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Cited by 19Gut microbiota and healthOral microbiology and periodontitis researchNitric Oxide and Endothelin Effects

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Role of oral and gut microbiomes in enterosalivary nitrate metabolism and their effects on systemic disease

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Yang, Zi, Du, Conglin, Chang, Zhichao, Yang, Yang, Hu, Liang·2025·Frontiers in Cellular and Infection Microbiology
DOI 10.3389/fcimb.2025.1612223PMC PMC12267184
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Abstract

Nitrate, which maintains hemostasis in systemic circulation, is obtained from nitrate-rich vegetables, concentrated, reabsorbed by the salivary glands, and reduced to nitrite and nitric oxide (NO•). The bioavailability of nitrate and nitrite depends on unique nitrate reductases present in specific bacterial communities in the mouth and gut of mammals. The dominant bacteria in the oral cavity, stomach, and gut differ among internal environments. Nitrate can modulate microbiota metabolism and has important pathophysiological functions in diseases such as cardiovascular diseases, gastrointestinal diseases, diabetes, metabolic diseases, and brain diseases via nitrate-reducing bacteria. Thus, in this review, we summarized the beneficial role of enterosalivary nitrate metabolism, focusing on the role of oral and gut bacterial communities in the enzymatic reduction of nitrate to nitrite. We have also discussed different nitrate-reduction pathways; influencing factors of nitrate-reducing bacteria; and the relationship among systemic health, nitrate intake, and bacteria. This review of enterosalivary nitrate and related microbiomes could provide a new perspective for the application of nitrate.

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Crossref · 10.3389/fcimb.2025.1612223

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Figures

Figure 1 Entero-salivary nitrate circulation (Created with BioRender.com). ① Exogenous nitrate is obtained via dietary intake. ② Dietary nitrate enters the stomach and gut. ③ Dietary nitrate is absorbed through the small intestinal tract to blood. ④ The plasma nitrate (70%–75%) is excreted in the urine. ⑤ Circulating nitrate is actively taken up by the salivary glands via sialin. ⑥ Nitrates flow into the mouth through saliva. ⑦ Salivary nitrate is reduced to nitrite by special commensal bacteria in the mouth. ⑧ Salivary nitrate and nitrite enter the stomach. ⑨ Salivary nitrate and nitrite enter the gut and nitrate is reduced to nitrite by gut bacteria. ⑩ Nitrite is absorbed into blood and nitrite is reduced to NO in the blood. Methemoglobin (metHb) reacts with nitrite to form a radical NO2-bound ferrohaem, which reacts rapidly with NO• to generate N2O3, responsible for S-nitrosothiol (RSNO) formation.
Figure 1 Entero-salivary nitrate circulation (Created with BioRender.com). ① Exogenous nitrate is obtained via dietary intake. ② Dietary nitrate enters the stomach and gut. ③ Dietary nitrate is absorbed through the small intestinal tract to blood. ④ The plasma nitrate (70%–75%) is excreted in the urine. ⑤ Circulating nitrate is actively taken up by the salivary glands via sialin. ⑥ Nitrates flow into the mouth through saliva. ⑦ Salivary nitrate is reduced to nitrite by special commensal bacteria in the mouth. ⑧ Salivary nitrate and nitrite enter the stomach. ⑨ Salivary nitrate and nitrite enter the gut and nitrate is reduced to nitrite by gut bacteria. ⑩ Nitrite is absorbed into blood and nitrite is reduced to NO in the blood. Methemoglobin (metHb) reacts with nitrite to form a radical NO2-bound ferrohaem, which reacts rapidly with NO• to generate N2O3, responsible for S-nitrosothiol (RSNO) formation.CC BY · PubMed Central
Figure 2 Three major bacterial nitrate reduction pathways (Adapted from Koch et al (Koch et al., 2017). and Goh et al (Goh et al., 2022), and created with BioRender.com). Bacterial nitrate reduction pathways, including assimilatory nitrate reduction, dissimilatory nitrate reduction to ammonium (DNRA), and respiratory denitrification pathways. Nas, cytoplasmic assimilatory reductases; Nar, cytoplasmic nitrate reductase; Nap, periplasmic nitrate reductase; NNP, nitrate/nitrite transporter; Nir, nitrite reductase; Nor, nitric oxide reductase; Nrf, ammonia-producing nitrite reductase, Nos, nitrous oxide reductase; Nif, nitrogenase; glu, glutamine; N2O, nitrous oxide; N2, dinitrogen; NH3, ammonia; NH4 +, ammonium; NO2, nitrite; NO3, nitrate; NO, nitric oxide.
Figure 2 Three major bacterial nitrate reduction pathways (Adapted from Koch et al (Koch et al., 2017). and Goh et al (Goh et al., 2022), and created with BioRender.com). Bacterial nitrate reduction pathways, including assimilatory nitrate reduction, dissimilatory nitrate reduction to ammonium (DNRA), and respiratory denitrification pathways. Nas, cytoplasmic assimilatory reductases; Nar, cytoplasmic nitrate reductase; Nap, periplasmic nitrate reductase; NNP, nitrate/nitrite transporter; Nir, nitrite reductase; Nor, nitric oxide reductase; Nrf, ammonia-producing nitrite reductase, Nos, nitrous oxide reductase; Nif, nitrogenase; glu, glutamine; N2O, nitrous oxide; N2, dinitrogen; NH3, ammonia; NH4 +, ammonium; NO2, nitrite; NO3, nitrate; NO, nitric oxide.CC BY · PubMed Central
Figure 3 The respiratory denitrification pathway (Created with BioRender.com). Respiratory denitrification comprises a four-step reductive process in which nitrate is reduced to nitrite catalyzed by Nar, nitrite is further reduced to NO• by nitrite reductase, and then NO• is converted to N2O and N2. Nar, cytoplasmic nitrate reductase (including narG, narH, and narI); Nir, nitrite reductase (including nirC, nirF, nirK, nirM, nirN, nirS); Nor, nitric oxide reductase (including norB and norC); Nos, nitrous oxide reductase (including nosL, nosR, nosZ); Cyto C, cytochrome c; UQ, ubiquinone; UQH2, ubiquinol; MQ, menaquinone; MQH2, menaquinol; N2O, nitrous oxide; N2, dinitrogen; NH3, ammonia; NO2, nitrite; NO3, nitrate; NO, nitric oxide.
Figure 3 The respiratory denitrification pathway (Created with BioRender.com). Respiratory denitrification comprises a four-step reductive process in which nitrate is reduced to nitrite catalyzed by Nar, nitrite is further reduced to NO• by nitrite reductase, and then NO• is converted to N2O and N2. Nar, cytoplasmic nitrate reductase (including narG, narH, and narI); Nir, nitrite reductase (including nirC, nirF, nirK, nirM, nirN, nirS); Nor, nitric oxide reductase (including norB and norC); Nos, nitrous oxide reductase (including nosL, nosR, nosZ); Cyto C, cytochrome c; UQ, ubiquinone; UQH2, ubiquinol; MQ, menaquinone; MQH2, menaquinol; N2O, nitrous oxide; N2, dinitrogen; NH3, ammonia; NO2, nitrite; NO3, nitrate; NO, nitric oxide.CC BY · PubMed Central
Figure 4 The DNRA pathway (Created with BioRender.com). Dissimilatory nitrate reduction to ammonia (DNRA) is a two-step process in which nitrate is reduced by Nap in the periplasm, converted to ammonia via an Nrf, and excreted. Nap, periplasmic nitrate reductase (including napA, napB, napC, napG and napH); Nrf, ammonia-producing nitrite reductase (including nrfA, nrfB, nrfC, nrfD), UQ, ubiquinone; UQH2, ubiquinol; MQ, menaquinone; MQH2, menaquinol; NH4 +, ammonium; NO2, nitrite; NO3, nitrate; NO, nitric oxide.
Figure 4 The DNRA pathway (Created with BioRender.com). Dissimilatory nitrate reduction to ammonia (DNRA) is a two-step process in which nitrate is reduced by Nap in the periplasm, converted to ammonia via an Nrf, and excreted. Nap, periplasmic nitrate reductase (including napA, napB, napC, napG and napH); Nrf, ammonia-producing nitrite reductase (including nrfA, nrfB, nrfC, nrfD), UQ, ubiquinone; UQH2, ubiquinol; MQ, menaquinone; MQH2, menaquinol; NH4 +, ammonium; NO2, nitrite; NO3, nitrate; NO, nitric oxide.CC BY · PubMed Central
Figure 5 Site-specific core bacterial genera composition in oral cavity (Created with BioRender.com). Representative genera across different locations in oral cavity. Genera with nitrate-reducing ability (brown). pO2, oxygen partial pressure.
Figure 5 Site-specific core bacterial genera composition in oral cavity (Created with BioRender.com). Representative genera across different locations in oral cavity. Genera with nitrate-reducing ability (brown). pO2, oxygen partial pressure.CC BY · PubMed Central

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Metadata

Authors
Yang, Z., Du, C., Chang, Z., Yang, Y., & Hu, L.
Affiliations
Capital Medical University (CN)
Corresponding author
Hu, Liang
ORCID
Venue
Frontiers in Cellular and Infection Microbiology
Publisher
Frontiers Media SA
Published
2025-07-03
Volume
15
Pages
1612223-1612223
ISSN
2235-2988 (ISSN-L)
DOI
10.3389/fcimb.2025.1612223
PMC
PMC12267184
OpenAlex
W4411963008
Semantic Scholar
d88f2ed1d64bf5192a148b9d5adfbad63bb4876f
Cited by
19
References
211
Citations by year
2026: 16 · 2025: 3
FWCI
1.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82001065, QML20211502)
  • Capital Medical University (YSP202204)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords
nitrate metabolism, oral microbiota, gut microbiota, nitrate-reducing bacteria, nitrite, nitric oxide, nitrate reductase, nitrate consumption, cardiovascular disease, gastrointestinal diseases, diabetes mellitus, metabolic disorders, brain disorders
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteria, Humans, Mouth, Nitrates, Nitric Oxide, Nitrites

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