors.affiliation: Institute for Infectious Diseases, University of BernBern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of BernBern, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Studer
authors.affiliation: Environmental Microbiology Laboratory, École Polytechnique Fédérale de Lausanne (EPFL) Lausanne, Switzerland.
authors.forename: Lyne
authors.initials: L
authors.lastname: Desharnais
authors.affiliation: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich (LMU) Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Beutler
authors.affiliation: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich (LMU) Munich, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Brugiroux
authors.affiliation: Institute for Infectious Diseases, University of Bern Bern, Switzerland.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Terrazos
authors.affiliation: Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL) Lausanne, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Menin
authors.affiliation: Institute of Pathology University of Bern, Bern, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Schürch
authors.affiliation: Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern Bern, Switzerland.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Clostridia Research Group, Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC) Synthetic Biology Research Centre, School of Life Sciences, University of Nottingham Nottingham, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Kuehne
authors.affiliation: Clostridia Research Group, Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC) Synthetic Biology Research Centre, School of Life Sciences, University of Nottingham Nottingham, UK.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Minton
authors.affiliation: Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich (LMU)Munich, Germany; German Center for Infection Research, Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Ludwig-Maximilians-University of Munich (LMU)Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Stecher
authors.affiliation: Environmental Microbiology Laboratory, École Polytechnique Fédérale de Lausanne (EPFL) Lausanne, Switzerland.
authors.forename: Rizlan
authors.initials: R
authors.lastname: Bernier-Latmani
authors.affiliation: Institute for Infectious Diseases, University of Bern Bern, Switzerland.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hapfelmeier
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001711:Biotransformation; D003013:Clostridium / Q000378:metabolism*; D003015:Clostridium Infections / Q000517:prevention & control*; D004195:Disease Models, Animal; D005856:Germ-Free Life; D007422:Intestines / Q000382:microbiology*; D051379:Mice
chemical_list: D001647:Bile Acids and Salts
keywords: 7α-dehydroxylation; Clostridium difficile; Clostridium difficile infection (CDI); Clostridium scindens; gnotobiotic mouse model; gut microbiota; intestinal infection; secondary bile acids