Nitrite Generating and Depleting Capacity of the Oral Microbiome and Cardiometabolic Risk: Results from ORIGINS

Charlene E. Goh, Bruno Bohn, Clarisse Marotz, Rebecca L Molinsky, Sumith Roy, Bruce J. Paster, Ching Yuan Chen, Michael Rosenbaum, Melana Yuzefpolskaya, Paolo C. Colombo, Moïse Desvarieux, Panos N. Papapanou, David Jacobs, Rob Knight, Ryan T. Demmer

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


BACKGROUND: The enterosalivary nitrate– nitrite– nitric oxide (NO3 – NO2 – NO) pathway generates NO following oral microbiota-mediated production of salivary nitrite, potentially linking the oral microbiota to reduced cardiometabolic risk. Nitrite depletion by oral bacteria may also be important for determining the net nitrite available systemically. We examine if higher abundance of oral microbial genes favoring increased oral nitrite generation and decreased nitrite depletion is associated with a better cardiometabolic profile cross-sectionally. METHODS AND RESULTS: This study includes 764 adults (mean [SD] age 32 [9] years, 71% women) enrolled in ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study). Microbial DNA from subgingival dental plaques underwent 16S rRNA gene sequencing; PICRUSt2 was used to estimate functional gene profiles. To represent the different components and pathways of nitrogen metabolism in bacteria, predicted gene abundances were operationalized to create summary scores by (1) bacterial nitrogen metabolic pathway or (2) biochemical product (NO2, NO, or ammonia [NH3 ]) formed by the action of the bacterial reductases encoded. Finally, nitrite generation-to-depletion ratios of gene abundances were created from the above summary scores. A composite cardiometabolic Z score was created from cardiometabolic risk variables, with higher scores associated with worse cardiometabolic health. We performed multivariable linear regression analysis with cardiometabolic Z score as the outcome and the gene abundance summary scores and ratios as predictor variables, adjusting for sex, age, race, and ethnicity in the simple adjusted model. A 1 SD higher NO versus NH3 summary ratio was inversely associated with a −0.10 (false discovery rate q=0.003) lower composite cardiometabolic Z score in simple adjusted models. Higher NH3 summary score (suggestive of nitrite depletion) was associated with higher cardiometabolic risk, with a 0.06 (false discovery rate q=0.04) higher composite cardiometabolic Z score. CONCLUSIONS: Increased net capacity for nitrite generation versus depletion by oral bacteria, assessed through a metagenome estimation approach, is associated with lower levels of cardiometabolic risk.

Original languageEnglish (US)
Article numbere023038
JournalJournal of the American Heart Association
Issue number10
StatePublished - May 17 2022

Bibliographical note

Funding Information:
This research was supported by National Institutes of Health (grants R00 DE018739, R21 DE022422, and R01 DK102932) to Dr Demmer. This publication was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health through grant number UL1TR001873. R. Molinsky was supported by institutional training grant number T32HL007779 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.


  • 16S rNA sequencing
  • blood pressure
  • epidemiology
  • insulin resistance
  • metagenomics
  • nitric oxide
  • oral microbiome

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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