{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:03:33Z","timestamp":1791846213892,"version":"4.3.4"},"reference-count":207,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100018526","name":"Cambridge Isotope Laboratories","doi-asserted-by":"publisher","award":["1ZIABC009283\u201036"],"award-info":[{"award-number":["1ZIABC009283\u201036"]}],"id":[{"id":"10.13039\/100018526","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Periodontology 2000"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Dietary nitrate, primarily sourced from vegetables, is reduced by oral bacteria to nitrite and subsequently to nitric oxide (NO), a molecule with antimicrobial and immunoregulatory properties, as well as vasodilatory and other cardiometabolic effects. Studies have shown that nitrate supplementation can lower blood pressure, reduce gingival inflammation, and lead to a shift toward microbial eubiosis in the periodontium. However, a paradox arises: nitrate and nitrite\u2014when produced via NO synthase (NOS) activity during chronic inflammation\u2014can serve as biomarkers of periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>This narrative review aims to (1) examine the molecular mechanisms underlying the health benefits of NO, particularly those stimulated by nitrate\u2010rich vegetable intake; and (2) explore how chronic inflammation can alter the local environment leading to nitrate and nitrite accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>A targeted literature search was conducted in PubMed and Google Scholar to identify articles related to NO, nitrate metabolism, inflammation, and\/or periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Under homeostatic conditions, NO can react with bacterial iron\u2013sulfur clusters, promoting the elimination of sensitive species, and with host soluble guanylyl cyclase (sGC), activating cGMP signaling pathways that suppress inflammation. In contrast, the inflammatory milieu of periodontitis is characterized by elevated levels of reactive oxygen species (ROS) and free heme, both of which act as NO scavengers, thereby diminishing its bioavailability. Importantly, the reaction of NO with ROS generates various reactive nitrogen species (RNS), which differ functionally from NO. These RNS can be converted into nitrate and\/or nitrite (e.g., peroxynitrite, ONOO<jats:sup>\u2212<\/jats:sup>, decomposes into nitrate), contributing to their accumulation. Additionally, oxidative stress promotes NOS uncoupling, converting NOS from a NO\u2010producing to a ROS\u2010producing enzyme. Furthermore, periodontitis is associated with an impaired nitrate\u2010reduction capacity of the oral microbiota, further decreasing NO levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Relevance<\/jats:title><jats:p>Oxidative stress and reduced NO availability may drive periodontal dysbiosis and contribute to the systemic impact of periodontitis. These disease\u2010related conditions could be mitigated through dietary interventions with nitrate\u2010rich vegetables and adjunctive use of nitrate\u2010reducing probiotics, which warrants further investigation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/prd.70006","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T04:31:12Z","timestamp":1760675472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Nitrate metabolism and periodontal health: The roles of nitric oxide in microbial killing and immunoregulation"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-6561","authenticated-orcid":false,"given":"Bob T.","family":"Rosier","sequence":"first","affiliation":[{"name":"Department of Genomics and Health FISABIO Foundation  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7392-8852","authenticated-orcid":false,"given":"George","family":"Hajishengallis","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Wink","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research National Cancer Institute, National Institutes of Health  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9127-3877","authenticated-orcid":false,"given":"Alex","family":"Mira","sequence":"additional","affiliation":[{"name":"Department of Genomics and Health FISABIO Foundation  Valencia Spain"},{"name":"CIBER Center for Epidemiology and Public Health  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1093\/database\/baq013","article-title":"The human oral microbiome database: a web accessible resource for investigating oral microbe taxonomic and genomic information","volume":"2010","author":"Chen T","year":"2010","journal-title":"Database"},{"key":"e_1_2_10_3_1","unstructured":"HOMD\u2010contributors.Expanded human oral microbiome database V3.1 (eHOMDB).2024https:\/\/www.homd.org\/"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1099\/mic.0.26082-0","article-title":"Are dental diseases examples of ecological catastrophes?","volume":"149","author":"Marsh PD","year":"2003","journal-title":"Microbiology"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/prd.12371","article-title":"Polymicrobial communities in periodontal disease: their quasi\u2010organismal nature and dialogue with the host","volume":"86","author":"Hajishengallis G","year":"2021","journal-title":"Periodontol 2000"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1902\/jop.1965.36.3.177","article-title":"Experimental gingivitis in man","volume":"36","author":"Loe H","year":"1965","journal-title":"J Periodontol"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0765.1966.tb01842.x","article-title":"Experimental gingivitis in man. 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