Academic Audience Piece Cover Letter

To: College Writing 161 Fall 2023 class, Prof. Kimberly Freeman, College Writing Program.
From: Stroumza, Adrien.
Date: October 20th, 2023.
Subject: An Overview of Oral Microbial Diversity Shaping the Oral Disease and Systemic
Health.

My literature review attempts to consolidate our understanding of the oral microbiome and its
implications on disease. Recent research has found many connections between the two broad
areas of research, especially in relation to periodontal disease and dental caries. This review
touches on the general diversity of oral microbiome, the specifics of the oral mucosal barrier, and
then addresses biofilm formation, periodontal disease, and dental caries, as well as the
connections to systemic disease. The goal of the review is to give a comprehensive overview of
an area of research that is not yet fully understood, however is undoubtedly the future of oral
microbial research.

The journal which I am writing this for is the International journal of molecular sciences. I
chose this journal because several papers of interest related to dental research can also be found
in this journal. The journal claims that any citation style is acceptable, however I chose to follow
suit with the other dental and oral health research articles I found in the journal by citing in AMA
style and ordering my references by their order of appearance in-text.

These few definitions will be helpful context when reading the review:

Periodontitis or periodontal disease, also called gum disease, is a serious gum infection that
causes inflammation and damages the soft tissue, often causing shrinkage of the gums and
loosening of the teeth.

The oral mucosal barrier is a mucous membrane that lines in the oral cavity and is a wet soft
tissue membrane that extends from the junction between the vermilion border of the lips and
labial mucosa anteriorly to the palatopharyngeal folds posteriorly.

Systemic diseases are health conditions that effect more than one part of the body.
 An Overview of Oral Microbial Diversity Shaping the Oral Disease and Systemic Health

Abstract

The human oral cavity hosts a diverse community of microorganisms. Specific bacteria

present can provide insight into health conditions and predispositions towards disease. The

presence of bacteria, such as Porphyromonas gingivalis and the bacteria that prevent the

colonization of harmful microorganisms, can result in the avoidance of significant oral

destruction. Immune barriers such as the oral mucosal layer and its antibacterial agents help in

the degradation of the protective biofilms created by bacterial colonies. Periodontal disease,

dental caries, and even systemic diseases show correlation with the presence of specific signaling

bacteria. While several different treatments (vaccines, probiotics, and stepwise treatment plans)

have been attempted, none of them are restorative but are rather focused on mitigating damage

done. In this review, we will discuss how the oral microbiome plays a key role in disease onset

and how new discoveries about the oral microbiome can shape treatments of the future. As

research continues to understand the complex human microbiome, the opportunity to improve

the standard of care through less invasive treatment and preventative care become reality.

Introduction

The oral cavity is a complex and diverse environment that has direct and profound

impacts on humans every day. While it is often researched in isolation, its relevance to the

greater human body as the start of the gastrointestinal tract and primary entry point for

nourishment, as well as pathogens, cannot be overlooked. As our understanding of

microorganisms and microbial communities’ advances, we have a greater idea of how microbial
communities affect oral health and disease. These advancements can be accredited to the rise

gene sequencing technology which allows researchers to quickly and accurately characterize

entire microbial communities at once. Complex interactions between both beneficial and harmful

bacteria shape the environment host wellbeing. From dental plaque to bone resorption, we find

oral microbes at the center of the story and understanding the relationships and interactions

between these bacteria and our health will surely continue to be the future of oral health care and

research. In this review, we will characterize the oral microbe and investigate how it interacts

with the human immune system to result in periodontal disease and dental caries. Connections to

systemic disease and the direction of future treatments will be discussed.

Diversity of the Oral Microbiome

To understand how the human mouth interacts with bacteria, it is essential to recognize

the magnitude and diversity of this micro-ecosystem. The oral microbiota is a complex diverse

community with ecological niches and ever-changing characteristics. Slight changes can have

great implications on oral health and onset of disease. The Human Oral Microbiome Database

(HOMD) (http://www.homd.org/) and CORE (http://microbiome.osu.edu/) databases use

analysis on ribosomal RNA and DNA sequences respective to identify around 600 taxa and

around 300 operational taxonomic units (OTUs) in the oral cavity [1]. In healthy individuals,

their oral microbiome will include bacterial phyla of Firmicutes, Proteobacteria, Actinobacteria,

Bacteroidetes, Fusobacteria, and Spirochaetes and less abundant, but still present, fungal core

phyla [2]. The specific host's genetics, immune system, and external environmental factors will

all contribute to the resulting bacteria in the host's microbiota [2].

 While different hosts' microbial communities often look similar, small colony differences

can lead to significant phenotypic differences; and it is not random. Based on specific microbial

niches within the oral cavity and the bacteria present, inflammatory diseases like periodontitis

and gingivitis arise. In the oral cavity, there are at least five distinct niches: the teeth, the saliva,

the surfaces of the tongue, the gingival sulcus and the periodontal pocket, and the epithelial

surfaces of the oral mucosa [1]. These environments vary significantly such that saliva lacks

indigenous microbiota and oral epithelia are constantly shedding cells however tooth surfaces

provide a consistent platform allowing anchoring and long-term biofilm development, the

precursor to caries and oral health issues when oral hygiene is poor [1]. Nevertheless, the host

immune response works alongside the helpful bacteria expressing sensors and toll-like receptors

to recognize dental plaque biofilm in the sulcular and junctional epithelium [1]. Some bacteria

like Porphyromonas gingivalis, a major agent in the presence of periodontitis can be harmful

however some bacteria, such as specific strains of S. mutans, help prevent invasion from harmful

agents by synthesizing bacteriocins (antimicrobial peptides) [2]. P. gingivalis in microbial

communities, although only present in low frequencies, are consistently associated with the onset

of periodontitis; Fusobacteria are also highly associated with disease [1]. Ultimately, small

changes in host microbial communities can result in allowing pathogenic bacteria to facilitate

unhealthy conditions.

Biofilm Features and Development

Destructive bacteria in the mouth can lead to poor oral health resulting in dental cavities

and gum disease from persistent dental plaques. These bacteria form biofilms which are highly
structurally organized and consistent of an extracellular polymeric matrix that protects other

harmful bacteria, allowing them to stabilize their microbial communities [1,3]. Biofilms tend to

form in humid environments, making the oral cavity a great host where niches are created to

provide bacteria with nutritional needs and protection [3]. The composition and structure of

biofilms make them especially difficult to chemically degrade however removal is essential to

avoid the effects of pathogenic bacteria. Saliva is vital as a combatant to biofilm as it can help

neutralize the acidic pH of the dental plaque and wash away byproducts of microbial metabolism

[3]. This is an essential role in mitigating the onset of oral disease. Both dental caries and

periodontal disorders will typically be preceded by the formation of biofilm on the tooth surface

or subgingival pockets respectively [3]. Most importantly for disease-causing bacteria like P.

gingivalis, biofilm niches provide bacteria with micronutrients which help the cells and

community proliferate [4]. Recent research identifies periodontal biofilm as a source for the

dissemination of pathogenic bacteria [5]. Research towards a deeper understanding of biofilm

formation and destruction may be the key to revolutionizing oral hygiene and oral care.

The Oral Mucosal Barrier and Immune Response

The first lines of defense in the innate immune system are physical barriers. In the mouth,

this is called the oral mucosal barrier. The oral mucosa has a tight relationship with general

health as it prevents the entry of pathogens and harmful substances. The oral mucosa houses a

complex microbiota and contributes greatly to the antimicrobial and immune defense systems

[6]. The maintenance of a careful balance of conditions and microbial communities is essential to

maintaining a healthy oral mucosa [7]. Divergences from this homeostasis can result in the onset
of disease such as periodontitis and other inflammatory diseases [7]. Recent discoveries show

that homeostasis is regulated by a fibrin-neutrophil system, of which future research will

investigate to developed preventative care for oral and systemic inflammatory diseases [7].

The oral mucosa is the start of the full gastrointestinal system. As such, it contains

immune antigen-presenting cells, lymphoid structures, as well as a complex microbiome of its

own [8]. Unlike tooth enamel which remains solid and constant, epithelial cells shed and

therefore oral mucosa is constantly being colonized by the microorganisms present in the oral

cavity [1]. External factors such as diet also play a key role in the makeup of this microbial

niche. In a study comparing individuals from a remote village in South America to individuals

on a diverse multiethnic modern diet, the oral mucosal microbiome was found to be greatly less

diverse in the remote village [1]. Diet plays are large role in oral mucosal microbial composition.

The oral mucosal barrier is a very complex and dynamic environment that serves many functions

and is the bridge between microbial diversity and oral health. In addition to the oral mucosal

barrier, saliva is part of the immune defense. Salivary flow is very important when considering

the washing away of bacteria and biofilm. Saliva plays a large role in the preservation of

beneficial microbe homeostasis and preventing disease from spreading [3]. Furthermore, another

analysis which discovered key taxa in individuals with peanut allergy demonstrated that the oral

mucosal composition could have much greater implications than originally perceived [8]. As the

precursor to the rest of the gastrointestinal system, the composition of oral microbial niches

effects far beyond the oral cavity.

Periodontal Disease and Gingival Health

Periodontal disease originates from subgingival plaque resulting in unhealthy conditions

and inflammation [3]. Several colony-forming microorganisms that are early signs of onset of

periodontal disease include: Streptococcus sanguinis, Gemella spp., Streptococcus mitis,

Fusobacterium nucleatum, Atopobium spp., and Capnocytopha [3]. The immune response to

these bacteria is initially classified as gingivitis but without proper attention, can develop into

periodontitis. At this stage, the innate immune system is in effect, defending against the

subgingival plaque with phagocytic cells, complement proteins and neuropeptides [2]. Over time,

if not addressed, the continual destruction of periodontal tissues can lead to resorption of bone

tissues which is not recoverable in many cases [9]. Bone resorption results in the permanent loss

of teeth due to the absence of sufficient bone surrounding the dental roots. Periodontitis can

become very destructive in the oral cavity and begins with uncleaned plaque hosting undesirable

microorganisms.

Typically, the immune response such as inflammation is a way to recruit more defense to

the site in need however, some bacteria have other plans. As mentioned before, P. gingivalis is a

microorganism that is often associated with the onset of periodontitis. P. gingivalis expresses

proteases to degrade nearby protein and use it as an energy source [1]. Surprisingly, the

additional inflammation that it causes, serves to help the bacteria in its survival strategy by

increasing the protein-rich environment in the gingival sulcus [1]. This results in a complex

inflammatory disease where the immune response progresses the disease rather than stopping it.

At our current state of knowledge, we understand that P. gingivalis increases the risk of

metabolic, inflammatory, and autoimmune disorders however we do not fully understand the
mechanism by which this occurs [2]. Research needs to be done on these mechanisms as well as

treatments for bone regeneration after the impacts of destructive cases of periodontists. Future

treatments aim to reduce tooth loss and hope to restore damaged periodontal tissues treatment is

currently focused more on mitigation than reconstruction [2].

Dental Caries in Context of Bacteria

Dental caries impacts a great portion of the world, seen mostly in children, and are

indiscriminate of factors like race and gender. It is closely related with oral hygiene; however, it

may also result from genetic factors making some individuals more susceptible. Dental caries are

characterized by the demolition of the tooth. It starts with tooth enamel and then destroys dentine

via the acidic results of bacterial fermentation in the patient's mouth. [3]. When comparing

caries-active and caries-free children, a study showed that there were significant differences in

the abundances of Megasphera, Oribacterium, Moryella and Corynebacterium [1]. Several other

bacteria have also been documented to be associated with caries: Bifidobacterium dentium,

Bifidobacterium adolescentis, Streptococcus mutans, Scardovia wiggsiae, Bifidobacterium

longum, Selenomounas spp., Prevotella spp., Lactobacillus spp [3]. It is unclear exactly what

role each bacteria play; however studies have drawn clean connections with the oral microbiome.

For young children, the oral microbiome is not fully developed and is greatly impacted by the

bacteria in their diet and environment. Specific emphasis is placed on the early years of

childhood development because the microbial communities that appear first have the greatest

effects on microbial ecological succession in the microbiome [10]. The oral microbiome has

strong implications and can provide early indications of an individual's oral condition and the
direction in which it is heading. Understanding more about these bacteria will help piece together

the causes of dental caries however it is important to remember that factors such as genetics may

also play a role not yet understood. Bacteria however, have been understood to impact more than

just the oral cavity.

Connections to Systemic Disease

Beyond oral disease, several studies have shown connections between the oral microbiota

and systemic disease. As mentioned earlier, one study found that individuals with peanut

allergies were characterized by a reduction of a specific and consistent set of bacteria and

furthermore found an elevation in immune response secretions [8]. While food-induced

anaphylaxis is not a disease, this finding is significant in connecting the oral microbiome to a

greater systemic response. Other studies show a more complex relationship between oral

inflammatory disease and to chronic inflammatory illnesses like diabetes, arthritis, and heart

disease. They find that effects may be reciprocal such that periodontal diseases effect the

progression of systemic disease while systemic diseases also impact the periodontium [11]. Other

research draws connections that expand to cancers, non-alcoholic fatty liver, and Alzheimer’s

disease as well [4]. While these connections are not yet well understood, P. gingivalis has been a

focal point of recent research [4]. Within the context of the gastrointestinal system, it is

unsurprising that we also find connections between the impacts of P. gingivalis on the oral

microbiota and possible impacts on the greater gut microbiome [12]. Findings relating oral health

to systemic health have become progressively more complex as they integrate greater
understanding of our bodies coordination with our microbes. Research in this direction will

continue to bridge to gap between oral and systemic health.

Current Treatments and Preventions

While treatments and prevention methods vary significantly, several different methods

have been developed. For example, recent studies have highlighted the synergistic effects of

mixed probiotics lozenges resulting in antibacterial activities and reduced plaque formation [13].

In the past vaccines for dental caries have also been attempted. However, currently the risk

associated with them vaccines exceeds the benefits of immunization [1]. While these can be

preventative, most of the help is needed after the tissue is already damaged. While treatments are

case-specific, often stepwise approaches to treatments for conditions like periodontitis are the

most effective [2].

Concluding Thoughts

Knowledge of microbes in the mouth is not a new discovery by any means; however,

recent research, emphasis, and deeper understandings of the complexities of microbial

communities has significantly shifted the perception of how humans’ interaction with disease and

the environment. One place where there appears to be the greatest knowledge gap is in our

understand of biofilms. Biofilm development presents an additional layer of complex interactions

between many microbial species. With a rich evolution behind them, the relationships shared by

these microbes allow them to develop communities to thrive in difficult environments. As our

understanding of these communities grows, we will be able to better investigate how oral disease
and even systemic disease occur and spread throughout the body. More effective treatments

focus on both prevention and rehabilitation will be able to be developed through the lens of the

body’s immune system action as a unified unit against the several pathogens present in various

part of the body. Developing treatment however, comes after we have laid the groundwork. It is

essential that research continues to understand how microbes play a large part in our wellbeing

and oral health. Only after a strong understanding on the complex dynamics of the oral

microbiota, will we be able to engineer this environmental of raise our standard of preventive

care and and treat oral health conditions more comprehensively.

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