Nutrient Niche Space of Clostridium difficile Across Susceptible Microbiomes and the Impact of Infection on Metabolism of the Murine Cecal Microbiota

Abstract

The nosocomial pathogen Clostridium difficile causes an antibiotic-associated diarrheal disease, and largest single cause of hospital-acquired infection as well as gastroenteritis-associated death in the United States. The connection with prior antibiotic therapy is due to the collateral damage induced by these drugs on the community of indigenous bacteria that reside along the gastrointestinal tract. In its healthy state, the gut microbiota prevents the establishment of C. difficile in the gut through the intrinsic property known as colonization resistance. Following a perturbation, like exposure to antibiotics, this community becomes susceptible to colonization by the pathogen and subsequent disease. Most antibiotic classes have been associated with C. difficile infection (CDI) susceptibility; many leading to distinct community structures with unique metabolic profiles stemming from variation in bacterial targets of action. Additionally, a subset of these antibiotics are more closely associated with recurrent or persistent infection. In this thesis I demonstrate that certain susceptible gut communities are more permissive of long-term C. difficile colonization, and that the pathogen has a disproportionate effect on the metabolic activity of communities where persistence occurs. Taxonomic analyses of altered gene expression revealed that this effect consistently impact minority bacterial genera of the community across infection groups. In order to measure the adaptive capacity of C. difficile to these diverse environments, I also generated a genomic/transcriptomic-enabled metabolic modeling platform to assess the differences in nutrient preference of C. difficile across different community contexts. This revealed the pathogen inhabited distinct nutrient niche spaces across susceptible gut environments. My dissertation work has strong implications in future research of targeted pre- and probiotic therapies that mitigate primary or established C. difficile colonization from the gastrointestinal tract.