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Cited by 37Oral microbiology and periodontitis researchNitric Oxide and Endothelin EffectsGut microbiota and health

Do Changes in Oral Microbiota Correlate With Plasma Nitrite Response? A Systematic Review

Open access
Zhurakivska, Khrystyna, Troiano, Giuseppe, Caponio, Vito Carlo Alberto, Dioguardi, Mario, Laino, Luigi, Maffione, Angela Bruna, Lo Muzio, Lorenzo·2019·Frontiers in Physiology
DOI 10.3389/fphys.2019.01029PMC PMC6700760
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Abstract

Background: Nitric Oxide (NO) has a role in immunitary defence, regulation of mucosal blood flow and mucus production, regulation of smooth muscle contraction, cerebral blood flow, glucose regulation and mitochondrial function. NO can be synthetized endogenously through the L-arginine-NO pathway or it can be absorbed by the human intestine through the dietary intake. Most of the ingested NO is in the form of nitrate (NO3-). NO3 - is a substrate of oral and intestinal microbiota and, at the end of the catabolic pathway, NO is released. Using antibacterial mouthwashes leads to an alteration of salivary NO3- metabolism, however, with unclear consequences on the circulating NO levels. The aim of this study is to perform a systematic review in order to elucidate if the alterations of oral microbiota lead to modifications in plasma NO content.Methods: Electronic databases were screened, using the following terms: (“oral bacteria” and (nitrate OR nitrite OR nitric)). Clinical studies reporting NO3- and NO2- measurements in blood and their correlation to oral microbiota variations were included. We focused on the correlation between the changes in oral microbiota and plasma concentrations of nitrites (primary outcome). Subsequently, we investigated if modifications in oral microbiota could lead to changes in blood pressure and salivary NO2- concentration (secondary outcome).Results: six studies, for a total of 82 participants were included in this review. In four studies, the use of mouthwash correlated to a reduction of plasma nitrite concentration (p<0.05);,Two studies did not find any difference in plasma nitrate or nitrite concentration. In five studies, a correlation between blood pressure (BP) changes and antibacterial mouthwashing emerged. Anyway, only three studies suggested a significant increase of systolic BP following mouthwashing compared with controls. Conclusions: Although, the role of oral bacteria has been unequivocally demonstrated in the regulation of salivary NO3- metabolism, their influence on plasma concentration of NO species remains ambiguous. Further studies with larger sample size are required in order to demonstrate if an alteration in oral microbiota composition may influence the blood content of NO3-/NO2-/NO and all the linked biological processes.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review examined whether changes in oral microbiota alter plasma nitric oxide species, focusing on plasma nitrite after antibacterial mouthwash use. Evidence was discordant: several studies found reduced plasma nitrite and increased blood pressure after mouthwashing, but others found no significant plasma nitrite change.

Key findings

  • Six studies with 82 participants were included; four studies found that mouthwash use significantly reduced plasma nitrite concentration (p < 0.05), while two found no significant difference in plasma nitrate or nitrite.
  • Salivary NO2− changes differed significantly between test and control groups in all six included mouthwash studies.
  • Blood pressure was evaluated in five studies; three reported significantly higher systolic blood pressure in mouthwash groups versus controls, one found no difference, and one found differences only during treadmill walking.
  • Three additional studies examined oral nitrate-reducing species; two found no correlation between NO3−-reducing species abundance and plasma NO2− changes, while one reported that NO3− supplementation increased Proteobacteria (+225%) and decreased Bacteroidetes (−46%; P < 0.05).

Methods

  • Systematic review following PRISMA guidelines, prospectively registered on PROSPERO (CRD42019124473).
  • PubMed, SCOPUS, and Web of Science were searched with [“oral bacteria” AND (nitrate OR nitrite OR nitric)]; inclusion required original clinical studies reporting NO3− and NO2− blood measurements correlated with oral microbiota variations.
  • From 200 records, 84 underwent title/abstract evaluation, 14 were full-text assessed, and 6 studies were included in the main qualitative analysis; 3 additional studies with different designs were presented separately. Primary outcome was correlation between oral microbiota changes and plasma nitrite concentrations; secondary outcomes were blood pressure and salivary NO2− changes.

Limitations

  • The authors state that heterogeneous experimental designs prevented a quantitative analysis and that different timing of fluid analysis could bias comparisons because nitrate metabolism changes rapidly over time.
  • The authors state that further RCTs with larger samples and well-defined designs are needed to establish whether oral microbiota alterations influence blood NO3−/NO2−/NO levels.
  • Evident from the text: the main analysis included only six studies and 82 participants, and all included mouthwash studies used chlorhexidine-containing mouthwashes, limiting generalizability to other antibacterial products.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fphys.2019.01029

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 54 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Two included studies found no significant difference in plasma nitrate or nitrite concentration between mouthwash and control.

    “Two studies did not find any difference in plasma nitrate or nitrite concentration.”
    • Also stated in: § Results · plain
      “Four studies (Govoni et al., 2008; Kapil et al., 2013; McDonagh et al., 2015; Woessner et al., 2016) detected a significant negative influence of mouthwashing on plasma nitrite concentration (p < 0.05), meanwhile other two studies (Bondonno et al., 2015; Sundqvist et al., 2016) found no significant alteration of plasma nitrate and nitrite, comparing mouthwash administration against placebo.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bondonno et al., 2015 source

      Not checked in the free run.

    • cites Sundqvist et al., 2016 source

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  • Findingcitation

    The experiments in Bondonno et al. (2015) were conducted in hypertensive men and women already in treatment with antihypertensive medication.

    “The experiments were conducted in hypertensive men and women already in treatment with antihypertensive medication.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bondonno et al., 2015 source

      Not checked in the free run.

  • Findingcitation

    In one included study, NO3− supplementation altered the salivary microbiome, increasing relative abundance of Proteobacteria (+225%) and decreasing Bacteroidetes (−46%; P < 0.05).

    “Furthermore, in one study emerged how NO3− supplementation influenced the salivary microbiome, leading to an increase in the relative abundance of Proteobacteria (+225%) and decrease of Bacteroidetes (−46%; P < 0.05; Vanhatalo et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vanhatalo et al., 2018 source

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  • Findingcitation

    In one included study, no difference in blood pressure between test and control group was reported.

    “One study did not report any difference between test and control group (Sundqvist et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sundqvist et al., 2016 source

      Not checked in the free run.

  • Findingown data

    In four included studies, use of mouthwash correlated with a reduction of plasma nitrite concentration (p < 0.05).

    “In four studies, the use of mouthwash correlated to a reduction of plasma nitrite concentration (p < 0.05);”
    • Also stated in: § Results · plain
      “Four studies (Govoni et al., 2008; Kapil et al., 2013; McDonagh et al., 2015; Woessner et al., 2016) detected a significant negative influence of mouthwashing on plasma nitrite concentration (p < 0.05), meanwhile other two studies (Bondonno et al., 2015; Sundqvist et al., 2016) found no significant alteration of plasma nitrate and nitrite, comparing mouthwash administration against placebo.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Govoni et al., 2008 source

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    • cites Kapil et al., 2013 source

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    • cites McDonagh et al., 2015 source

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  • Classified as probably not a substantial claim. 20
  • May combine two claims. 9

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    After first screening and duplicates removing, 84 records were chosen for title and abstract evaluation.

    “After the first screening and duplicates removing, 84 records were chosen for title and abstract evaluation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingreasoning

    Three additional studies with a different design were identified and deemed valid to be included in the review.

    “Other three studies with a different design were identified and deemed valid to be included in the present review (Burleigh et al., 2018; Vanhatalo et al., 2018; Liddle et al., 2019).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Burleigh et al., 2018 source

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    • cites Vanhatalo et al., 2018 source

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    • cites Liddle et al., 2019 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A total of 200 records were retrieved after application of the search strategy.

    “A total of 200 records were retrieved after the application of search strategy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Eight studies were excluded because they did not meet inclusion criteria.

    “Eight studies were excluded because did not meet inclusion criteria (Lundberg et al., 2004; Doel et al., 2005; Hyde et al., 2014; Clodfelter et al., 2015; Qu et al., 2016; Koch et al., 2017; Kapil et al., 2018; Preshaw, 2018).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Lundberg et al., 2004 source

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    • cites Doel et al., 2005 source

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    • cites Hyde et al., 2014 source

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  • May combine two claims.

    Findingown data

    Six studies, for a total of 82 participants, were included in this systematic review.

    “Six studies, for a total of 82 participants were included in this review.”
    • Also stated in: § Results · plain
      “At the end, six papers were included in the systematic review (Table 2; Govoni et al., 2008; Kapil et al., 2013; Bondonno et al., 2015; McDonagh et al., 2015; Sundqvist et al., 2016; Woessner et al., 2016).”
    • Also stated in: § Results · plain
      “A total of 82 participants were enrolled in the included studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    All mouthwashes used in the included studies contained chlorhexidine.

    “The types of mouthwashes used in the studies were different; nevertheless all of them contained chlorhexidine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Fourteen studies were selected for full text examination.

    “Fourteen studies, resulting after this step, were selected for full text examination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The designs of the included experiments were heterogeneous, so a quantitative analysis was not possible.

    “The designs of the experiments were heterogeneous among studies, so it was not possible to perform a quantitative analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    In two included studies, more than one mouthwash was tested, resulting in some differences in outcomes.

    “In two studies more than one mouthwash was tested (McDonagh et al., 2015; Woessner et al., 2016), resulting in some differences in the outcomes (Table 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites McDonagh et al., 2015 source

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    • cites Woessner et al., 2016 source

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  • May combine two claims.

    Findingcitation

    Effects of mouthwashes on blood pressure were the most analyzed among the clinical repercussions, given the strong effect of nitrate-rich food intake on blood pressure.

    “Among these, the effects of the mouthwashes on Blood Pressure were those more analyzed, given the strong effect that the intake of rich in nitrates food has on blood pressure (Ashworth and Bescos, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ashworth and Bescos, 2017

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  • May combine two claims.

    Findingcitation

    Govoni et al. (2008) found a marked attenuation after mouthwash but noted that a significant rise in plasma nitrite occurred.

    “Govoni et al. (2008), despite having found a marked attenuation after mouthwash, noted that a significant rise in plasma nitrite occurred.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Govoni et al., 2008 source

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  • May combine two claims.

    Findingcitation

    In Govoni et al. (2008), the rise in plasma nitrite occurred despite nitrite formation in the mouth being completely abolished by the intervention, excluding its salivary origin.

    “Interestingly, this occurred despite the fact that the nitrite formation in the mouth has been completely abolished by the intervention, excluding its salivary origin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Govoni et al., 2008 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Electronic databases PubMed, SCOPUS, and Web of Science were screened independently by two authors.

    “Electronic databases PubMed, SCOPUS, and Web of Science were screened independently by two authors, KZ and GT, in order to select studies suitable for inclusion in this review.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Studies eligibility was independently assessed in a joint session by two authors.

    “Studies eligibility was independently assessed in a joint session by two authors (KZ and GT).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The controversial result in Bondonno et al. (2015) could be linked to a bias in the kind of patients included.

    “This controversial result could be linked to a bias in the kind of the patients included.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The systematic review was prospectively registered on PROSPERO with registration number CRD42019124473.

    “In addition, it was prospectively registered on the online database PROSPERO (International prospective register of systematic reviews) with the registration number CRD42019124473.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The protocol for this systematic review followed PRISMA guidelines.

    “The protocol for this systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Liberati et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liberati et al., 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Alterations in oral microbiota could lead to variations in systemic availability of NO.

    “Subsequently, it was supposed that such alterations could also lead to variations in the systemic availability of NO (Govoni et al., 2008; Kapil et al., 2013; Woessner et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Govoni et al., 2008 source

      Not checked in the free run.

    • cites Kapil et al., 2013 source

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    • cites Woessner et al., 2016 source

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  • May combine two claims.

    Premisereasoning

    Salivary nitrate is metabolized to nitrite by oral commensal bacteria and can be further reduced to nitric oxide.

    “Salivary nitrate is metabolized to nitrite by oral commensal bacteria and it can be further reduced to nitric oxide (NO).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Most nitrate is excreted in urine, while up to 25% of plasma nitrate is taken up by the salivary glands and placed in the enterosalivary circulation.

    “Most of the nitrate is then excreted in the urine, while up to 25% of plasma nitrate is taken up by the salivary glands and placed in the enterosalivary circulation (Spiegelhalder et al., 1976).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Spiegelhalder et al., 1976 source

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  • May combine two claims.

    Premisecitation

    Numerous bacteria express nitrate reductase genes and are capable of reducing nitrate to nitrite in vitro.

    “Numerous bacteria express nitrate reductase genes and are capable to reduce nitrate to nitrite in vitro (Torres et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Torres et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The main dietary source of nitrate is vegetables.

    “The main dietary source of nitrate is represented by vegetables (Ysart et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ysart et al., 1999 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Plasma analysis may contribute to better understand NO blood availability because of changes in the oral microbiota.

    “Plasma analysis may contribute to better understand the NO blood availability because of changes in the oral microbiota.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Nitrate metabolism is subject to sudden changes in association with time.

    “since the nitrate metabolism is subject to sudden changes in association with time.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Changes in oral microbiota composition were assumed to affect final NO production.

    “Considering this physiological pathway, the oral microbiota gained a fundamental role; changes in its composition were assumed to affect the final NO production (Hyde et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hyde et al., 2014 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Antimicrobial mouthwashing could inhibit nitrite formation in saliva.

    “In particular, since the 1980s, it has been proposed that antimicrobial mouthwashing could inhibit the nitrite formation in saliva (Tannenbaum et al., 1976).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tannenbaum et al., 1976 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NO2− can be stored in blood and tissues and used when there is decreased endogenous production of NO.

    “NO2− can be stored in blood and tissues and used when there is a decreased endogenous production of NO (Bryan and Loscalzo, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bryan and Loscalzo, 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Endogenous nitrate mainly derives from the L-arginine-NO pathway.

    “Here, it mixes to the endogenous nitrate, which mainly derives from the L-arginine-NO pathway (Leaf et al., 1989).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Leaf et al., 1989 source

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28 of 28

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Mouthwashes are said to all contain chlorhexidine

    Minor

    The Results make this claim, but Table 2 identifies a tested mouthwash as non-chlorhexidine.

  • Blood-pressure association is claimed for all five evaluated studies

    Minor

    The abstract says an association emerged in five studies, whereas the Results explicitly say one of those studies reported no difference between groups.

2 of 2

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Authors
Zhurakivska, K., Troiano, G., Caponio, V. C. A., Dioguardi, M., Laino, L., Maffione, A. B., & Lo Muzio, L.
Affiliations
  • University of Foggia (IT)
  • University of Campania "Luigi Vanvitelli" (IT)
Corresponding author
Zhurakivska, Khrystyna
ORCID
Venue
Frontiers in Physiology
Publisher
Frontiers Media SA
Published
2019-08-13
Volume
10
Pages
1029-1029
ISSN
1664-042X (ISSN-L)
DOI
10.3389/fphys.2019.01029
PMC
PMC6700760
OpenAlex
W2965198565
Semantic Scholar
d4e697dfbc684dccd408f93639a559ee8566feab
Cited by
37
References
40
Citations by year
2026: 3 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 3 · 2021: 4 · 2020: 7
FWCI
0.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
Topics
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
oral microbiota, plasma nitrite, nitric oxide, nitrate, antibacterial mouthwash, blood pressure, oral bacteria, nitric oxide pathway

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