There is a big wave of recent research on the oral microbiome and its relationship to systemic health. In this article, we will focus on links between the oral microbiome and the autoimmune disorders, Sjogren’s Syndrome, Lupus, and Rheumatoid Arthritis.
Dysbiosis (an out-of-balance ecosystem of commensal and pathogenic bacteria living in the oral cavity) may be a key factor in a variety of disorders. This includes not only obvious ones like dental caries and periodontal disease, but also systemic illnesses, like cardiovascular disease, chronic obstructive pulmonary disease (COPD), and maybe even cancer (1)(2)(3). This growing body of research offers us a more ecological and holistic understanding of the role of the oral microbiome. It also begs the question:
What other diseases could be triggered by oral dysbiosis?
To answer this question, we first look at autoimmune diseases.
What is An Autoimmune Disease?
An autoimmune disease is a disorder in which a body’s immune system mistakenly attacks its own healthy cells. For example, in multiple sclerosis, the current understanding is that the patient’s own immune system T-cells mistakenly attack myelin cells that make up the tissue that sheathes motor nerves (axons). This, in turn, triggers a cascade of inflammation that damages not only the myelin sheath but also the cells that produce myelin and the axons themselves. The result is a loss of motor control and even paralysis. Why these people’s T-cells go haywire is not yet fully understood, although genetic susceptibility triggered by viral and other environmental insults (e.g., smoking) is likely.
The classic understanding is that, in these cases, the immune system mistakes a normal protein on its own cells for a foreign antigen and mounts a response against the cells displaying such auto-antigenic triggers. We still have an incomplete picture of how the immune system learns to differentiate its own cells from foreign molecules and how both genetic susceptibility and environmental factors can trigger this self-destructive immune response.
New insights into immune disorders place autoimmune diseases in a larger category of immune-mediated inflammatory diseases (IMID). IMID’s are conditions which result from any abnormal activity of the body’s immune system, from allergic reactions to diabetes. Autoimmune diseases are a subset of IMIDs. They are defined as disorders in which the immune system reacts specifically against its own cells and tissues as if they were pathogens or infected cells. Researchers have also recently developed another sub-category of autoinflammatory diseases…but we’ll leave the specifics of those disorders to another post.
The last few years have seen an increase in awareness of autoimmune diseases as well as a new focus on providing better care and more health solutions for the millions suffering from these disorders. To this end, researchers have been investigating potential causes and associated risk factors that increase individual susceptibility to autoimmune disorders. One of the newest research efforts explores the relationships between the oral microbiome and systemic diseases with a special focus on systemic autoimmune diseases.
The Oral Microbiome-Systemic Disease Connection
The new understanding of the oral microbiome is shaping how we think about dental caries, periodontal and systemic diseases. While the traditional view held that these diseases were caused by a small number of pathogens, we now consider the oral microbiome to be a finely tuned ecosystem, a balanced (or unbalanced) community of microorganisms that mediates not only oral health and disease but also some systemic diseases (5).
So far, three pathways that link oral infections to secondary systemic effects have been proposed:
- Metastatic Infection: Transient bacteria from oral infection or dental procedures can gain entrance into the blood and circulate throughout the body. Such disseminated microorganisms may find favorable conditions, settle at a given site where they may multiply, colonize, and infect.
- Metastatic Injury: Certain bacteria can produce toxins that, when excreted or introduced into a host body, trigger tissue damage, an immune response or produce other pathological manifestations.
- Metastatic Inflammation: Soluble molecules that enter the bloodstream may react with circulating antibodies to produce large complexes that give rise to acute and chronic inflammatory reactions. (6)
A number of autoimmune diseases have been linked to multiple pathogenic factors, including genetic susceptibilities, environmental triggers, and dysregulated immune responses. Dysregulated immune responses may involve over-activated B-cells stimulated by toll-like receptors (TLRs). TLRs are one of a larger category of pattern recognition receptors (PRRs). PPRs have evolved to detect proteins on or secreted by pathogens. They have also been implicated in the production of autoantibodies to nuclear and cytoplasmic autoantigens and the presence of anti‐citrullinated protein antibodies (ACPA) (7)(8). Such dysregulated immune responses can trigger progressive inflammation of certain tissues that manifests in particular autoimmune diseases such as Sjogren’s Syndrome, Systemic Lupus Erythematosus, and Rheumatoid Arthritis.
Common Oral Symptom: Extremely Dry Mouth
Sjogren’s Syndrome is an autoimmune disease that mainly affects the lachrymal (tear) and salivary glands. Thus, common symptoms include dry eyes and a significant decrease in saliva production that can cause difficulty in speaking, eating, and swallowing. Saliva is an important component in the composition of the oral microbiome due to its role in protein precipitation and biofilm formation. Insufficient saliva is associated with high bacterial species counts, as well as the frequent occurrence of caries.
In this disease, cytokines and lymphocytic infiltrates in exocrine glands cause damage that reduces secretion. Activated B-cells and T-cells stimulated by TLRs produce increased levels of inflammatory cytokines, IFN-𝛾 and IL-17, that disrupt epithelial cells in the salivary and lacrimal glands, inhibiting their production of saliva or tears and altering the mucin content. (9).
Systemic Lupus Erythematosus (SLE)
Common Oral Symptom: Lichenoid Lesions, Lupus Cheilitis
SLE is a complex, multifactorial connective-tissue disease that commonly affects joints and many organ systems including the skin, joints, heart, lungs, kidneys, and nervous system (10). The disease is characterized by the presence of autoantibodies to nuclear and cytoplasmic autoantigens.
Oral symptoms of SLE include lichenoid lesions and lupus cheilitis. Lichenoid lesions resemble a white spider web or film on the inner cheeks, tongue, and roof of the mouth. Lupus cheilitis may appear as a rash on or swelling of the upper and lower lips, sometimes including the surrounding areas of the mouth.
So far there are a couple of proposed mechanisms that link the oral microbiome to SLE. The first suggests that certain viral infections of the mouth, such as the Epstein-Barr Virus (EBV, the pathogen that causes mononucleosis, aka mono) are implicated in SLE pathogenesis. Certain EBV antigens have structural and functional molecular similarities to SLE autoantigens. Impaired EBV-specific T-cell responses in genetically susceptible individuals may trigger autoantibody responses to self-cellular antigens (11). In other words, EBV antigens share molecular similarities to SLE antigens and other cellular components, causing the cells of our acquired immune system–normally the defenders of the body–to mistakenly attack cells free of viral infection.
Another proposed mechanism that links SLE to oral microbiomes is based on recent research that organisms in the blood (blood microbiome) are associated with a number of non-communicable chronic diseases. Although the gut microbiome is the main site of origin for pathogenic microbes that infiltrate the blood, the oral cavity is another source for translocated microbes (12). A high dormant blood microbiome (i.e., the presence of detectable, but not culturable, microbes) is associated with chronic inflammatory diseases, including SLE.
Common Oral Symptom: Presence or Early Onset of Periodontal Disease
Rheumatoid Arthritis is a well-known disease (not to be confused with osteoarthritis, which is not considered autoimmune). Many people are unaware that it is categorized as an autoimmune disease, the abnormal immune reaction triggering inflammation that causes the tissue lining inside of joints to thicken. Not only joints may be affected, but also other tissues, including the valves of the heart. At the molecular level, the presence of autoantibodies, like anti‐citrullinated protein antibodies (ACPAs) contributes to a loss of immune tolerance to self-antigens and is one of the first steps toward inflammation (7).
ACPAs are a group of autoantibodies found in 50-70% of RA patients, but infrequently associated with other diseases or found in healthy individuals, making them uniquely predictive factors for disease pathogenesis. The presence of ACPAs, along with the maturation of ACPA response mechanisms, are associated with the prodrome of the disease that precedes the onset of clinically apparent RA. This preclinical RA is an entire subset of the disease itself, and has been broadly defined and broken down into six phases by the European League Against Rheumatism (EULAR).
What’s also interesting about ACPAs is that they are associated with periodontal infection with P. gingivalis, suggesting that periodontitis could be a significant risk factor for RA. Periodontal disease refers to inflammatory processes in the tissues surrounding the teeth (gums, etc.) in response to bacterial accumulations, or dental plaque, on the teeth (15). Although it originates in the mouth, it has been linked to systemic diseases–more information can be found here. The image below illustrates in further detail a step-wise process of how periodontal disease can lead to chronic inflammation in rheumatoid arthritis.
Source: Current Rheumatology Reports
Keep In Mind…
Autoimmune disease is an umbrella term for more than 100 different illnesses, each presenting a variable array of symptoms. Due to the variability of symptoms and a history of disease definition by body part (joints, nerves, skin) which does not reflect our current understanding of the systemic nature of the immune system, these diseases have been difficult to diagnose and treat.
Recognizing similarities between autoimmune diseases will provide more insight into the pathophysiological processes deranging the immune response.
This will help us understand the interactions of genetic susceptibility and environmental triggers that lead to these disorders.
The mounting research on the oral microbiome and its connection to systemic autoimmune diseases is exciting. Not only could the detection of imbalances in the microbial composition facilitate the early diagnosis of autoimmune diseases, but also correcting these microbial imbalances may have potential as a treatment for autoimmune diseases.
- Bingham, Clifton O., and Malini Moni. “Periodontal Disease and Rheumatoid Arthritis: the Evidence Accumulates for Complex Pathobiologic Interactions.” Current Opinion in Rheumatology, vol. 25, no. 3, 2013, pp. 345–353., doi:10.1097/BOR.0b013e32835fb8ec.
- Ramesh, Asha, et al. “Chronic Obstructive Pulmonary Disease and Periodontitis – Unwinding Their Linking Mechanisms.” Journal of Oral Biosciences, vol. 58, no. 1, 2016, pp. 23–26., doi:10.1016/j.job.2015.09.001.
- Heikkilä, Pia, et al. “Periodontitis and Cancer Mortality: Register‐Based Cohort Study of 68,273 Adults in 10‐Year Follow‐Up.” International Journal of Cancer, vol. 142, no. 11, 11 Jan. 2018, pp. 2244–2253., doi:10.1002/ijc.31254.
- Smith, D A, and D R Germolec. “Introduction to Immunology and Autoimmunity.” Environmental Health Perspectives, vol. 107, no. Suppl 5, Jan. 1999, pp. 661–665., doi:10.1289/ehp.99107s5661.
- Zhang, Xuan, et al. “The Oral and Gut Microbiomes Are Perturbed in Rheumatoid Arthritis and Partly Normalized after Treatment.” Nature Medicine, vol. 21, no. 8, 2015, pp. 895–905., doi:10.1038/nm.3914.
- Babu, Nchaitanya, and Andreajoan Gomes. “Systemic Manifestations of Oral Diseases.” Journal of Oral and Maxillofacial Pathology, vol. 15, no. 2, 2011, pp. 144–147., doi:10.4103/0973-029x.84477.
- Nikitakis, Ng, et al. “The Autoimmunity-Oral Microbiome Connection.” Oral Diseases, vol. 23, no. 7, 2016, pp. 828–839., doi:10.1111/odi.12589.
- Browne, Edward P. “Regulation of B-Cell Responses by Toll-like Receptors.” Immunology, vol. 136, no. 4, Feb. 2012, pp. 370–379., doi:10.1111/j.1365-2567.2012.03587.x.
- Gonzales, S, et al. “Oral Manifestations and Their Treatment in Sjogren′s Syndrome.” Oral Diseases, vol. 5, pp. 153–161., doi:10.1111/odi.12105.
- Kuhn, Annegret, et al. “The Diagnosis and Treatment of Systemic Lupus Erythematosus.” Deutsches Ärzteblatt, vol. 112, no. 25, 19 June 2015, pp. 423–432., doi:10.3238/arztebl.2015.0423.
- Draborg, Anette Holck, et al. “Epstein-Barr Virus and Systemic Lupus Erythematosus.” Clinical and Developmental Immunology, vol. 2012, 2012, pp. 1–10., doi:10.1155/2012/370516.
- Potgieter, Marnie, et al. “The Dormant Blood Microbiome in Chronic, Inflammatory Diseases.” FEMS Microbiology Reviews, vol. 39, no. 4, 4 May 2015, pp. 567–591., doi:10.1093/femsre/fuv013.
- Willemze, Annemiek, et al. “The Influence of ACPA Status and Characteristics on the Course of RA.” Nature Reviews Rheumatology, vol. 8, no. 3, 2012, pp. 144–152., doi:10.1038/nrrheum.2011.204.
- Arkema, Elizabeth V, et al. “Anti-Citrullinated Peptide Autoantibodies, Human Leukocyte Antigen Shared Epitope and Risk of Future Rheumatoid Arthritis: a Nested Case–Control Study.” Arthritis Research & Therapy, vol. 15, no. 5, 2013, doi:10.1186/ar4342.
- Bingham, Clifton O., and Malini Moni. “Periodontal Disease and Rheumatoid Arthritis.” Current Opinion in Rheumatology: the Evidence Accumulates for Complex Pathobiologic Interactions, vol. 25, no. 3, May 2013, pp. 345–353., doi:10.1097/bor.0b013e32835fb8ec.