Nitrate metabolism and periodontal health: The roles of nitric oxide in microbial killing and immunoregulation.

Abstract

BACKGROUND 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-when produced via NO synthase (NOS) activity during chronic inflammation-can serve as biomarkers of periodontitis. AIM This narrative review aims to (1) examine the molecular mechanisms underlying the health benefits of NO, particularly those stimulated by nitrate-rich vegetable intake; and (2) explore how chronic inflammation can alter the local environment leading to nitrate and nitrite accumulation. MATERIALS AND METHODS A targeted literature search was conducted in PubMed and Google Scholar to identify articles related to NO, nitrate metabolism, inflammation, and/or periodontitis. RESULTS Under homeostatic conditions, NO can react with bacterial iron-sulfur 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-, decomposes into nitrate), contributing to their accumulation. Additionally, oxidative stress promotes NOS uncoupling, converting NOS from a NO-producing to a ROS-producing enzyme. Furthermore, periodontitis is associated with an impaired nitrate-reduction capacity of the oral microbiota, further decreasing NO levels. CLINICAL RELEVANCE Oxidative stress and reduced NO availability may drive periodontal dysbiosis and contribute to the systemic impact of periodontitis. These disease-related conditions could be mitigated through dietary interventions with nitrate-rich vegetables and adjunctive use of nitrate-reducing probiotics, which warrants further investigation.