Grant: Catalyst Grant: Human Microbiome

Clostridium difficile-associated diarrhea (CDAD) is the most important cause of hospital-acquired diarrhea and has emerged as a significant public health issue in Québec. Risk factors for CDAD include hospitalization, antibiotic use, underlying disease severity, and the overgrowth of C. difficile in the gut. The relationship between these risk factors, the intestinal microbiota and the development of CDAD has not been well studied. We will conduct a case-control study, embedded in the large cohort study of C. difficile epidemiology in Québec (the Fonds de recherche en santé du Québec (FRSQ) Clostridium difficile Consortium) to address this relationship. CDAD cases and matched controls (n = 75) have been retrospectively identified from the FRSQ cohort between 2006 and 2007. Results from our 16S rDNA microarray ("DNA chip"), designed to capture species diversity from fecal samples, indicate that there is a significant difference (p < 0.001) in the mean intestinal microbial diversity between cases and controls. This difference remained after adjusting for CDAD risk factors. In our proposed project, we will extend these initial results by performing high-throughput 16S rDNA and random shotgun sequencing of bacterial genomes present in samples collected just prior to CDAD diagnosis (an approach termed microbial metagenomics). The project will also address computational limitations of analytic approaches to microbial metagenomic data. We will develop a combinatorial algorithm to identify associations (association rules) between bacterial species or patterns of species present in intestinal samples; this information will be will be used to study functional changes to the intestinal microbiota that result from hospitalization-related exposures in patients at risk of CDAD. The project will advance research in the epidemiology of intestinal microbiota-mediated disease processes and may improve the management and treatment of C. difficile infected patients.