Image caption: Fragments of amyloid precursor protein aggregate in β-amyloid plaques, seen here in dark brown. These plaques have been found in the brains of patients with Alzheimer’s disease. Credit: Wikimedia Commons.

By Daniel Erenstein, Neurobiology, Physiology & Behavior ‘21

Author’s Note: I first learned about research on the oral microbiome while covering this year’s annual meeting of the American Association for the Advancement of Science in February. Under the theme of “Understanding Dynamic Ecosystems,” the conference, which was held virtually, welcomed scientists, journalists, students, and science enthusiasts for four days of sessions, workshops, and other talks. The human microbiome, home to trillions of bacteria and other microbes, is as dynamic an ecosystem as they come. This article focuses on the bacteria that live in our mouths and their fascinating role in diseases such as diabetes and chronic kidney disease. With this article, I hope that readers consider further reading on the diverse, lively ecosystems within our bodies. For more stories on the microbiome, The Aggie Transcript is a great place to start.

There is more to the oral microbiome than meets the mouth. Established within a few minutes of birth, this diverse community of bacteria, fungi, and other microbes lives on every surface of our mouths throughout our lives [1]. For decades, scientists have researched these microorganisms and their role in dental diseases.

But far less is known about the interactions of these bacteria and their products with other parts of the body, and these interactions could hold a particularly important role in human health.

“We’ve always thought of the mouth as somehow in isolation, that oral health does not somehow impact the rest of the body,” said Purnima Kumar, DDS, MS, PhD, professor of periodontology at Ohio State University, during a session at the American Association for the Advancement of Science annual meeting that took place on February 8 [2].

Scientists, though, are increasingly looking to the oral microbiome for answers to questions about health and disease [3].

“The time is absolutely right for us to start putting the mouth back into the body,” Kumar said during the session “Killer Smile: The Link Between the Oral Microbiome and Systemic Disease.”

Panelists highlighted three systemic diseases — diabetes mellitus, rheumatoid arthritis, and Alzheimer’s disease — and their unexpected connection to disturbances in the oral microbiome [4-6]. A common thread running through all three diseases is an association with periodontitis, a gum disease triggered by the accumulation of bacteria, viruses, and even fungi in dental biofilm, or plaque, on the surface of teeth [7].

In health, there is peace between oral microbes and our immune system. Healthy and frequent communication — molecular diplomacy between bacteria and immune surveillance — maintains stable relations. But microbial imbalances due to bacterial buildup in plaque can cause inflammatory immune reactions, resulting in the gradual breakdown of the barrier between biofilm and gum tissue.

“When you have gum disease, that crosstalk, that communication, that harmony is broken down,” Kumar said.

When bacteria subsequently invade our gum tissues, there are consequences for human disease [8].

Mark Ryder, DMD, professor of periodontology at University of California, San Francisco, studies the role of one such bacterium, Porphyromonas gingivalis, in disease [9]. This bacterium secretes enzymes called gingipains, which are essential for its survival.

In the case of Alzheimer’s disease, these gingipains can travel through the bloodstream, cross the blood-brain barrier, and accumulate in brain regions like the hippocampus, which is involved in memory. There, they help break down an embedded membrane protein called amyloid precursor protein into fragments, which group together in deposits found in people with Alzheimer’s disease.

Further study of gingipains and other microbial products could provide insight into a “critical early event in the initiation and progression of Alzheimer’s disease,” Ryder said.

Similarly, rheumatoid arthritis can be triggered by immune responses to other by-products of P. gingivalis, including protein antibodies that cause joint inflammation, according to Iain Chapple, BDS, PhD, professor of periodontology at the University of Birmingham [5].

Past research on links between the oral microbiome and systemic disease has even shown that these effects can travel a two-way street.

This is apparent in the research of Dana Graves, DDS, DMSc, professor of periodontics at University of Pennsylvania, whose work has examined the effects of diabetes on our microbiome, and vice versa [4].

“Diabetes impacts the mouth in a very profound way,” said Graves, adding that the inflammatory responses to bacteria caused by diabetes lead to disruption of the microbiome.

“This bidirectionality is something we saw first with diabetes, we’ve seen it now with rheumatoid arthritis, and it appears now that we’re starting to see it with chronic kidney disease,” Chapple said. “We need to start really digging down into [biological mechanisms] to understand more about that relationship.”

However, the verdict is still out on how much bacterial products such as gingipains contribute to disease. For Ryder and others, the existing data is insufficient — fully answering that question depends on carefully constructed clinical trials.

“When we’re trying to establish a link between something like the microbiome and the mouth and Alzheimer’s, association studies are important, the actual underlying biological mechanisms are important, but finally what sort of seals the deal, of course, is the actual effects of intervention,” Ryder said.

An ongoing clinical trial with more than 600 patients is evaluating the success of gingipain inhibitors in preventing symptoms of Alzheimer’s disease [10]. The results, expected by the end of this year, could carry implications not just for the treatment of Alzheimer’s disease but any disease with underlying roots in the oral microbiome.

Regardless of the results, it’s clear that breaking out the toothbrush and floss every day is crucial to our overall well-being.

References:

1. Ursell LK, Metcalf JL, Parfrey LW, Knight R. 2012. Defining the human microbiome. Nutr Rev. 70 Suppl 1: S38-S44. https://doi.org/10.1111/j.1753-4887.2012.00493.x.
2. Kumar P, D’Souza R, Shaddox L, Burne RA, Ebersole J, Graves D, Ryder MI, Chapple I. 2021. Killer Smile: The Link Between the Oral Microbiome and Systemic Disease [Conference presentation]. AAAS Annual Meeting [held virtually]. https://aaas.confex.com/aaas/2021/meetingapp.cgi/Session/27521.
3. Deo PN, Deshmukh R. 2019. Oral microbiome: Unveiling the fundamentals. J Oral Maxillofac Pathol. 23(1): 122-128. doi:10.4103/jomfp.JOMFP_304_18.
4. Graves DT, Ding Z, Yang Y. 2020. The impact of diabetes on periodontal diseases. Periodontol 2000. 82(1): 214-224. https://doi.org/10.1111/prd.12318.
5. Lopez-Oliva I, Paropkari AD, Saraswat S, Serban S, Yonel Z, Sharma P, de Pablo P, Raza K, Filer A, Chapple I, et al. 2018. Dysbiotic subgingival microbial communities in periodontally healthy patients with rheumatoid arthritis. Arthritis Rheumatol. 70(7): 1008-1013. https://doi.org/10.1002/art.40485.
6. Dioguardi M, Crincoli V, Laino L, Alovisi M, Sovereto D, Mastrangelo F, Lo Russo L, Lo Muzio L. 2020. The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer’s Disease: A Systematic Review. J Clin Med. 9(2): 495. https://doi.org/10.3390/jcm9020495.
7. Arigbede AO, Babatope BO, Bamidele MK. 2012. Periodontitis and systemic diseases: A literature review. J Indian Soc Periodontol. 16(4): 487-491. https://doi.org/10.4103/0972-124X.106878.
8. Curtis MA, Diaz PI, Van Dyke TE. 2020. The role of the microbiota in periodontal disease. Periodontol 2000. 83(1): 14-25. https://doi.org/10.1111/prd.12296.
9. Ryder MI. 2020. Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies. J Periodontol. 91 Suppl 1: S45-S49. https://doi.org/10.1002/JPER.20-0104.
10. Cortexyme Inc. 2021. GAIN Trial: Phase 2/3 Study of COR388 in Subjects With Alzheimer’s Disease. ClinicalTrials.Gov. Identifier NCT03823404. https://clinicaltrials.gov/ct2/show/NCT03823404.