Oral Microbiome, Nitric oxide Metabolism, and Oral and 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. 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