Role of Oral Microbiome in Disease Predictions - Current Advances

The oral cavity besides the gastrointestinal tract is known to harbour the most abundant microbiota. Oral microbiota is an integral part of human health and encompasses thousands of species, creating an ecosystem in the oral cavity. A shift in this equilibrium has many implications that may precede or accompany many diseases. While the oral microbiota was earlier known to be associated predominantly with oral diseases, the growing body of evidences presently seem to advocate the correlation of oral microbiota with many of the systemic diseases through various modes. They can also find applications in microbiomics. This review aims at understanding the role of oral microbiota and their implications to the chronic ailments like diabetes, obesity, cancers, cardiovascular diseases etc. It also supports the idea of using these microbial abundances in microbiota as biomarkers to predict the onset or progression of oral or systemic diseases. Role of Oral Microbiome in


Introduction
The human body is more of microbes and less of humans. Over the millions of years, microbiome and the human body have coevolved for the betterment of each other. Human gastrointestinal tract (GIT) harbours the most abundant number and varieties of microbes. The second most abundance is found in the oral cavity.
The oral microbiota is dynamic and comprises of spectrum of microbial species possessing functions ranging from acidogenic, acidouric, inflammatory, and anti-inflammatory activities. A sum of all the microbes present in oral cavity (habitats like buccal mucosa, hard palate, gingiva, tonsils, saliva, sub-lingual, throat and tongue dorsum) is what comprises the oral microbiota and their genomes collectively constitutes the oral microbiome. Today, the oral microbiome is an expanding field of research based on the pioneering work of Dutchman Antony van Leeuwenhoek. He was the first to study the microbes in his tooth plaque using his selfconstructed microscope. Reports that he submitted to the Royal society, in 1670s, revealed that several forms of microorganisms were present on the tooth surface [1].
The human oral flora comprises of hundreds of microbial species ranging from bacteria, archaea, fungi, protozoa to viruses. Table 1 enlists some of the more dominating phyla of the oral microbiota. The technological properties of the oral microbiota have been recently reviwed by Arweiler and Netuschil, [2].A balanced ecosystem exists among the microorganisms in oral cavity, which is responsible for health. However, destruction of this equilibrium (dysbiosis) encourages growth of pathogens. The composition of oral microbiota keeps evolving throughout life, but the early oral microbiome dictates the composition of longterm stable adult oral microbiome [3,4]. Perhaps, the first dynamic alteration of oral microbiota was due to shifts in diet, as is the case with increased intake of sugars, consumption of processed or junk foods etc [5]. Several other factors influence the composition of the oral microbiota, including diet, oral hygiene, smoking, age, use of antimicrobials and vaccines, construction of biomaterials like denture, implants etc. [6]. Host genetics may also influence this composition [7] along with availability of nutrients, oxygen tension, host immunological factors etc. Oral microbiota composition reflects the host's immune status and diversity and perturbations in the abundance of specific strains of the oral microbiota, can serve as 'biomarkers' that can be used to predict several diseases. The rapidly growing area of application of microbiome in therapeutic applications is called microbiomics, where oral microbiota holds a great potential. Early diagnosis and prompt treatment of several chronic diseases are essential to prevent or delay complications by making timely lifestyle changes and delaying or possibly preventing these diseases like diabetes, hypertension or obesity [8,9].Oral cavity including soft and hard tissues shows early and delayed signs and symptoms of these ailments; however, awareness of these complications is lacking worldwide and needs further scale of understanding. In depth understanding of the disease development and involved pathways coupled with pharmacological response to therapeutic interventions has enabled the scientific community to identify biomarkers that holds great promise in predictive medicines [10][11][12]. Advent of omics technologies (metagenomics, transcriptomics, metabolomics etc) has made it even easier to identify and measure such biomarkers [13,14].  [18].
Multiple omics technologies have been adopted, data collected has been integrated and analysed to achiever deeper understanding of the microbiota and its interactions with the hosts [19].

Obesity
Abnormal or excessive accumulation of fats leading to increased risks of many other severe ailments is termed as obesity. Obesity is a global healthcare pandemic and is no more limited to high income countries alone. It is also one of the primary risk factors to an array of chronic conditions like periodontics, cardiovascular diseases, cancer, diabetes, rheumatoid arthritis etc. Adipose tissue, earlier thought to be only storing fats, has now been discovered to be a complex and metabolically active endocrine gland, which secretes several immuno-modulatory factors [20]. A strong causal link exists between excess adiposity and several metabolic diseases as depicted in (Figure 1) [21]. Adipose and related cells secrete over 50 bioactive molecules termed as adipokines, the concentration of which partly defines the individual's metabolic health [22,23].
Low-grade inflammation is a guaranteed characteristic of adult obesity.Alterations in the oral microbiome have potential in sentinel diagnostic and prognostic applications, especially in case of predicting obesity [24][25][26]. Literature cites several studies that have associated obesity with dysbiosis in the oral (and gut microbiomes). Oral cavity in obese individuals has higher levels of several bacteria than in nonobese controls, and it seems likely that those bacterial species could serve as biological indicators of obesity. Obesity may be a factor contributing to periodontitis severity via a modulation of the immune system and vice versa [27].The family Gemellaceae has been reported to be more abundant in saliva samples from obese participants than in normal weight individuals [28].Many studies have concluded that oral microbiome composition significantly differed between obese and non-obese patients. Dominance of Bacteroidetes, Spirochaetes and Firmicutes in the subgingival plaque acts as a biomarker for identification or early detection of obesity. Amongst the oral microflora, over representation of Proteobacteria, Chloroflexi and Firmicutes, with the noted absence of representatives from the phylum Bacteroidetes also reflects risks of obesity. Notably, the phylum Firmicutes was identified in obese patients as an independent significantly discriminative feature with an abundance of over four orders of magnitude [29]. In saliva, [30] identified Selenomonasnoxia, a representative of the Firmicutes phylum, to be a robust predictor of obesity.
Higher abundances of the genus Granulicatella, in the family Gemellaceae, was observed in diabetic and non-diabetic obese participants compared to the normal weight controls [38,39].

Inverse relationship exists between abundance of the genus
Bifidobacteria in the phylum Actinobacteria and diabetes [40,50].
Another study by Kampoo and coworkers reported significantly higher abundances of two genera in the phylum Firmicutes-Streptococcus and Lactobacillus in diabetic patients, indicating their use as markers to predict diabetes. Multiple studies have correlated the dominance of periodontal pathogenic bacteria -P. gingivalis, Treponema denticola and Tannerellaforsythiawith diabetes risk and glycemic control [51][52][53][54][55]. In general, higher abundances of most taxa in the phylum Actinobacteria were associated with a decreased risk of diabetes [56].

Oral Cancer
Squamous cell carcinoma is the most frequently occurring malignancy of the oral cavity and adjacent sites, representing over 90% of all cancers [57].

Cardiovascular Diseases
Atherosclerotic diseases like stroke and myocardial infarction are amongst the main causes of death worldwide.
Several studies on the these aspects have collectively detected the following species associated with cardiovascular diseases-Aggregatibacteractinomycetemcomitans, Fusobacterium nucleatum, Porphyromonasgingivalis, Prevotella intermedia, and Tannerella forsythia. In particular, predominance of A actinomycetemcomitans (facultative aerobe) and P gingivalis, (obligate anaerobe), has been associated with atherosclerosis.
Abundance of Anaeroglobus has been correlated to symptomatic atherosclerosis [73].In certain studies infectious agents like Chlamydophyla pneumonia, Treponema denticoland Cytomegalovirus also have been implicated with cardiovascular problems In such infections, prolonged periodontal treatments influencing the oral hygiene habits lead to reduction in oral anaerobes, and decreased inflammatory biomarkers. In some cases, thickening of the carotid artery (associated with stroke) was reversed.

Adverse Pregnancy Outcomes (Apos) And Post-Partum
Several Adverse pregnancy outcomes (APOs) have been correlated withfluctuations in oral microbiota of pregnant females. Brain Health [51], studied the oral and skin microbiota of aging males This also affects the way one ages. Oral dysbiosis has been correlated to cognitive decline in many studies especially in patients with

The increased counts of Bacteroides forsythusand Campylobacter
Alzheimer's disease (AD), associated with neuroinflammation presumptively caused by the release of inflammatory mediators by oral microbiota. One of the mechanisms states that the oral bacteria or their endotoxins gain entry to the brain, resulting in microglial activation (especially astrocytes). This, in turn triggers the production of pro-inflammatory cytokines such as TNFα and