Title: The role of nitrate-reducing oral bacteria in the etiology of insulin resistance and elevated blood pressure
Description: Increasing evidence suggests that the oral microbiome is highly relevant to cardiometabolic outcomes. Associations between the oral microbiome and extra-oral outcomes are most commonly hypothesized to result from a chronic inflammatory response to a dysbiotic oral microbiome. However, an alternative mechanism hypothesized to link the oral microbiome to cardiometabolic risk is via the production of nitric oxide, a physiologically important gaseous transmitter. The enterosalivary nitrate-nitrite-nitric oxide pathway of nitric oxide generation is dependent on the presence of nitrate-reducing oral bacteria in the mouth to reduce salivary nitrates to nitrite, which are then swallowed and made systemically bioavailable for further reduction into nitric oxide in the blood vessels and tissues. Thus, this pathway presents a mechanism for oral bacteria to exert a beneficial influence on cardiometabolic health. The overall objective of this dissertation is to advance the understanding of the role of nitrate-reducing oral bacteria in cardiometabolic outcomes in a population setting.

This objective was met using three aims. First, a systematic literature review was conducted to identify and assess the associations between nitrate-reducing oral bacteria and insulin resistance, plasma glucose, diabetes, blood pressure and hypertension found in the existing literature. The literature review found no study that explicitly tested the hypothesis of an association between nitrate-reducing oral bacteria and the cardiometabolic outcomes of interest. In addition, there were very few observed associations between nitrate-reducing oral bacteria and these cardiometabolic outcomes, and the findings were inconsistent across studies. Secondly, the associations between nitrate-reducing oral bacteria and insulin resistance, plasma glucose, blood pressure, prediabetes and hypertension were assessed using baseline data from a cohort of diabetes-free participants. Increased levels of oral nitrate-reducing bacteria were associated with lower insulin resistance, plasma glucose and mean systolic blood pressure cross-sectionally, but no associations were found with prediabetes and hypertension.

Finally, as dietary nitrate intake influences the level of salivary nitrate in the mouth for the nitrate-reducing oral bacteria to act on, the associations between dietary nitrate and insulin resistance, plasma glucose, blood pressure, prediabetes and hypertension were assessed. No clear associations between higher dietary nitrate intake and the cardiometabolic outcomes were found. However, there was some indication that higher dietary nitrate intake was associated with lower systolic blood pressure. The interaction of dietary nitrate intake with nitrate-reducing oral bacteria was then considered, but no evidence of such interaction was found. Overall, the results of this dissertation suggest that higher levels of nitrate-reducing oral bacteria may confer health benefits across the range of bacterial levels likely observed in human populations. These findings help inform future public health research aimed at utilizing the enterosalivary pathway of nitric oxide generation to improve cardiometabolic health.