Oral Nitrate-Reducing Bacteria and Nitric Oxide Homeostasis: Functional Host-Microbe Interactions in Oral and...

Nitric oxide (NO) is a key regulator of vascular homeostasis and host-microbe interactions. In addition to the endogenous nitric oxide synthase (NOS) pathway, the enterosalivary nitrate-nitrite-NO pathway provides an alternative source of NO and critically depends on oral nitrate-reducing bacteria (ONRB). This review examines the oral microbiome-NO axis and its role in nitrate metabolism, NO homeostasis, and oral-systemic interactions. A narrative review integrating microbiological, mechanistic, and clinical evidence on oral nitrate metabolism, ONRB activity, and their impact on oral and systemic outcomes, including dietary and antiseptic interventions. The functional activity and nitrate-reducing capacity of the oral microbiome are key determinants of nitrate reduction and systemic NO bioavailability. Oral dysbiosis, periodontal disease, and antiseptic mouthwash use impair ONRB activity and nitrite production, potentially affecting vascular function and blood pressure. Conversely, dietary nitrate enhances ONRB activity and nitrate-to-nitrite conversion, supporting oral and vascular health. Interindividual variability, partly influenced by sex-related factors, may contribute to heterogeneous responses. The oral microbiome-NO axis represents a functional interface between host physiology and microbial metabolism, linking oral ecology with vascular regulation. Through their activity, ONRB contribute to NO homeostasis, highlighting nitrate bioactivation as an important component of host-microbe interactions with implications for oral and systemic physiology. Recognition of this pathway expands current understanding of host-microbe cooperation in NO homeostasis and may inform future microbiome-based approaches to support oral and cardiovascular health.