Oral Microbiome, Nitric oxide Metabolism, and Oral and Cardiometabolic Health

口腔微生物组作为一氧化氮（NO）代谢的关键参与者已经获得了很多关注， 相应地在心脏代谢健康中。共生口腔细菌减少外源性（饮食）和内源性 硝酸盐转化为亚硝酸盐，亚硝酸盐转化为NO，NO是一种调节血管张力，炎症和 胰岛素敏感性随机临床试验表明，通过使用本品消除口腔微生物植物群 抗菌漱口水的使用降低了全身NO的生物利用度，伴随着胰岛素敏感性的丧失， 血压升高亚硝酸盐还可以被口腔细菌进一步还原成无机氮化合物， 例如氨通过异化硝酸盐还原为氨（DNRA）途径，这可能起重要作用 口腔健康的生物学作用;这些途径也可能影响全身NO生物利用度。我们最近 圣胡安超重成人纵向研究（SOALS）的出版物显示，经常使用超重 非处方漱口水与三年内糖尿病前期/糖尿病风险增加显著相关 随访，独立于主要糖尿病风险因素。口腔微生物组尚未被表征， 直接关系到它的硝酸盐还原能力和它在NO生物利用度和相关的口服和心脏代谢中的作用 健康成果。因此，我们建议评估以下具体目标。(1)口腔微生物鉴定 与一氧化氮生物利用度（血清亚硝酸盐水平）相关的曲线。(2)为了评估纵向 与一氧化氮生物利用度相关的口腔微生物概况与高血压的发展的关联， 糖尿病前期/糖尿病、龋齿和牙周炎的进展。(3)为了评估漱口水的影响 使用这些微生物谱和全身NO生物利用度。此外，我们还将评估协会 口腔微生物谱与口腔硝酸盐代谢的其他组分（唾液硝酸盐、亚硝酸盐、硝酸盐 还原酶和DNRA活性）。可改变的生活方式因素，如可能影响口服硝酸盐减少的饮食 将评估细菌和途径。超过1,000名SOALS参与者拥有相关的高质量数据， 基线和3年随访访视时可获得标本（保留率为79%），以实现及时的成本效益 study.唾液和血液样本、口服和心脏代谢临床指标以及关键协变量，包括 收集了详细的饮食，体力活动和口腔卫生指标。我们将分析 唾液微生物组使用16 S rRNA测序，我们将测量内源性和 外源性NO代谢（血清和唾液中的亚硝酸盐和硝酸盐， 唾液）。这项研究的结果将有助于确定口腔细菌，NO代谢， 心脏代谢和口腔健康，并帮助了解有关漱口水的使用和心脏代谢的途径 条件这项研究具有很高的潜在公共卫生影响，因为其结果可能会为开发 调节口腔微生物组的新干预措施，这对预防和 控制口腔和心脏代谢疾病。

The oral microbiome has been gaining a lot of attention as a key player in nitric oxide (NO) metabolism, and accordingly in cardiometabolic health. Commensal oral bacteria reduce exogenous (dietary) and endogenous nitrate to nitrite, which is converted to NO, a signaling molecule that regulates vascular tone, inflammation and insulin sensitivity. Randomized clinical trials have shown that eliminating the oral microbial flora through the use of antiseptic mouthwash decreases systemic NO bioavailability with concomitant loss of insulin sensitivity and increased blood pressure. Nitrite can also be further reduced by oral bacteria into inorganic nitrogen compounds, such as ammonia via Dissimilatory Nitrate Reduction to Ammonia (DNRA) pathway, which can play important biological roles in oral health; these pathways could also impact systemic NO bioavailability. Our recent publication from the San Juan Overweight Adults Longitudinal Study (SOALS) shows that regular use of over- the-counter mouthwash is significantly associated with increased risk of pre-diabetes/diabetes over a three-year follow-up, independently of major diabetes risk factors. The oral microbiome has not yet been characterized in direct relation to its nitrate reducing capacity and its role in NO bioavailability and related oral and cardiometabolic health outcomes. Accordingly, we propose to evaluate the following specific aims. (1) To identify oral microbial profiles associated with nitric oxide bioavailability (serum nitrite levels). (2) To evaluate the longitudinal association of oral microbial profiles related to nitric oxide bioavailability with the development of hypertension, pre-diabetes/diabetes, dental caries and progression of periodontitis. (3) To evaluate the impact of mouthwash use on these microbial profiles and systemic NO bioavailability. In addition, we will also evaluate the association of oral microbial profiles with other components of oral nitrate metabolism (salivary nitrate, nitrite, nitrate reductase and DNRA activity). Modifiable lifestyle factors such as diet that may impact oral nitrate reducing bacteria and pathways will be assessed. Over 1,000 SOALS participants have pertinent high quality data and specimens available at baseline and 3-year follow-up visits (with 79% retention) to enable a timely cost-efficient study. Saliva and blood samples, oral and cardiometabolic clinical measures, and key covariates including detailed dietary, physical activity and oral hygiene measures have been collected. We will perform analysis of the salivary microbiome using 16S rRNA sequencing, and we will measure key components of endogenous and exogenous NO metabolism (nitrite and nitrate in serum and in saliva, nitrate reductase and DNRA activities in saliva). The results from this study will help define the interrelationships between oral bacteria, NO metabolism, cardiometabolic and oral health, and help understand pathways relating mouthwash use and cardiometabolic conditions. This study has a high potential public health impact, as the results will likely inform development of novel interventions for the modulation of the oral microbiome, which could be important for the prevention and control of oral and cardiometabolic diseases.