Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis
ABSTRACT Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-08-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01904-22 |
| _version_ | 1811281731439820800 |
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| author | Madeline R. Barron Kelly L. Sovacool Lisa Abernathy-Close Kimberly C. Vendrov Alexandra K. Standke Ingrid L. Bergin Patrick D. Schloss Vincent B. Young |
| author_facet | Madeline R. Barron Kelly L. Sovacool Lisa Abernathy-Close Kimberly C. Vendrov Alexandra K. Standke Ingrid L. Bergin Patrick D. Schloss Vincent B. Young |
| author_sort | Madeline R. Barron |
| collection | DOAJ |
| description | ABSTRACT Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility are not well understood. To explore the intersection between CDI and IBD, we recently described a mouse model where colitis triggered by the murine gut bacterium, Helicobacter hepaticus, in IL-10−/− mice led to susceptibility to C. difficile colonization without antibiotic administration. The current work disentangles the relative contributions of inflammation and gut microbiota in colonization resistance to C. difficile in this model. We show that inflammation drives changes in microbiota composition, which leads to CDI susceptibility. Decreasing inflammation with an anti-p40 monoclonal antibody promotes a shift of the microbiota back toward a colonization-resistant state. Transferring microbiota from susceptible and resistant mice to germfree animals transfers the susceptibility phenotype, supporting the primacy of the microbiota in colonization resistance. These findings shine light on the complex interactions between the host, microbiota, and C. difficile in the context of intestinal inflammation, and may form a basis for the development of strategies to prevent or treat CDI in IBD patients. IMPORTANCE Patients with inflammatory bowel disease (IBD) have an increased risk of developing C. difficile infection (CDI), even in the absence of antibiotic treatment. Yet, mechanisms regulating C. difficile colonization in IBD patients remain unclear. Here, we use an antibiotic-independent mouse model to demonstrate that intestinal inflammation alters microbiota composition to permit C. difficile colonization in mice with colitis. Notably, treating inflammation with an anti-p40 monoclonal antibody, a clinically relevant IBD therapeutic, restores microbiota-mediated colonization resistance to the pathogen. Through microbiota transfer experiments in germfree mice, we confirm that the microbiota shaped in the setting of IBD is the primary driver of susceptibility to C. diffiicile colonization. Collectively, our findings provide insight into CDI pathogenesis in the context of intestinal inflammation, which may inform methods to manage infection in IBD patients. More broadly, this work advances our understanding of mechanisms by which the host-microbiota interface modulates colonization resistance to C. difficile. |
| first_indexed | 2024-04-13T01:38:52Z |
| format | Article |
| id | doaj.art-9296a471e6e64121b35e6265edf3b08e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-13T01:38:52Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-9296a471e6e64121b35e6265edf3b08e2022-12-22T03:08:15ZengAmerican Society for MicrobiologymBio2150-75112022-08-0113410.1128/mbio.01904-22Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of ColitisMadeline R. Barron0Kelly L. Sovacool1Lisa Abernathy-Close2Kimberly C. Vendrov3Alexandra K. Standke4Ingrid L. Bergin5Patrick D. Schloss6Vincent B. Young7Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USADepartment of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor Michigan, USADivision of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USADivision of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USADivision of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USAThe Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USADepartment of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USADepartment of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USAABSTRACT Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility are not well understood. To explore the intersection between CDI and IBD, we recently described a mouse model where colitis triggered by the murine gut bacterium, Helicobacter hepaticus, in IL-10−/− mice led to susceptibility to C. difficile colonization without antibiotic administration. The current work disentangles the relative contributions of inflammation and gut microbiota in colonization resistance to C. difficile in this model. We show that inflammation drives changes in microbiota composition, which leads to CDI susceptibility. Decreasing inflammation with an anti-p40 monoclonal antibody promotes a shift of the microbiota back toward a colonization-resistant state. Transferring microbiota from susceptible and resistant mice to germfree animals transfers the susceptibility phenotype, supporting the primacy of the microbiota in colonization resistance. These findings shine light on the complex interactions between the host, microbiota, and C. difficile in the context of intestinal inflammation, and may form a basis for the development of strategies to prevent or treat CDI in IBD patients. IMPORTANCE Patients with inflammatory bowel disease (IBD) have an increased risk of developing C. difficile infection (CDI), even in the absence of antibiotic treatment. Yet, mechanisms regulating C. difficile colonization in IBD patients remain unclear. Here, we use an antibiotic-independent mouse model to demonstrate that intestinal inflammation alters microbiota composition to permit C. difficile colonization in mice with colitis. Notably, treating inflammation with an anti-p40 monoclonal antibody, a clinically relevant IBD therapeutic, restores microbiota-mediated colonization resistance to the pathogen. Through microbiota transfer experiments in germfree mice, we confirm that the microbiota shaped in the setting of IBD is the primary driver of susceptibility to C. diffiicile colonization. Collectively, our findings provide insight into CDI pathogenesis in the context of intestinal inflammation, which may inform methods to manage infection in IBD patients. More broadly, this work advances our understanding of mechanisms by which the host-microbiota interface modulates colonization resistance to C. difficile.https://journals.asm.org/doi/10.1128/mbio.01904-22Clostridioides difficileHelicobacter hepaticusanimal modelsgut inflammationgut microbiotaintestinal colonization |
| spellingShingle | Madeline R. Barron Kelly L. Sovacool Lisa Abernathy-Close Kimberly C. Vendrov Alexandra K. Standke Ingrid L. Bergin Patrick D. Schloss Vincent B. Young Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis mBio Clostridioides difficile Helicobacter hepaticus animal models gut inflammation gut microbiota intestinal colonization |
| title | Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis |
| title_full | Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis |
| title_fullStr | Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis |
| title_full_unstemmed | Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis |
| title_short | Intestinal Inflammation Reversibly Alters the Microbiota to Drive Susceptibility to Clostridioides difficile Colonization in a Mouse Model of Colitis |
| title_sort | intestinal inflammation reversibly alters the microbiota to drive susceptibility to clostridioides difficile colonization in a mouse model of colitis |
| topic | Clostridioides difficile Helicobacter hepaticus animal models gut inflammation gut microbiota intestinal colonization |
| url | https://journals.asm.org/doi/10.1128/mbio.01904-22 |
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