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Oral Dysbiosis and Alzheimer’s Disease Risk

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The oral microbiome is implicated in many systemic illnesses such as cardiovascular disease, metabolic syndrome, respiratory infections, and cognitive decline, with the common link between them being inflammation.1-4 A connection between oral health, inflammation, and neurodegenerative conditions such as Alzheimer’s disease (AD) has long been speculated, and recent findings have suggested that chronic bacterial infections from periodontitis may contribute to neurodegenerative processes and thus may be lifelong risk factors for AD development.5

Bacterial communities form biofilm (dental plaque) on teeth and in oral and gingival tissue, and high pathogenic load can disrupt the oral microbiome, causing inflammation and dysregulation of the immune system response.6 While bacterial overgrowth and chronic inflammation can lead to a variety of local diseases like periodontitis and dental caries, translocation of pathogenic bacteria into the bloodstream can reach other organs in the body, including the heart,7 liver,8,9 and brain.10 In brain tissue, oral bacteria can cause neuroinflammation and damage to neuronal cells, which, over time, contributes to cognitive decline and neurodegenerative diseases like AD. Identifying the root causes of a patient’s oral dysbiosis may help to inform the most effective treatment strategy to optimize both mouth and brain health.

AD Risk Factors: Chronic Periodontal Disease & Bacterial Translocation

Impacting an estimated 42.7% of adults over 30,11 periodontal disease manifests as the accumulation of Porphyromonas gingivalis (P. gingivalis) bacteria in the mouth and the formation of biofilm on oral tissue surfaces. Periodontal disease is more common in adults over 65, with an estimated occurrence of 70.1% of this population.11 Oral tissue depletion, gingival inflammation, and edentulism in older populations is associated with increased presence of P. gingivalis, which can lead to greater inflammatory burden and immune system dysregulation.12-13 P. gingivalis has been suggested as a potential microbial driver in neurodegenerative diseases such as AD.14 Significant oral pathogenic load is considered to be a risk factor for AD for any age group, and studies have shown that chronic periodontal disease lasting 10 years or longer increases this risk twofold.5,13

Altered microbiota in the oral cavity can spread via the lymphatic and vascular systems, infecting tissue in the brain and indirectly contributing to inflammatory pathways through immune system activation.5 P. gingivalis can enter the bloodstream and perivascular spaces when localized tissue trauma occurs from brushing, flossing, and chewing, or in cases of gingival bleeding or bacterial permeation of weakened periodontal tissue.5 In vivo, P. gingivalis secretes cysteine proteases called gingipains that damage neuronal cells. Immunoreactivity to gingipains is consistent with increased neuroinflammation in AD-afflicted brains as compared to those without, and colonization of P. gingivalis has been documented post-mortem in both human and animal brain studies.10 In addition, patients with AD are observed to have higher dental plaque weight and more missing teeth than their healthy counterparts, suggesting that higher rates of bacterial colonization in the mouth may accelerate the disease processes in the brain.13

Nutrition and Probiotics: Not Just for Gut Health

Nutrition is an important consideration for patients experiencing periodontal diseases as several nutrient deficiencies may lead to a dysbiotic oral microbiome.15 Plant-based diets include key micronutrients that support healthy oral microflora such as vitamin C and D, calcium, phosphorous, fluorine, and nitrite.15-17 In addition, polyphenols found in certain food sources have anti-inflammatory, anti-oxidative, and demonstrated antibacterial properties against P. gingivalis, including the catechin epigallocatechin-3-gallate found in green tea, curcumin, cranberries, pomegranate, mango, resveratrol from grapes and wine, and rice extracts.16,18,19 These polyphenols are also noted for inhibiting gingipain activity in the brain and are emerging as potential therapeutic treatments to mitigate cell damage and disease progression.18,20

Much like the gut microbiome, therapeutic use of probiotics has shown effectiveness in maintaining microbial balance in the mouth. Research has demonstrated that oral probiotics have similar effects of promoting microbiota diversity and reducing plaque accumulation as manual disruption of the biofilm through brushing and flossing.21-22 Several bacterial strains have demonstrated inhibitory effects on pathogen growth, the formation of oral biofilms, and the disruption of pre-formed biofilms, including Lactobacillus,21-24 Bifidobacterium,22 Lactococcus,25 and Streptococcus.23-24 A 2021 study found that Streptococcus salivarius is able to adhere to gingival fibroblasts and inhibit inflammatory cytokine IL-6 and IL-8 production in the presence of anaerobic bacteria such as P. gingivalis.26 Bifidobacterium and Lactobacillus were also shown to improve the clinical indicators of periodontitis such as attachment loss and pocket depth and bleeding on probing.24 In addition to their efficacy as antimicrobial agents, the use of these commensal bacteria may also support the integrity of oral tissue and, in turn, is likely to decrease the incidence of bacterial translocation through permeation.

A small 2018 double-blind placebo controlled randomized clinical trial of middle-aged adults tested the total cultivable bacteria of the mouth before and after mechanical plaque removal against treatment with an orally administered probiotic sachet of Lactobacillus rhamnosus. At the six and nine-month time points, bacterial cultures in both groups had decreased, with no significant difference in efficacy between the two modalities.21 Furthermore, other studies suggest that oral probiotics as an adjunctive to daily hygiene habits yield the lowest concentrations of overall pathogenic bacteria.21,27

Improving oral health may help to minimize risk factors associated with the onset of a range of chronic neurodegenerative conditions, including dementia. Dysbiosis in the oral microbiome may be mitigated by several strategies common to the functional medicine framework, including nutritional approaches and lifestyle changes. Common over-the-counter oral health products containing probiotics such as toothpastes, mints, or lozenges may be cost-effective strategies for improving a patient’s oral health at home. In addition to daily brushing and flossing, increasing dietary intake of probiotics, nitrite-rich foods, and polyphenols can optimize oral microbiota and decrease overall inflammatory burden. Oral hygiene is an important lifestyle factor for patients, and addressing early manifestations of disease originating in the mouth can help maintain proper function and health throughout the body.

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References

  1. Haumschild MS, Haumschild RJ. The importance of oral health in long-term care. J Am Med Dir Assoc. 2009;10(9):667-671. doi:1016/j.jamda.2009.01.002
  2. Hirai K, Yamaguchi-Tomikawa T, Eguchi T, Maeda H, Takashiba S. Identification and modification of Porphyromonas gingivaliscysteine protease, gingipain, ideal for screening periodontitis. Front Immunol. 2020;11:1017. doi:3389/fimmu.2020.01017
  3. Radaic A, Kapila YL. The oralome and its dysbiosis: new insights into oral microbiome-host interactions. Comput Struct Biotechnol J. 2021;19:1335-1360. doi:1016/j.csbj.2021.02.010
  4. Mei F, Xie M, Huang X, et al. Porphyromonas gingivalisand its systemic impact: current status. Pathogens. 2020;9(11):944. doi:3390/pathogens9110944
  5. Singhrao SK, Harding A.Is Alzheimer’s disease a polymicrobial host microbiome dysbiosis? Expert Rev Anti Infect Ther. 2020;18(4):275-277. doi:1080/14787210.2020.1729741
  6. Kriebel K, Hieke C, Müller-Hilke B, Nakata M, Kreikemeyer B. Oral biofilms from symbiotic to pathogenic interactions and associated disease–connection of periodontitis and rheumatic arthritis by peptidylarginine deiminase. Front Microbiol.2018;9:53. doi:3389/fmicb.2018.00053
  7. Mougeot JC, Stevens CB, Paster BJ, Brennan MT, Lockhart PB, Mougeot FK. Porphyromonas gingivalisis the most abundant species detected in coronary and femoral arteries. J Oral Microbiol. 2017;9(1):1281562. doi:1080/20002297.2017.1281562
  8. Ishikawa M, Yoshida K, Okamura H, et al. Oral Porphyromonas gingivalis translocates to the liver and regulates hepatic glycogen synthesis through the Akt/GSK-3beta signaling pathway. Biochim Biophys Acta. 2013;1832(12):2035-2043. doi:1016/j.bbadis.2013.07.012
  9. Seyama M, Yoshida K, Yoshida K, et al. Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver. Biochim Biophys Acta Mol Basis Dis. 2020;1866(6):165731. doi:1016/j.bbadis.2020.165731
  10.  Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalisin Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333. doi:1126/sciadv.aau3333
  11.  Centers for Disease Control and Prevention. Periodontal disease. Reviewed July 10, 2013. Accessed July 20, 2021. https://www.cdc.gov/oralhealth/conditions/periodontal-disease.html
  12.  Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017;9(1):56. doi:10.1186/s13195-017-0282-6
  13.  Wu YF, Lee WF, Salamanca E, et al. Oral microbiota changes in elderly patients, an indicator of Alzheimer’s disease. Int J Environ Res Public Health. 2021;18(8):4211. doi:10.3390/ijerph18084211
  14.  Olsen I, Kell DB, Pretorius E. Is Porphyromonas gingivalis involved in Parkinson’s disease? Eur J Clin Microbiol Infect Dis. 2020;39(11):2013-2018. doi:1007/s10096-020-03944-2
  15.  Rowinska I, Szyperska-Slaska A, Zariczny P, Paslawski R, Kramkowski K, Kowalczyk P. The influence of diet on oxidative stress and inflammation induced by bacterial biofilms in the human oral cavity. Materials (Basel). 2021;14(6):1444. doi:3390/ma14061444
  16.  Basu A, Masek E, Ebersole JL. Dietary polyphenols and periodontitis—a mini-review of literature. Molecules. 2018;23(7):1786. doi:3390/molecules23071786
  17.  Vanhatalo A, L’Heureux JE, Kelly J, et al. Network analysis of nitrate-sensitive oral microbiome reveals interactions with cognitive function and cardiovascular health across dietary interventions. Redox Biol. 2021;41:101933. doi:1016/j.redox.2021.101933
  18.  Olsen I, Potempa J. Strategies for the inhibition of gingipains for the potential treatment of periodontitis and associated systemic diseases. J Oral Microbiol. 2014;6. doi:3402/jom.v6.24800
  19.  Sánchez MC, Ribeiro-Vidal H, Esteban-Fernández A, et al. Antimicrobial activity of red wine and oenological extracts against periodontal pathogens in a validated oral biofilm model. BMC Complement Altern Med. 2019;19(1):145. doi:1186/s12906-019-2533-5
  20.  Ryder MI. Porphyromonas gingivalis and Alzheimer disease: recent findings and potential therapies. J Periodontol. 2020;91(Suppl 1):S45-S49. doi:1002/JPER.20-0104
  21.  Morales A, Gandolfo A, Bravo J, et al. Microbiological and clinical effects of probiotics and antibiotics on nonsurgical treatment of chronic periodontitis: a randomized placebo- controlled trial with 9-month follow-up. J Appl Oral Sci. 2018;26:e20170075. doi:1590/1678-7757-2017-0075
  22.  Ishikawa KH, Mita D, Kawamoto D, et al.Probiotics alter biofilm formation and the transcription of Porphyromonas gingivalis virulence-associated genes. J Oral Microbiol. 2020;12(1):18055553. doi:1080/20002297.2020.1805553
  23.  Jansen PM, Abdelbary MMH, Conrads G. A concerted probiotic activity to inhibit periodontitis-associated bacteria. PLoS One. 2021;16(3):e0248308. doi:1371/journal.pone.0248308
  24.  Matsubara VH, Bandara HM, Ishikawa KH, Mayer MP, Samaranayake LP. The role of probiotic bacteria in managing periodontal disease: a systematic review. Expert Rev Anti Infect Ther. 2016;14(7):643-655. doi:1080/14787210.2016.1194198
  25.  Radaic A, Ye C, Parks B, et al.Modulation of pathogenic oral biofilms towards health with nisin probiotic. J Oral Microbiol. 2020;12(1):1809302. doi:1080/20002297.2020.1809302
  26.  MacDonald KW, Chanyi RM, Macklaim JM, Cadieux PA, Reid G, Burton JP. Streptococcus salivarius inhibits immune activation by periodontal disease pathogens. BMC Oral Health. 2021;21(1):245. doi:1186/s12903-021-01606-z
  27.  Allaker RP, Stephen AS. Use of probiotics and oral health. Curr Oral Health Rep. 2017;4(4):309-318. doi:1007/s40496-017-0159-6

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