Type 2 diabetes (T2D) is a significant and increasingly prevalent disease in the US population. In addition, the prevalence of diabetes among Hispanics is nearly twice that of non-Hispanics. Diabetes is further associated with an increase in the prevalence and progression of periodontitis. Comprehensive analysis of the microbiome associated with periodontitis in type 2 diabetics (T2Ds) is lacking, leaving a significant gap in our understanding of the role of the periodontal microbiome in periodontitis in this population. The host immune response in T2Ds is known to be altered and evidence suggests a dysregulation in connective tissue metabolism. In the periodontal tissues these changes may result from, as well as impact, the associated microbiome. We will investigate the microbiome associated with periodontal disease and diabetes in a high- risk Hispanic population. We hypothesize that the subgingival microbiome associated with chronic periodontitis in T2Ds harbors bacterial species and genetic elements (genes, metabolic pathways, insertion sequences or pathogenicity islands) constituting a metagenomic signature that is distinct from that of chronic periodontitis in systemically healthy subjects, or resolved periodontitis or periodontal health in subjects with or without T2Ds. We further hypothesize that the response to initial periodontal treatment in chronic periodontitis of T2Ds will be less effective in reducing or eliminating species and genetic elements associated with pathogenesis as compared that of non-diabetic patients. To test these hypotheses we will conduct deep 16S rDNA analyses on subgingival samples from periodontitis subjects with or without T2D (Aim 1). Controls will include periodontally healthy and periodontally treated (resolved periodontitis) subjects with or without T2D. We will additionally conduct deep metagenomic sequence analysis on subgingival samples from periodontitis patients with or without T2D (Aim 2) with controls as described above. Finally we will validate the top and virulence-related metagenomic signature differences found in Aim 2 in a different sample set from periodontally healthy and diseased subjects with or without T2D. We will assess the relative abundance of the bacterial metagenomic signature molecules in the metagenome and metatranscriptome (Aim 3). This study will define the microbial community and metagenomic signatures that distinguish the subgingival microbiome associated with chronic periodontitis in type 2 diabetics from those of systemically healthy patients in a high risk Hispanic population. This research will address a fundamental gap in our knowledge of the periodontal microbiome in population at high risk for periodontitis and may lead to further studies for the development of innovative clinical approaches to diagnosing, preventing and managing the disease in diabetics. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2D) is a significant and increasingly prevalent disease in the US population, particularly among Hispanics, and is further associated with an increase in the prevalence and progression of gum (periodontal) disease caused by periodontal microorganisms. This investigation will comprehensively characterize the periodontal microbial population in subjects with or without T2D. The findings will address a fundamental gap in our understanding of the etiological agents of periodontitis and may lead to innovative strategies for diagnosing, preventing and managing periodontitis.