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Role of Dietary Nitrates in Modulating the Oral and Gut Microbiomes: Optimizing Nitric Oxide Production and Oral-Systemic Health

Adult Airway and Sleep Disorders Gut Health and Microbiome

 

By: Cathy Eason, MS, BCHN, Clinical Education Specialist at Berkeley Life, May 2025

Abstract

Nitric oxide (NO) is a critical signaling molecule involved in cardiovascular health, immune function, neurotransmission, metabolism, and cellular respiration1. While the endogenous L-arginine-NO synthase (NOS) pathway is extensively studied, the complementary nitrate-nitrite-NO reduction pathway has garnered increasing research attention due to its dependence on dietary nitrates and microbiome-mediated bioconversion2. This review explores the interactions between dietary nitrate intake, the oral and gut microbiomes, and their synergistic roles in NO homeostasis. We examine the mechanisms of microbial nitrate reduction, the influence of microbiota composition, and implications for cardiovascular, metabolic, and cognitive health.

Introduction

Nitric oxide (NO) is a short-lived, diatomic signaling molecule essential for multiple physiological processes1. Previously, most NO synthesis was attributed primarily to nitric oxide synthase (NOS) conversion of L-arginine to NO. However, recent research discoveries emphasize the importance of the enterosalivary nitrate-nitrite-NO pathway, particularly under hypoxic conditions where NOS activity is limited2.

Dietary nitrates, abundant in leafy greens and root vegetables (e.g., spinach, arugula, beetroot), serve as substrate for microbial nitrate reductase, especially in the oral cavity. The subsequent systemic absorption and reduction of nitrite to NO in blood and tissues are influenced by both oral and gut microbial communities. Therefore, the composition and functionality of these microbiomes are crucial in modulating nitrate metabolism and NO bioavailability2.

The Enterosalivary Nitrate-Nitrite-Nitric Oxide Pathway

  1. Ingestion/Assimilation: Dietary nitrate (NO₃⁻) ingestion from nitrate-rich foods allows “nitrate bathing” of nitrate-reducing oral microbes and initiates nitrate reductase activity in the oral cavity. Nitrate and nitrite (NO₂⁻) are absorbed in the upper gastrointestinal tract and circulate in plasma. With a serum half-life of approximately 8 hours (NO₃⁻) and 45 minutes (NO2--) respectively, replenishment with dietary nitrates is important to ensure optimal NO substrate reserves2. 
  2. Oral Reduction: NO₃⁻ is reduced to NO₂⁻ by exposure to nitrate-reducing bacteria in the oral cavity. There are over twenty known nitrate-reducing bacterial families within the oral microbiome, with the most prevalent nitrate-reducing genera being Rothia, Actinomyces, Propionibacterium, Streptococcus, Prevotella, Neisseria, Granulicatella, and Corynebacterium3. 
  3. Swallowing and Systemic Reduction: Dietary NO₃⁻ and reduced NO₂⁻ is swallowed, absorbed, and further reduced to NO in acidic environments (e.g., stomach) or via enzymatic reduction in tissues3.
  4. Salivary Concentration: About 25% of plasma NO₃⁻ is taken up via sialin protein transport into acinar cells of the salivary glands and concentrated in saliva4. Continual saliva output ensures ongoing nitrate-bathing of the oral microbiome, crucial to NO₃⁻/ NO₂⁻ recycling through the enterosalivary pathway. 
  5. Excess Nitrate Excretion: An estimated 60% of circulating nitrates/nitrites are filtered through the kidneys and excreted via urine4. 

Significance of Microbial Nitrate Conversion

Human cells lack nitrate reductase enzymes; thus, bacteria play a pivotal role in initiating this reduction pathway via nitrate reductase activity. Disruption in the balance and diversity of microbial populations can impair nitrate metabolism and reduce systemic NO levels5.

Oral Microbiome and Nitrate Reduction: Key Nitrate-Reducing Bacteria

Prominent oral genera involved in nitrate reduction include Neisseria, Rothia, Actinomyces, Veillonella and Haemophilus. These microbes inhabit the posterior dorsal surface of the tongue and utilize nitrate as a terminal electron acceptor under anaerobic conditions6.

Impact of Oral Hygiene and Antimicrobials

Mouthwashes containing antiseptics (e.g., chlorhexidine) can indiscriminately kill oral bacteria, including beneficial nitrate reducers. Studies show that habitual use of such products can decrease salivary and plasma nitrite levels, impairing blood pressure regulation and increasing cardiovascular risk markers7. Maintaining a balanced and diversified oral microbiome is thus essential for optimal NO production.

Gut Microbiome and Nitrate Metabolism: Nitrate-Reducing Gut Bacteria

Though less efficient than oral bacteria, multiple gut microbes can reduce nitrate and nitrite, particularly in the colon, including Escherichia coli, Clostridium spp., and Bacteroides spp. These bacteria contribute to NO production under anaerobic conditions and modulate local vascular tone and immune responses8.

Crosstalk with the Oral Microbiome

Emerging evidence suggests that oral nitrate-reducing bacteria can be swallowed and influence the gut microbiome composition. Conversely, diet-induced changes in the gut microbiome can affect systemic inflammation and nitrate metabolism indirectly9.

Influence of Diet and Fiber

Dietary fibers can promote the growth of beneficial gut microbes that facilitate nitrate metabolism, indirectly enhancing NO production. Prebiotic-rich foods and polyphenols also modulate the gut microbiome in ways that support vascular and metabolic health10.

Disruption of the Nitrate-Microbiome-NO Axis

  • Dysbiosis - Dysbiosis in either the oral or gut microbiome—due to poor diet, antibiotic use, or oral hygiene products—can impair nitrate metabolism and reduce NO availability, with consequences for vascular and metabolic health2,7
  • Aging and Comorbidities - Aging is associated with reduced abundance of nitrate-reducing bacteria and impaired salivary nitrate circulation. Chronic diseases (e.g., diabetes, hypertension) further exacerbate this decline, making dietary nitrate strategies increasingly relevant11.

Health Implications of Nitrate-Microbiome-NO Axis

  • Cardiovascular Health - Dietary nitrate supplementation can lower blood pressure via enhanced NO bioavailability12. Improved endothelial function measured by flow-mediated dilation and reduced arterial stiffness are linked to nitrate intake12.
  • Metabolic Effects - Nitrate-induced NO production improves insulin sensitivity and glucose uptake13. Microbiome-mediated nitrate metabolism may reduce inflammation and oxidative stress, supporting metabolic resilience14.
  • Cognitive and Neurovascular Function - NO facilitates cerebral blood flow and neurovascular coupling. High-nitrate diets have been associated with improved cognitive performance, potentially mediated by oral microbiota15.

Optimizing Nitrate Intake and Microbiome Health

Dietary Strategies

  • Consume nitrate-rich vegetables daily: beetroot, spinach, celery, lettuce, and arugula16.
  • Include prebiotics (inulin, oligosaccharides, nitrates) to support gut microbial diversity16.
  • Consider daily supplementation with dietary nitrates and antioxidant nutrients to ensure sustainable levels of serum substrate for optimal NO production12.

Probiotic Interventions

Emerging probiotics targeting nitrate-reducing bacteria (e.g., Rothia, Neisseria) are under investigation. Such targeted interventions may restore the nitrate-reducing capacity of the oral microbiome in aging or disease17.

Conclusion

The interplay between dietary nitrates and the microbiome—especially in the oral cavity and gastrointestinal tract—is crucial for maintaining optimal nitric oxide production. This nitrate-microbiome-NO axis supports cardiovascular, metabolic, and cognitive health in addition to other systemic benefits. Future research should focus on identifying microbial signatures of efficient nitrate metabolism and developing personalized nutrition and microbiome-targeted therapies to enhance NO bioavailability. 

References

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