Microbiome nitrate reductase (NR) (NR)

Microbiome nitrate reductase refers to the enzymatic system found in commensal bacteria, primarily within the oral cavity, that facilitates the reduction of inorganic nitrate to nitrite. This process is the rate-limiting step of the enterosalivary nitrate-nitrite-nitric oxide (NO) pathway, which serves as a critical alternative to the endogenous L-arginine-NOS pathway for NO generation [1, 2]. By producing NO, this pathway regulates essential physiological functions including vascular tone, blood pressure, and mitochondrial respiration [3]. It is particularly significant in conditions of hypoxia or endothelial dysfunction where classical NO synthesis is compromised [1]. Therapeutic strategies focus on supplementing inorganic nitrate to enhance this pathway for treating hypertension and heart failure [3, 5]. However, the pathway's efficacy is highly dependent on the composition of the oral microbiome and can be significantly impaired by the use of antibacterial mouthwashes [2, 4].

Other names

Nitrate-nitrite-nitric oxide pathwayEnterosalivary nitrate-nitrite-NO pathwayBacterial nitrate reductaseOral microbiome nitrate reductase

The pathway begins with the ingestion of inorganic nitrate, which is absorbed in the small intestine and concentrated in the salivary glands. Commensal oral bacteria, such as Veillonella and Prevotella species, utilize microbiome nitrate reductase enzymes to reduce salivary nitrate into nitrite [1, 2]. Upon swallowing, this nitrite is converted to nitric oxide (NO) in the acidic environment of the stomach or enters the systemic circulation, where it is reduced to NO by various proteins like deoxyhemoglobin and myoglobin, especially under hypoxic conditions [1, 4]. This backup pathway for NO production bypasses the oxygen-dependent L-arginine-NOS pathway, providing a therapeutic mechanism to restore NO bioavailability in cardiovascular diseases [3, 5].