Microbiota collectively refers to all the microorganisms such as bacteria, virus, fungi, archaea, and protists that exists in a commensal, symbiotic, or pathogenic relationship with the host. Correspondingly, the microbiome refers to the genetic elements of the microbes living inside and on the skin, gut, and mucosal surfaces
[2][3][4][5]. These microbes participate in several physiological processes ranging from digestion, synthesis of vitamins, regulation of inflammation and immune system, and more importantly, surface barrier protection against pathogenic invasion
[6][7]. Notably, environmental factors, dietary habits, age, and genetic make-up strongly influence the microbiota, which, in turn, impacts health through direct or indirect strategies
[8]. In normalcy, homeostasis is maintained through a cordial interaction between the host and the infinite number of resident microbes that populate the entire stretch of our body. Amassed scientific reports have emphasized the critical role of the microbiota and microbiome in human health and disease and have underscored that microbial dysbiosis contributes to the pathogenesis of lifestyle disorders, auto-immune, neuropsychiatric, and even neoplastic diseases
[9][10]. Hence, the microbiota is regarded as the master key and clinical experts have embarked on the journey to explore and target the human microbiome to treat various eye diseases.
2. Ocular Microbiome
The initial efforts at characterizing the core human microbiome disregarded the eye; however, there are now rigorous research efforts aimed at defining the ocular microbiome and emphasizing the concept of the “microbiota–gut–retina axis”
[11][12][13]. The eyes are one type of organ that is constantly exposed to the environment and attracts diverse microorganisms. The tear film and mucin secretions protect the eye from foreign objects with their antimicrobial components, namely lysozyme, lactoferrin, and defensins, which prevent microbial colonization
[14]. The conjunctiva and the cornea of the eye lodge the majority of the ocular microbiome. As evidenced by previous research efforts, relative to other microbiomes of the human hosts, which reside in the gut, mouth, nose, and skin, a healthy eye has a small unique, and expansive microbiome with low diversity
[15][16][17]. Similar to other mucosal sites, the ocular microbiome plays a vital role in optimally regulating homeostasis and establishing host defense against pathogen invasion and its proliferation. The consortium of microbes inhabiting the eye includes bacteria, fungi, and viruses, while the bacterial groups are extensively focused. Among these, the fungi and viruses constitute less than 2% of the specimens
[18][19]. Strikingly, tremendous research works and advancements in technologies (next-generation sequencing of 16S rDNA) have identified more than 500 bacterial genera from the conjunctival swabs
[20]. The most abundantly cultivated bacterial organisms in a normal healthy eye are coagulase-negative staphylococci,
Acinetobacter,
Methylobacterium,
Propionibacterium,
Pseudomonas,
Streptophyta,
Sphingomonas, and
Corynebacterium species
[16][21].
Even though the eye has adopted a harmonious relationship with the commensals, a compositional variation in the ocular microbiota is associated with ocular surface disorders
[22][23] and that of the non-ocular microbiome
[24] in scleritis, glaucoma, diabetic retinopathy (DR)
[25], uveitis
[26][27][28][29], Retinitis Pigmentosa, Sjogren’s Syndrome, and AMD. A plethora of recent research has indicated the involvement of microbes of extra-ocular origin in the development and prognosis of ophthalmic pathologies (
Table 1), which include bacteria, fungi, and viruses. It is noteworthy that more recent studies have identified the association of viral components in eye diseases such as uveitis in chronic infections of hepatitis B and hepatitis C viruses
[30][31], cytomegalovirus in AMD
[32][33], and glaucoma
[34], and more interestingly, coronavirus (COVID-19) is also implicated in ocular diseases
[35][36][37][38]. Several studies have determined that homeostasis of the ocular surface is directly or indirectly impacted by the complex intestinal microbiome
[39]. In this regard, the following content focus on the oral microbiome, especially the bacterial species that have been identified with a conspicuous role as a cofactor in the etiopathogenesis of a wide range of eye diseases.
Table 1. Extra and Intra Ocular Pathogens and Diseases.
3. Oral Microbiome
The neonatal human oral cavity, the first part of our digestive tract, is comparatively sterile and the acquisition of microbial species commences with the first feeding
[45]. The oral cavity has the second-largest diverse microbial consortium following the gut and harbors over 700 species of bacteria
[46]. The diverse microbial biofilms that live harmlessly regulating immune homeostasis are unique to different intraoral locations
[47]. The periodontal tissue has the favorable architecture and environment for the microorganisms to be a successful inhabitant niche. Remarkably, the interaction between these microbial species within the oral community forms a crucial element in determining the pathogenesis of a multitude of oral (dental caries, periodontitis, endodontic infections, tonsillitis, and alveolar osteitis) and extra-oral diseases. These bacterial species produce opportunistic infections under altered settings, particularly poor oral hygiene, change in dietary habits, pH, host immune response, and genetic factors
[48]. Periodontal disease (PD) is one such local disease that results from subgingival plaque accumulation and perturbation in the microbial community, which shifts the equilibrium from health to disease
[49].
Streptococcus gordonii (
S. gordonii) and
Streptococcus sanguinis are the pioneer species critical in the initiation and progression of dental plaque formation by their ability to adhere to components of the salivary pellicle and other oral bacteria
[50][51]. In the subgingival environment,
Porphyromonas gingivalis (
Pg),
Treponema denticola (
T. denticola), and
Tannerella forsythia (
T. forsythia) form a consortium as the prime “red complex” periodontopathogenic bacteria.
Aggregatibacter actinomycetemcomitans (
A. actinomycetemcomitans),
Fusobacterium nucleatum (
F. nucleatum),
Prevotella intermedia,
Campylobacter rectus, and
Eikenella corrodens are other notable species involved in PD
[52]. The red complex groups were most prevalent and strongly correlated with pocket depth and bleeding on probing, especially
F. nucleatum, which was detected at high levels in all the samples
[53].
In addition to the pathogenic effects in the oral cavity, the oral microbes often become certified disease-causing pathogens in immune-compromised subjects. The prototype periodontal pathogen
Pg has been implicated in the pathogenesis of pancreatic cancers following
A. actinomycetemcomitans [54]. A perturbed balance in the oral microbiome conglomerate culminates in a variety of chronic systemic disorders, including cardiovascular disease, stroke, preterm birth, diabetes, and pneumonia
[55]. Oral dysbiosis especially through periodontal inflammation is linked to oral, esophageal, gastric, lung, pancreatic, prostate, and breast cancers
[56]. During the 18th century, the “germ theory of disease” proposed by Louis Pasteur and Robert Koch and Miller’s “focal theory of infection” revolutionized the field of microbiology and listed a variety of diseases, namely septicemia, meningitis, pneumonia, tuberculosis, and syphilis, as having their origins from communication with the oral cavity. The inflammation of the tonsils, middle ear, lungs, meninges, and pericardium was also linked to oral infections
[57]. In the late 1980s, epidemiological studies showed evidence linking oral dysbiosis
[58] through periodontal diseases as a risk factor in a wide spectrum of systemic diseases. Offenbacher, in 1996, presented the concept of “periodontal medicine,” confirming this correlation in human and animal study models
[59]. Sampaio-Maia et al. highlighted that the oral microbiome modifies the balance between health and disease, locally and systemically
[60]. Moreover, the following studies hypothesized that the periodontal pathogens contribute to cardiovascular and respiratory disorders, diabetes mellitus, adverse pregnancy outcomes, neurodegenerative diseases, chronic kidney diseases, and osteoporosis, stretching the list to oral and extra-oral cancers. Therefore, activities of the oral microbiome may serve as potential biomarkers in the diagnosis of systemic diseases and in optimizing therapeutic targets.
Although the theory of oral foci of infection belongs to the prehistoric days, the link between periodontal disease and eye disorders has resurfaced lately. It is intriguing to note that the oral cavity function as the gateway for external microorganisms and those that inhabit the mouth and associated structures impact distant systems and organs such as the eye. As it is scientifically proven that many systemic diseases manifest in the oral cavity, it is also known that chronic inflammation originating from the oral cavity influence the pathogenesis of diseases at the systemic level
[61]. Several latest studies have strongly suggested the existence of a gut-retinal axis, emphasizing the role of dysbiosis of gut microbiota in the inception and advancement of uveitis
[62], AMD
[63], and glaucoma
[64]. Yet, as early as the 4th century, Hippocrates discussed a case of arthritis healing with the extraction of an infected tooth. In the following 90s, an outburst of research ensued, based on the association between periodontitis and systemic diseases
[65][66]. It is noteworthy that the correlation between eye diseases and oral health is being reevaluated in late years through limited evidence. In this line, developing research intends to enlighten the involvement of oral microorganisms in the inception and prognosis of eye diseases, especially AMD and glaucoma. Chronic periodontal inflammation and the microbiome share various significant elements with many systemic conditions including pro-inflammatory mediators, bacterial metabolites, and genetic predisposition. Hence, a thorough analysis of the anomalous alterations in the mouth is vital for the meticulous identification and prevention of certain systemic diseases. The observation that the oral cavity is being recognized as the “diagnostic mirror” of the entire body has inspired the research arena to dissect the contribution of periodontal pathogens to the risk of ocular disorders
[67].