PLMI Blog

A growing body of evidence reveals that dysbiosis of the oral microbiome impedes systemic health, in part by reducing nitric oxide (NO) production. NO, a key gaseous signaling molecule, has been well demonstrated to be involved in a host of regulatory physiological functions in the body (1).

Beneficial microbiota in both the oral cavity and gut can produce NO. Dysbiosis, or imbalance in both of these ecosystems, therefore, can greatly impede NO production, manifesting in a host of symptoms impacting health and well-being.

The connection between oral dysbiosis and low NO synthesis involves a number of interrelated processes.

CONNECTIONS – ORAL DYSBIOSIS & REDUCED NO

Systemic Inflammation

Alterations in the collective microbiome have been well evidenced to contribute to a number of chronic health conditions, as imbalances negatively affect systemic health. Levels of NO production are mediated by healthy microbiome composition. Sufficient NO is crucial in regulating integral processes of the body related to systemic balance, including vascular, metabolic, immune, and gut barrier integrity functions.

Oral dysbiosis and low nitric oxide production have been shown to induce systemic inflammation, as these regulatory processes are impeded. Dysbiosis in the oral cavity and gut are intricately related and bidirectional. Inflammatory mediators and pathogens can translocate from the oral cavity to the gut, and vice versa, further perpetuating microbiota imbalances, altering functions and reducing NO production (1, 2).

Microbiome Overlap

Recent research highlights a significant relationship between dysbiosis of the oral cavity and the gut. A report published in The Journal of Genome Biology revealed a 45% overlap between the microbiota in the oral cavity and the gastrointestinal (GI) tract (3).

A healthy microbiome is governed by microbiota diversity, metabolites and the immune system, in addition to NO synthesis (1). Oral dysbiosis arises when the balance of the oral microbiome is altered, allowing harmful bacteria to proliferate, increasing this risk of chronic disease.

Disruptions in oral microbiota can reduce NO production, which is essential for maintaining healthy gut function, in addition to systemic health. Conditions such as periodontal disease are associated with GI issues, underscoring the interconnected nature of these microbiomes. Dysbiosis in the oral cavity and gut has been implicated to induce endotoxemia, or elevated levels of lipopolysaccharides (LPS), by altering gut permeability, microbiota balance, and inflammation in the system.

Oral Microbiome & NO Pathway

Oral dysbiosis can contribute to low NO production. The presence of pathogenic bacteria in the mouth results in inflammation while reducing the availability of NO. Conversely, low NO levels can affect oral health, further compounding dysbiosis.

A healthy oral microbiome helps convert dietary nitrate (NO3-) into nitrite (NO2-), which is then used to produce NO. In a balanced oral microbiome, beneficial bacteria, such as Nitrospira and Veillonella, facilitate this conversion (4).

Disruptions in the oral microbiome, characterized by an imbalance between harmful and beneficial bacteria, affect this nitrate-nitrite-nitric oxide pathway, leading to decreased nitrite levels and impaired nitric oxide synthesis (5, 6).

Oral dysbiosis and low NO production can show up in a multitude of signs and symptoms, underscoring their impact on overall health. 

ORAL DYSBIOSIS SIGNS & SYMPTOMS

Oral dysbiosis can manifest through various signs and symptoms, as the ratio of the microbiome is altered, impeding overall systemic balance.

Gingival Inflammation and Gum Disease – Increased levels of pathogenic bacteria can result in gingivitis and periodontitis, characterized by swollen and bleeding gums. Studies have shown that oral dysbiosis is strongly associated with these conditions due to the overgrowth of bacteria such as Porphyromonas gingivalis (7). An imbalance in the oral microbiome, with an overgrowth of pathogenic bacteria, has been found to contribute to these oral health conditions (8).

Halitosis – Dysbiosis often results in the production of volatile sulfur compounds by harmful bacteria, leading to persistent bad breath (halitosis). Research indicates that an imbalance in the oral microbiota can impede the balance of bacteria responsible for modulating these compounds (9). Bacteria associated with halitosis include Porphyromonas, Fusobacterium, and Prevotella.

Canker Sores & Dry Mouth – Frequent canker sores or oral ulcers have been associated with an imbalanced oral and gut microbiome. Alterations in oral bacteria can affect saliva production, leading to dry mouth (xerostomia), increasing the risk of further oral issues.

Cavities & Plaque Formation – Imbalances in the oral microbiome can contribute to increased plaque formation and tooth decay. Cavity causing bacteria, such as Streptococcus mutans, Veillonella, and Actinomyces can increase when beneficial bacteria are reduced, contributing to compromised oral health. Periodontal disease has interestingly been shown to also be altered by bacteria associated with halitosis (8, 10).

Altered Taste Perception – Imbalances in the oral microbiome can affect taste sensation by influencing taste bud function and saliva production, as evidenced by recent findings (11).

Impeded Cardiovascular & Metabolic Health – Disruptions in the oral microbiome have been linked to compromised cardiovascular and metabolic health, including systemic health conditions such as obesity, diabetes, atherosclerosis, and cardiovascular disease (8). This connection is suggested to be mediated by the nitrate-nitrite-nitric oxide pathway, where oral and gut bacteria convert nitrate to nitrite, and further reduce it to form bioactive NO (12).

LOW NO LEVELS – SIGNS & SYMPTOMS

Low nitric oxide levels can also have a range of systemic effects on the body, presenting with a number of signs and symptoms.

Hypertension & Compromised Vascular Function – Nitric oxide plays a crucial role in regulating blood vessel dilation. Reduced NO levels can lead to increased vascular resistance, elevated blood pressure, increased risk of heart disease, and overall impeded cardiovascular health, as evidenced by clinical studies (13-14).

Poor Metabolic & Gut Health  – Impeded metabolic health and associated conditions such as obesity, insulin resistance, and metabolic syndrome have been associated with reduced NO levels (15-16). Reduced NO production can also affect gut motility and contribute to digestive issues, including microbiome imbalances, bloating, intestinal permeability, constipation, and GI discomfort (17). This is because sufficient NO levels have integral roles in protecting and maintaining GI health.

Reduced Exercise Tolerance – NO is involved in improving blood flow and oxygen delivery to muscles during physical activity. Low NO levels, therefore, can result in decreased exercise performance and endurance, as demonstrated by research linking NO deficiency to reduced exercise capacity and fatigue.

Impacted Brain Function – Nitric oxide is important for brain health, including memory and cognitive function. Research indicates that low NO levels can contribute to cognitive decline and neurodegenerative conditions by affecting neuronal signaling and brain blood flow, and inducing inflammation (18). Emerging findings also demonstrate a connection between reduced NO and compromised mental health via these processes and hormonal signaling (19).

Sexual Dysfunction & Aging – Low NO levels are associated with erectile dysfunction due to impaired blood flow, and its role as a neuromodulator (20). This can impede libido and sexual function. Reduced NO levels have also been associated with aging, as NO exerts antioxidant, cellular adaptation, and anti-inflammatory properties (21). Adequate levels of NO improve oxygen utilization, mitochondrial function, and efficacy.

Impaired Immune Function – Nitric oxide is involved in immune responses and tissue repair, therefore reduced or insufficient levels of NO can impair the body’s ability to fight off infections, modulate inflammation, and impede the process of wound healing (22).

SUPPORTING THE ORAL MICROBIOME & NO PRODUCTION

The oral microbiome is a pivotal and dynamic component of health and chronic disease. It responds to both internal and external factors – including stress, diet, and lifestyle. The composition of this microbiome has important implications for overall health, including its vital role in modulating NO production, affecting various integral physiological processes that regulate our health. Understanding these connections underscores the importance of microbial balance in both oral and gut ecosystems for modulating systemic and overall health (15-16).

Maintaining oral hygiene is crucial for preventing dysbiosis. Regular brushing, flossing, and oil pulling can help in reducing harmful bacteria build up. It is also important to be mindful of mouthwash. A 2024 systematic review published in The Journal of Oral Microbiology found that mouthwash containing chlorhexidine is associated with an increase in blood pressure and dysbiosis of the natural microbiome, and may even induce antimicrobial resistance (23).

A balanced, nutrient dense diet rich in vegetables, prebiotics, and probiotics supports a healthy oral microbiome, while limiting sugar and processed foods helps prevent dysbiosis. Studies show that consuming sources of dietary nitrate (such as beetroot and spinach) influences the oral microbiome’s production of nitrite, and also suggest that targeting the oral microbiota could help in addressing low nitric oxide (NO) levels.

Research shows that this can boost the levels of beneficial bacteria linked to good oral health while decreasing harmful bacteria associated with oral health conditions. In contrast, an imbalance from factors such as inadequate or misinformed oral hygiene practices, a diet rich in sugars and refined carbohydrates, toxicants, stress, and chlorhexidine mouthwashes can disrupt the natural microbial balance (24).

Nasal breathing, exercise, sufficient sleep, sunlight exposure, and mitigating stress also promote healthy NO levels while supporting microbiome balance (25).

Significance of Balance for Maintaining Health

The quality and composition of the oral and gut microbiome are essential for nitric oxide (NO) production, which influences key processes that regulate overall health. Similarly, NO synthesis is integral for maintaining homeostasis and adequate functioning of these environments. Recognizing these relationships highlights the importance of maintaining microbial balance in both oral and gut ecosystems to support systemic health, while also being mindful of factors that promote and impede NO production.

Join us for our free upcoming virtual event, The Gateway to Healing: Exploring the Connection Between the Oral Microbiome, Gut Health, and Chronic Disease on August 27th from 5 to 7 pm, with Dr. Chris Easton, Dr. Haroldo Magarinos, and Jeffrey Bland, PhD. This event will examine the links between oral and gut microbiome health and chronic disease, revealing their overlap and the integral role of NO synthesis, providing compelling insights for improving health.

References:

1. Lam GA, Albarrak H, McColl CJ, Pizarro A, Sanaka H, Gomez-Nguyen A, Cominelli F, Paes Batista da Silva A. The Oral-Gut Axis: Periodontal Diseases and Gastrointestinal Disorders. Inflamm Bowel Dis. 2023 Jul 5;29(7):1153-1164. doi: 10.1093/ibd/izac241. PMID: 36527679; PMCID: PMC10320234.
2. Olsen I, Yamazaki K. Can oral bacteria affect the microbiome of the gut? J Oral Microbiol. 2019 Mar 18;11(1):1586422. doi: 10.1080/20002297.2019.1586422. PMID: 30911359; PMCID: PMC6427756.
3. Segata N, Haake SK, Mannon P, et al. Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biol. 2012;13(6):R42
4. Bryan, N.S., Tribble, G. & Angelov, N. Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure. Curr Hypertens Rep 19, 33 (2017). https://doi.org/10.1007/s11906-017-0725-2
5. Vanhatalo A, Blackwell JR, L’Heureux JE, Williams DW, Smith A, van der Giezen M, Winyard PG, Kelly J, Jones AM. Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans. Free Radic Biol Med. 2018 Aug 20;124:21-30. doi:
6. Rosier BT, Johnston W, Carda-Diéguez M, Simpson A, Cabello-Yeves E, Piela K, Reilly R, Artacho A, Easton C, Burleigh M, Culshaw S, Mira A. Nitrate reduction capacity of the oral microbiota is impaired in periodontitis: potential implications for systemic nitric oxide availability. Int J Oral Sci. 2024 Jan 5;16(1):1. doi: 10.1038/s41368-023-00266-9. Erratum in: Int J Oral Sci. 2024 Jan 26;16(1):8. doi: 10.1038/s41368-024-00283-2. PMID: 38177101; PMCID: PMC10767001.
7. Kinane, D.F. and Lappin, D.F. (2002), Immune Processes in Periodontal Disease: A Review. Annals of Periodontology, 7: 62-71. https://doi.org/10.1902/annals.2002.7.1.62
8. Burcham ZM, Garneau NL, Comstock SS, Tucker RM, Knight R, Metcalf JL; Genetics of Taste Lab Citizen Scientists. Patterns of Oral Microbiota Diversity in Adults and Children: A Crowdsourced Population Study. Sci Rep. 2020 Feb 7;10(1):2133. doi: 10.1038/s41598-020-59016-0. PMID: 32034250; PMCID: PMC7005749.
9. Hampelska K, Jaworska MM, Babalska ZŁ, Karpiński TM. The Role of Oral Microbiota in Intra-Oral Halitosis. Journal of Clinical Medicine. 2020; 9(8):2484. https://doi.org/10.3390/jcm9082484
10. Costalonga M, Herzberg MC. The oral microbiome and the immunobiology of periodontal disease and caries. Immunol Lett. 2014 Dec;162(2 Pt A):22-38. doi: 10.1016/j.imlet.2014.08.017. Epub 2014 Nov 8. PMID: 25447398; PMCID: PMC4346134.
11. Schwartz M, Canon F, Feron G, Neiers F, Gamero A. Impact of Oral Microbiota on Flavor Perception: From Food Processing to In-Mouth Metabolization. Foods. 2021 Aug 26;10(9):2006. doi: 10.3390/foods10092006. PMID: 34574116; PMCID: PMC8467474.
12. Vanhatalo A, Blackwell JR, L’Heureux JE, Williams DW, Smith A, van der Giezen M, Winyard PG, Kelly J, Jones AM. Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans. Free Radic Biol Med. 2018 Aug 20;124:21-30. doi: 10.1016/j.freeradbiomed.2018.05.078. Epub 2018 May 25. PMID: 29807159; PMCID: PMC6191927.
13. Bryan NS. Nitric oxide deficiency is a primary driver of hypertension. Biochem Pharmacol. 2022 Dec;206:115325. doi: 10.1016/j.bcp.2022.115325. Epub 2022 Nov 5. PMID: 36349641.
14. Taddei, S., & Virdis, A. (2023). Nitric oxide and cardiovascular disease: Current understanding and therapeutic prospects. Journal of the American College of Cardiology, 81(1), 1-14. doi:10.1016/j.jacc.2022.10.011.
15. Ley R. E., Turnbaugh P. J., Klein S., Gordon J. I. Microbial ecology: human gut microbes associated with obesity. 2006;444(7122):1022–1023. doi: 10.1038/4441022a. [PubMed] [CrossRef] [Google Scholar]
16. Zeevi D., Korem T., Zmora N., et al. Personalized nutrition by prediction of glycemic responses. 2015;163(5):1079–1094. doi: 10.1016/j.cell.2015.11.001. [PubMed] [CrossRef] [Google Scholar]
17. Leclerc M, Bedu-Ferrari C, Etienne-Mesmin L, Mariadassou M, Lebreuilly L, Tran SL, Brazeau L, Mayeur C, Delmas J, Rué O, Denis S, Blanquet-Diot S, Ramarao N. Nitric Oxide Impacts Human Gut Microbiota Diversity and Functionalities. 2021 Oct 26;6(5):e0055821. doi: 10.1128/mSystems.00558-21. Epub 2021 Sep 14. PMID: 34519530; PMCID: PMC8547463.
18. Dawson TM, Dawson VL. Nitric Oxide Signaling in Neurodegeneration and Cell Death. Adv Pharmacol. 2018;82:57-83. doi: 10.1016/bs.apha.2017.09.003. Epub 2017 Oct 25. PMID: 29413528.
19. Jankovic T, Bogicevic M, Knezevic NN. The role of nitric oxide and hormone signaling in chronic stress, anxiety, depression and post-traumatic stress disorder. Mol Cell Endocrinol. 2024 Sep 1;590:112266. doi: 10.1016/j.mce.2024.112266. Epub 2024 May 6. PMID: 38718853.
20. Melis MR, Argiolas A. Erectile Function and Sexual Behavior: A Review of the Role of Nitric Oxide in the Central Nervous System. Biomolecules. 2021 Dec 11;11(12):1866. doi: 10.3390/biom11121866. PMID: 34944510; PMCID: PMC8699072.
21. Wink DA, Vodovotz Y, Grisham MB, DeGraff W, Cook JC, Pacelli R, Krishna M, Mitchell JB. Antioxidant effects of nitric oxide. Methods Enzymol. 1999;301:413-24. doi: 10.1016/s0076-6879(99)01105-2. PMID: 9919590.
22. Karpuzoglu E, Ahmed SA. Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis. Nitric Oxide. 2006 Nov;15(3):177-86. doi: 10.1016/j.niox.2006.03.009. Epub 2006 May 2. PMID: 16647869.
23. Moran SP, Rosier BT, Henriquez FL, Burleigh MC. The effects of nitrate on the oral microbiome: a systematic review investigating prebiotic potential. J Oral Microbiol. 2024 Feb 27;16(1):2322228. doi: 10.1080/20002297.2024.2322228. Erratum in: J Oral Microbiol. 2024 May 15;16(1):2350309. doi: 10.1080/20002297.2024.2350309. PMID: 38420038; PMCID: PMC10901185.
24. Maier T. Oral Microbiome in Health and Disease: Maintaining a Healthy, Balanced Ecosystem and Reversing Dysbiosis. Microorganisms. 2023 May 31;11(6):1453. doi: 10.3390/microorganisms11061453. PMID: 37374955; PMCID: PMC10304820.
25. Gut G, Tauman R, Greenfeld M, Armoni-Domany K, Sivan Y. Nasal nitric oxide in sleep-disordered breathing in children. Sleep Breath. 2016 Mar;20(1):303-8. doi: 10.1007/s11325-015-1189-8. Epub 2015 May 7. PMID: 25948164.