The microbiome and aging in Clostridioides difficile infection

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ABSTRACT The indigenous microbiota plays a critical role in the health of their host by contributing to an ecosystem (the microbiome) that reflects a stable environment shaped by the host and the resident microbes. Normal resident microbes contribute to homeostatic functions including fostering immune system maturation, protecting against pathogen invasion and assisting digestion of food. Conversely, many age-associated conditions such as cardiovascular disease, neurodegenerative diseases, cancer and diabetes have been associated with abnormal host-microbe interactions. The ultimate goal of this work is to develop therapeutic strategies and tactics that permit us to foster beneficial host-microbe interactions and improve disease outcomes in older adults. In order to accomplish this goal, we need to understand how the microbiota changes over the lifespan of the individual and how this alters host function. The specific objective of this proposal is to understand how age-related changes in the microbiota alters susceptibility to outcomes of infection with the pathogen Clostridioides difficile. C. difficile infection (CDI) following disruption of the gut microbiota due to antibiotic administration causes significant morbidity and mortality. Elderly patients are more susceptible to CDI and are at increased risk of developing disease-related complications following infection. We hypothesize that changes in the microbiota and host related to aging underlie the increased susceptibility to CDI that contributes to worse outcome of infection in older adults. We will test our hypothesis with 3 specific aims conducted in a robust animal model of CDI. 1) Compare and contrast the structure and function of the microbiome over the age range of mice. 2) Determine the role that the microbiome has on shaping host immune responses related to age using CDI as a model disease condition. 3) Investigate the possibility of manipulating the host and the indigenous microbiota to alter health and disease. In this proposal, we intend to perform detailed investigations on the effects of aging on the microbiome and the outcome of C. difficile infection. We will leverage a murine model of CDI for these studies. The results of these studies should provide important insights on the relationship between advancing age, the host and the microbiota that could improve our ability to deal with CDI and other conditions that are influenced by the microbiota over the lifespan.