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

共生口腔细菌将外源性（饮食）和内源性硝酸盐转化为亚硝酸盐，亚硝酸盐转化为NO，这是一种调节血管张力、炎症和胰岛素敏感性的信号分子。我们最初的拨款旨在评估这种“肠-唾液途径”和相关微生物图谱在圣胡安超重成人纵向研究（SOALS）中1000多名参与者的心脏代谢健康中的作用，这些参与者在基线和3年随访（保留率为79%）时拥有相关的高质量数据和生物标本。内源性NO还在呼吸系统中发挥重要的生物学功能，如支气管扩张、肺血管扩张和细胞因子产生的调节，这可能与COVID-19的结局有关。此外，一氧化氮可以帮助预防COVID-19呼吸道感染，因为它参与睫状体运动，并且对COVID-19的病原体SARS-CoV-2具有抗病毒活性。漱口水最近被认为是减少口腔病毒载量的一种潜在策略，从而减少SARS-CoV-2的传播。然而，经常使用漱口水可能会严重破坏肠道-唾液硝酸盐途径中NO的产生，并且还可能干扰使用口腔或口咽样本的COVID-19诊断测试。目前尚不清楚通过肠道-唾液途径外源性产生的一氧化氮在多大程度上有助于呼吸健康和COVID-19，也不清楚漱口水的使用或口腔微生物组的其他调节剂如何影响这一点。在本次修订中，我们建议扩大家长资助的范围，以进一步评估这一途径以及漱口水使用这一关键可改变因素在COVID-19症状、诊断和结局中的作用。我们提出了三个新的具体目标：1)评估定期使用非处方漱口水（任何漱口水和少数特定品牌）与COVID-19症状、诊断和结局之间的关系；2)评估唾液中一氧化氮代谢物（硝酸盐和亚硝酸盐）与COVID-19症状、诊断和结局的关系；3)评估漱口水使用和一氧化氮代谢与全身炎症标志物（IL-6、TNF-a、CRP）和内皮功能（sICAM、VCAM）的关系，这可能影响COVID-19的进展。作为次要目的，我们还将评估唾液一氧化氮代谢物和口腔微生物组与慢性呼吸道疾病（哮喘和慢性阻塞性肺病）的关系。关于COVID-19和相关协变量的数据将通过电话中进行的两组访谈进行评估。这笔补充资金将父母资助的范围扩大到与COVID-19的传播、诊断和预后相关的高度相关和紧急的研究领域，并将评估其他呼吸道疾病。通过该项目获得的额外分析和见解将丰富家长补助金，预计将有很高的回报

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. Our original grant aims to evaluate the role of this “entero-salivary pathway” and the related microbial profiles in cardiometabolic health in over 1,000 participants from the San Juan Overweight Adults Longitudinal Study (SOALS) who have pertinent high quality data and biospecimens available at baseline and 3-year follow-up visits (with 79% retention). Endogenous NO also plays important biological functions in the respiratory system such as bronchodilation, vasodilation of the pulmonary blood vessels, and modulation of cytokine production, which could be relevant to COVID-19 outcomes. Furthermore, NO could help prevent COVID-19 infection of the airways because it is involved in ciliary movement and has a demonstrated antiviral activity against SARS-CoV-2, the causative agent of COVID-19. Mouthwash has been recently proposed as a potential strategy for reducing the oral viral load, thus reducing transmission of SARS-CoV-2. However, regular mouthwash use could significantly disrupt the NO production from the entero-salivary nitrate pathway, and it could also possibly interfere with COVID-19 diagnostic tests that use oral or oropharyngeal samples. It is not known to what extent the NO produced exogenously via the entero-salivary pathway contributes to respiratory health and in COVID-19, or how could this be influenced by mouthwash use or other modulators of the oral microbiome. In this revision, we propose to expand the scope of the parent grant to additionally evaluate the role of this pathway, and a key modifiable factor, mouthwash use, in COVID-19 symptoms, diagnosis and outcomes. We propose three new specific aims: 1)To evaluate the association between regular over-the-counter mouthwash use (any mouthwash and few specific brands) and COVID-19 symptoms, diagnosis and outcomes; 2)To evaluate the association of nitric oxide metabolites (nitrate and nitrite) in the saliva with COVID-19 symptoms, diagnosis and outcomes; 3) to evaluate the association of mouthwash use and nitric oxide metabolism with systemic markers of inflammation (IL-6, TNF-a, CRP) and endothelial function (sICAM, VCAM), which may impact COVID-19 progression. As a secondary aim we will also evaluate the association of the salivary nitric oxide metabolites and the oral microbiome with chronic respiratory disease (asthma and chronic obstructive pulmonary disease). Data on COVID-19 and pertinent covariates will be assessed through two sets of interviews conducted over the calls. This supplement expands the scope of the parent grant into a highly relevant and urgent research area pertinent to the transmission, diagnosis and prognosis of COVID-19, and will also evaluate other respiratory outcomes. The additional analyses and insight obtained through this project, will enrich the parent grant, and is expected to have a high