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The Oral Microbiota Affects More Than Just the Mouth

For World Oral Health Day, Lily Berrin, daughter of a periodontist and dental hygienist, highlights recent PLOS Pathogens content to remind us that oral pathogens do more than just cause cavities.

There is more going on behind that smile than you know; brushing, flossing, and seeing the dentists regularly are only the beginning to a healthy mouth and a healthy body. Bacteria, fungi, and even protozoa can inhabit the mouth, leading to more than just bad breath and cavities. If not treated, these pathogens can cause more severe ailments, from inflammatory diseases, such as cardiovascular disease and rheumatoid arthritis, to cancer. In addition to being partly responsible for causing and exacerbating these diseases, and the critters in your mouth can also help inform scientists about the health in other parts of the body.

Coronation Dental Specialty Group, Wikimedia Commons
Image credit: Coronation Dental Specialty Group, Wikimedia Commons

The oral microbial community is one of the most diverse in the human body, including over 700 different species of bacteria and some species of fungi. Both mutualistic and pathogenic microbes reside in the mouth. Pathogens often exist on pellicile, coating the dental tissues (enamel, dentin, cementum) and forming a complex matrix, or biofilm, more commonly known as dental plaque. These pathogens primarily affect the teeth, causing dental caries, also known as tooth decay. Mary Ann Jabra-Rizk and colleagues summarized the usual suspects of dental decay– Streptococcus mutans, a Gram-positive bacteria, and Candida albicans, a commensal fungus that infects many human mucosal surfaces but can become an opportunistic pathogen under the right conditions. As Jabra-Rizk and colleagues reported, these two pathogens actually work together to create the perfect pathogenic storm that leads to dental caries, a chronic disease second in human infection only to the common cold.

Mature mixed biofilms formed on discs of hydroxyapatite, demonstrating the affinity of S. mutans to the hyphal elements of C. albicans. Image credit: Metwalli KH, Khan SA, Krom BP, Jabra-Rizk MA (2013)
Mixed biofilms formed on discs of hydroxyapatite, demonstrating the affinity of S. mutans to the hyphal elements of C. albicans.
Image credit: Metwalli KH, Khan SA, Krom BP, Jabra-Rizk MA (2013)

Although tooth decay is a severe consequence of oral pathogens and infects the widest audience, from children to adults, inflammatory diseases caused by the oral bacteria Porphyromonas gingivalis are also highly prevalent human infections. P. gingivalis, most known for causing periodontitis, or chronic inflammation of the gingiva, has also been shown to exacerbate arthritis. Previous studies have found a causative link between periodontal disease and rheumatoid arthritis via bacteria-dependent induction of a pathogenic response to citrullinated epitopes. Piotr Mydel, Jan Potempa and colleagues recently showed that infection with P. gingivalis exacerbates collagen-induced arthritis in a mouse model through earlier onset, more rapid acceleration, and increased severity of the disease, leading to ncreased bone and cartilage destruction. This is due to expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), an enzyme expressed in P. gingivalis, but which is not present in other prokaryotic bacteria.

Although these two inflammatory diseases occur in different systems (P. gingivalis is a bacterium that causes periodontal disease, or chronic inflammation in the mouth leading to destruction of the supporting structures of the teeth and rheumatoid arthritis is an autoimmune disease, causing severe inflammation and bone and cartilage destruction in the joints), there is much correlation between them, and researchers have found that individuals with periodontal disease have an increased prevalence of rheumatoid arthritis, and vice versa. Not only is periodontal disease known to exacerbate rheumatoid arthritis, as reported by Mydel, Potempa, and colleagues, but it has also been shown as a precursor to arthritis, and as a likely factor in causing and contributing to the autoimmune disease.

P. gingivalis is also involved in other chronic inflammatory diseases, such as inflammation of the vasculature, which is also known as cardiovascular disease or atherosclerosis. P. gingivalis evades host immune detection to establish persistent low-grade inflammation by expressing an atypical lipopolysaccharide (LPS) structure containing heterogeneous lipid A species. Genco and colleagues infected mice with two different strains of Porphyromonas gingivalis, one that expressed antagonistic lipid A and another that produced exclusively agonistic lipid A. Their results demonstrate that the agonist lipid A production caused decreased vascular inflammation and atherosclerosis progression. They conclude that Porphyromonas gingivalis evades TLR4-mediated bacterial clearance in the host, allowing it to exacerbate vascular inflammation.

Their study also provides some primary insight into how P. gingivalis disseminates from the oral cavity to other parts of the body, such as the vasculature and joints, wreaking inflammatory havoc as it spreads across the body.

In addition to inflammatory diseases such as those mentioned above, oral bacteria has been reported to contribute to cancer. Whitmore and Lamont summarize the literature on the roles of Porphyromonas gingivalis and Fusobacterium nucleatum (another oral microbe indigenous to the oral cavity) in cancer. The chronic or dysregulated inflammation caused by these two bacteria leads to their having a significant role in cancer development and progression, most notably in oral squamous cell carcinoma (OSCC). OSCC surfaces are reported to include higher amounts of P. gingivalis and F. nucleatum than other mucosal surfaces. Oral bacteria may influence cancer at many stages of the disease, from precancerous lesions aiding in the growth of oral bacteria to P. gingivalis contributing to OSCC metastasis. Wherever the cause and effect lie, oral bacteria play a role in cancer etiology and progression.

Efficacy of Pichia spent medium (PSM) in an experimental murine morel of oral candidiasis. Histology analyses of tissue section of tongue from mouse infected with Candida, followed by (C) no treatment or treated with (D) vehicle control, (E) nystatin, or (F) PSM. Arrows – fungal hyphae. Image credit: Mukherjee PK, Chandra J, Retuerto M, Sikaroodi M, Brown RE, et al. (2014)
Histology analyses of tongue tissue from mouse infected with Candida, followed by (C) no treatment or treated with (D) vehicle control, (E) nystatin, or (F) Pichia Spent Medium.
Image credit: Mukherjee PK, Chandra J, Retuerto M, Sikaroodi M, Brown RE, et al. (2014)

The oral microbiota can also provide information on the health effects of other diseases, such as HIV. Ghannoum and colleagues identified the core mycobiome and bacteriome of HIV-infected patients and non-infected individuals, describing that although the bacteriome did not differ significantly between groups, the mycobiome did. They found a decreased abundance of Pichia (an oral fungus) in uninfected individuals that coincided with an increased abundance of Candida (another oral fungus). This suggests an antagonistic relationship between the two fungi, which is line with previous studies that reported that Pichia is able to outcompete Candida for nutrients. Not only do oral microbiota contribute and exacerbate diseases, but they can also be used as research tools in understanding the oral environment in infected patients and provide insight into patient health and drug discovery.

Oral pathogens infect more than just gums and teeth. Although they do contribute to dental caries, bad breath, and gum disease, there is more going on behind the scenes than what you hear in the dentists’ office. As these PLOS Pathogens studies and many others describe, there are severe health implications from periodontal disease caused by oral bacteria and fungi. Chronic inflammation of the oral bacteriome leads to increased inflammation in rheumatoid arthritis and atherosclerosis. Oral bacteria also contribute to cancer, in both early and late cancer stages. The oral microbiota, including bacteria and fungi, can also reveal important information about patients with chronic diseases such as HIV. So this world oral health day, don’t forget to brush and floss your teeth– it may help you in more ways than you know.

 

 

lil1Lily Berrin grew up in northern California, leaving for Los Angeles to pursue a B.A. from Occidental College in Cognitive Science (with a neuroscience emphasis) and Spanish.  After dabbling in research, she realized science communication was more her thing and landed a job at PLOS, working as a Senior Publications Assistant for PLOS Pathogens. 

 

Discussion
  1. This post was updated on March 24, 2015. There was a typographical error in the third paragraph. We have replaced the word “eukaryotic” with “prokaryotic.”

  2. Excellent article. However, for many people, brushing and flossing are not enough to prevent periodontal disease and it’s consequences. At present, there is a comprehensive and thoroughly researched program that can achieve oral health but it is rarely used.

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