title: Dynamics and establishment of Clostridium difficile infection in the murine gastrointestinal tract.
abstract: Clostridium difficile infection (CDI) following antibiotic therapy is a major public health threat. While antibiotic disruption of the indigenous microbiota underlies the majority of cases of CDI, the early dynamics of infection in the disturbed intestinal ecosystem are poorly characterized. This study defines the dynamics of infection with C. difficile strain VPI 10463 throughout the gastrointestinal (GI) tract using a murine model of infection. After inducing susceptibility to C. difficile colonization via antibiotic administration, we followed the dynamics of spore germination, colonization, sporulation, toxin activity, and disease progression throughout the GI tract. C. difficile spores were able to germinate within 6 h postchallenge, resulting in the establishment of vegetative bacteria in the distal GI tract. Spores and cytotoxin activity were detected by 24 h postchallenge, and histopathologic colitis developed by 30 h. Within 36 h, all infected mice succumbed to infection. We correlated the establishment of infection with changes in the microbiota and bile acid profile of the small and large intestines. Antibiotic administration resulted in significant changes to the microbiota in the small and large intestines, as well as a significant shift in the abundance of primary and secondary bile acids. Ex vivo analysis suggested the small intestine as the site of spore germination. This study provides an integrated understanding of the timing and location of the events surrounding C. difficile colonization and identifies potential targets for the development of new therapeutic strategies.
authors.affiliation: Department of Internal Medicine/Division of Infectious Diseases, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koenigsknecht
authors.affiliation: Department of Internal Medicine/Division of Infectious Diseases, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Casey M
authors.initials: CM
authors.lastname: Theriot
authors.affiliation: Unit for Laboratory Animal Medicine, In Vivo Animal Core, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Bergin
authors.affiliation: Department of Internal Medicine/Division of Infectious Diseases, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Cassie A
authors.initials: CA
authors.lastname: Schumacher
authors.affiliation: Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Patrick D
authors.identifier: http://orcid.org/0000-0002-6935-4275
authors.initials: PD
authors.lastname: Schloss
authors.affiliation: Department of Internal Medicine/Division of Infectious Diseases, The University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, Michigan, USA youngvi@umich.edu.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Young
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001647:Bile Acids and Salts / Q000737:chemistry; D016360:Clostridioides difficile / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000209:etiology / Q000382:microbiology / Q000401:mortality / Q000473:pathology*; D003092:Colitis / Q000209:etiology / Q000382:microbiology / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D004768:Enterotoxins / Q000096:biosynthesis / Q000378:metabolism; D005243:Feces / Q000382:microbiology; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects; D013171:Spores, Bacterial / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D004768:Enterotoxins; C035598:enterotoxin, Clostridium