Project Summary Metabolic syndrome (MetS), a global epidemic that affects more than 1/3rd of the US adult population, is a cluster of biochemical and physiological abnormalities that predisposes to Type 2 Diabetes (T2D) and Cardiovascular Diseases (CVD). Emerging evidence indicates that Metabolic Syndrome (MetS), an adverse consequence of obesity, is associated with an increase in the extent and severity of periodontitis. Periodontitis is a microbially induced chronic inflammatory disease that destroys the supporting structures of teeth, eventually leading to tooth loss and the severe form of the disease affects ~10% of the American adults. Although there are narrative reviews and a handful of cross-sectional studies that suggest the association between MetS and increased prevalence of periodontitis, the mechanism(s) behind these associations have not been investigated. Dysbiosis in the oral environment leads to periodontal disease, however, the mechanisms of these disruptions and subsequent functional alterations in the oral microbiome of MetS patients remain undefined. Therefore, our central hypothesis is that MetS creates an at-risk-for-harm environment, even before the onset of clinical periodontal disease by altering the microbial functions and metabolites. We will test our hypothesis by carrying out two aims: In Specific Aim 1, we will determine the effects of MetS on the oral metagenome, by comparing and quantifying changes in microbial gene abundances and associated functional pathways between MetS and controls, using a multi-arm, cross-sectional study design with whole-metagenome sequencing. In Specific Aim 2 we will map the microbially-derived metabolites (the end products) in the subgingival environment of patients with MetS using gas chromatography/mass spectrometry (GC/MS) analysis. The expected outcomes of the proposed studies are the determination of effects of MetS on the functional and metabolic landscape of the subgingival environment. We anticipate that our integrative systems biology approach combined with clinical epidemiology will lay the foundation for future mechanistic investigations. Driven by the startling statistics of economic and health burden caused by the MetS in the backdrop of the prevalence of the periodontal disease in the US adult population, we are proposing a much-needed study in a severely under-explored area: the impact of Metabolic Syndrome on oral health. Our long- term goal is to identify personalized, experimentally validated biomarkers/potential indicators of health and future periodontal disease in this high-risk cohort.