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

口腔微生物组作为一氧化氮(NO)代谢的关键角色，一直受到人们的极大关注。 因此，在心脏代谢健康方面。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是一种信号分子，调节血管张力、炎症和 胰岛素敏感性。随机临床试验表明，通过使用该药可以消除口腔微生物群 消毒漱口水降低了全身NO的生物利用度，并伴随着胰岛素敏感性的丧失和 血压升高。亚硝酸盐还可以被口腔细菌进一步还原为无机氮化合物， 例如通过异化硝酸盐还原为氨(DNRA)途径的氨，这可以发挥重要的作用 口腔健康中的生物学作用；这些途径也可能影响全身NO的生物利用度。我们最近 圣胡安成年人超重纵向研究(SOALS)发表的研究报告显示，经常使用超重- 非处方含口水与三年内糖尿病前期/糖尿病风险的增加显著相关 随访，不受主要糖尿病危险因素的影响。口腔微生物组还没有被描述为 与硝酸盐还原能力的直接关系及其在NO生物利用度及相关口服和心脏代谢中的作用 健康结果。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)相关的概况。(2)纵向评价 与一氧化氮生物利用度相关的口腔微生物谱与高血压发病的关系 糖尿病前期/糖尿病、龋齿和牙周炎进展。(3)评估漱口水的影响 在这些微生物图谱上使用，系统没有生物利用度。此外，我们还将对协会进行评估 口腔微生物谱与口腔硝酸盐代谢的其他成分(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 将对细菌和途径进行评估。超过1,000名SOALS参与者拥有相关的高质量数据和 在基线和3年跟踪访问(保留79%)时提供样本，以实现及时的成本效益 学习。唾液和血液样本、口服和心脏代谢临床测量，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措施。我们将执行以下分析 唾液微生物组使用16S rRNA测序，我们将测量内源和 外源性NO代谢(血清和唾液中的亚硝酸盐和硝酸盐，硝酸还原酶和DNRA活性) 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，并帮助了解有关使用漱口水和心脏代谢的途径 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 调节口腔微生物群的新干预措施，这可能对预防和 控制口腔和心脏代谢性疾病。

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.