Project Summary John P. Haran, MD is an Assistant Professor of Emergency Medicine at the University of Massachusetts Medical School. His goal is to acquire advanced research training and mentoring support to develop his patient-oriented research career with a focus on the aging microbiome. The ultimate goal of the proposed research program is to identify specific factors in the microbiome that can be intervened upon to prevent Clostridium difficile (C. difficile) in the long-term care facility (LTCF) elderly population. The prevalence and virulence of C. difficile infection (CDI) in the U.S. has increased over the past decade and it disproportionally affects the elderly. Recently, the burden of CDI has shifted with a predominance of patients affected being from a LTCF. Predictors of CDI such as advanced age and the presence of multiple comorbidities do not adequately explain the increased risk of CDI infection in LTCF patients. Hypothesis: Specific microbiome population and the metagenomic profiles will identify residents living in a LTCF at increased risk for C. difficile carriage. This hypothesis will be addressed in the following Specific Aims: (1) characterize the microbiome of LTCF residents that is associated with a C. difficile carrier state; (2) characterize the microbiome changes that occur in elderly residents with incident hospitalizations and antimicrobial exposures and describe the effect of the microbiome on the risk of incident C. difficile carriage; and (3) describe the association between microbiome patterns and risk of developing CDI. These objectives will be accomplished in a longitudinal cohort study of (n=145) LTCF residents ages ≥65 years who have been living at the facility for >90 days without incident hospitalizations or antimicrobial exposures in that period. Longitudinal stool samples will be collected monthly for 12 months and residents followed for exposure to antibiotics and hospitalizations. Additional samples will be collected during the time surrounding a healthcare intervention. We will characterize the microbiome by using both 16S rRNA sequencing and metagenomic analysis. We will use next-generation Illumina MiSeq high-throughput sequencing for changes in bacterial genes. C. difficile density will be quantified using standard rtPCR techniques. This proposal and training plan will provide Dr. Haran with the skills in both geriatrics and microbiome investigations to lead studies that expand our understanding of the elderly microbiome and it's role in health and disease. The innovative aspects of this project lie in our ability to identify microbiome factors specific to the elderly that change as they are hospitalized and exposed to antimicrobials. It is significant because establishing these changes that occur which lead to a C. difficile carrier state will lay the foundation for targeted interventions to prevent the spread of CDI. In summary, this proposal has the potential to impact the growing public health problem of CDI in elderly LTCF residents.

Project Narrative Clostridium difficile infection, the leading cause of gastroenterologic hospitalizations and associated deaths in the United States, accounts for over half a million infections and 29,000 deaths annually. The burden of Clostridium difficile infection predominantly affects older patients especially those living in long-term care. Because the healthy bacterial community that normally resides in the healthy human intestine works to prevent Clostridium difficile infection, we will study the bacterial community profiles of older adults living in nursing homes over time in order to identifying specific factors we can intervene upon to help prevent this spreading health-care associated disease.