Ocular Surface Microbiome

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Introduction

The microbiome can be defined as a community of microbes including bacteria, fungi, and viruses that live on or inside our bodies.[1] The microbiome of the eye most commonly refers to the flora found on the conjunctiva and the cornea, for flora found in the eyelid and eyelashes are widely considered to be a part of the skin microbiome.[1] The microbiome of a healthy ocular surface is relatively stable and has a comparatively low diversity, and the diversity of the microbiome is likely small due to the enzymes in tears having antimicrobial properties, breaking down cell walls and preventing bacteria from reproducing.[1][2] The ocular surface microbiota is postulated to serve a role in maintaining homeostasis and modulating immune function.[2]

Composition of the Microbiome

Bacteria

Figure 1:Relative Abundance of Bacteria in Ocular Surface Microbiome (Phylum Level)[3]

The microbiome of the ocular surface has low diversity. A study conducted by Zhou et al. that performed deep sequencing of healthy conjunctival microbiome samples using Dacron swabs found that the three most dominant phyla were Actinobacteria, Proteobacteria, and Firmicutes, accounting for 46%, 24%, and 22% of the total bacterial community, respectively.[3] In addition, this study found that on the genus level, 6 were shared by at least 80% of conjunctival of all samples, accounting for more than a third of the bacterial community.[3] These 6 were Corynebacterium, Simonseilla, Streptococcus, Propionibacterium, Bacillus, and Staphylococcus.[3] Corynebacterium was the most abundant genus and was found in all samples from healthy conjunctiva.[3] Other common bacteria seen in the conjunctival microbiome also include Pseudomonas, Bradyrhizobium, Acinetobacter, Brevundimonas, Aquabacterium, Sphingomonas, Streptophyta, and Methylobacterium.[4] [5]

Figure 2:Relative Abundance of Bacteria in Ocular Surface Microbiome (Genus Level)[3]

Viruses

The ocular microbiome also hosts several viruses such as the torque teno virus (TTV) , Merkel Cell Polyomavirus (MCP), and the human papillomavirus (HPV).[1] These viruses, which can be harmful if they enter the eye, may serve as watchdogs in the ocular microbiome, alerting the immune system of other viruses that may appear in the microbiome.[1]

A study conducted by Doan et al. that used DNA sequencing techniques found that the top three viruses found in human healthy conjunctiva were multiple sclerosis–associated retrovirus (MSRV), HERV-K, and TTV, but because MSRV and HERV-K are human endogenous viruses, the clinical significance of their presence is unclear.[6] [7] This study suggested that most ocular surface microbiomes host a resident DNA viral community, with TTV typically being predominant.[6]

Fungi

The human ocular surface fungal microbiome varies widely. Studies have found that C. albicans can be present on the normal ocular surface of children and adolescents.[8] Another study found that out of 25 out of 34 healthy conjunctiva in 17 individuals showed the presence of fungi, with the phyla Ascomycota and Basidiomycota and the genera Aspergillus, Setosphaeria, Malassezia, and Haematonectria being present in all 25 eyes.[9]

Wang et al. found that out of 90 eyeballs from 45 adults, phyla Basidiomycota (78.67%) and Ascomycota (19.54%), and five genera, Malassezia (74.65%), Rhodotorula (1.93%), Davidiella (1.89%), Aspergillus (1.25%) and Alternaria (0.61%), which accounted for >80% of the fungal microbiome and presented in >80% of the individuals tested, were seen and potentially make up the core fungi seen on a normal ocular surface.[10] The healthy ocular surface fungal microbiomes can contain opportunistic pathogens such as Emericella, Fusarium, Malassezia, Aspergillus, and Setosphaeria, all of which are opportunistic pathogens.[11]

Factors that Affect the Diversity of the Microbiome

Gender and ethnicity do not have a significant effect on the composition of the microbiome.[3] However, factors such as age and seasonality (dry versus wet climate) can affect the composition of the microbiome.[3] Corynebacterium, Propionibacterium, Myceligenerans, Paracoccus are typically more abundant in older populations.[3] A study found that Streptococcus is on average about 6.2 times more abundant in children than in older populations.[3] Children aged younger than 11 have greater diversity in bacteria in their ocular microbiomes than older populations.[3]

Changes in the Microbiome

The healthy conjunctiva microbiome contains bacteria that are commonly identified as pathogens.[4] Any changes or microbiome imbalances could increase the risk of various eye diseases and trigger inflammatory events.[1] [12] Imbalances of native species of bacteria in other microbiomes in the body have been shown to affect health and lead to disease.[1] Some of these pathogens are “opportunistic pathogens” that can become more virulent and overcome the innate immune response of a host through quorum sensing when enough of a certain bacteria is present.[12] It has been shown that Staphylococcus aureus can perform quorum sensing in biofilms.[13]

Ocular surface microbes have been associated with keratitis, Sjorgen’s syndrome, dry eye disease (aqueous and evaporative), meibomian gland dysfunction, blepharitis, trachoma, contact lens-induced dysbiosis, Stevens Johnson Syndrome, and diabetes-induced dysbiosis and retinopathy.

Pathologies Associated with Ocular Microbiome Dysbiosis

Keratitis

Patients with bacterial keratitis have been shown to have dysbiotic changes in the bacterial microbiome of the conjunctiva and cornea compared to those with healthy eyes.[14] A consistent increase in the abundance of pathogenic bacteria is seen in those with bacterial keratitis such as Streptococcus, Staphylococcus, Paracoccus, Bosea, Gemella, Capnocytophaga, Corynebacterium, and Methylobacterium.[14] Patients who present with keratitis may also potentially have uncontrolled growth of Pseudomonas strains. [12][15]

Patients with fungal keratitis have also shown alterations in the fungal microbiome. Fungal keratitis patients may have a significantly higher abundance of Ascomycota as well as a significantly lower abundance of Basidiomycota.[11]

Sjögren’s syndrome

Sjögren’s syndrome in the setting of ocular surface dysbiosis has not been significantly studied and their association is unclear. It has been shown that patients with Sjögren’s syndrome have greater bacterial loads than those with healthy eyes.[16][17] However, another study has shown that there are no significant differences in composition between those with Sjögren’s syndrome and those with healthy eyes .[18]

Dry eye

Aqueous Tear-Deficient Dry Eye (ADDE)

Patients with ADDE have been shown to have an aberrant and less diverse ocular surface microbiome than those with healthy eyes.[5] For example, at the genus level, those with ADDE can have an increased abundance in Brevibacterium while having significantly reduced abundance of Pseudomonas compared to those with healthy eyes.[5] However, a study conducted by Paiva et al. found no difference in alpha diversity in those with aqueous tear-deficient dry eye, and so the association between ocular surface dysbiosis and ADDE is unclear.[18]

Evaporative/Meibomian Gland Dysfunction

Dry eye disease associated with meibomian gland dysfunction (MGD) has been associated with ocular surface bacterial dysbiosis. MGD has also been associated with a greater number of ocular surface bacteria and an increased bacteria flora has been associated with reduced goblet density.[19][20] At the phylum level, those with MGD have higher abundances of Firmicutes and Proteobacteria while the abundance of Actinobacteria is lower.[21][22] At the genus level, Staphylococcus and Sphingomonas are more abundant in those with MGD, while Corynebacterium is significantly lower.[22] Furthermore, the severity of MGD is strongly correlated with dysbiosis of the ocular surface microbiome that is composed of non-S. epidermidis bacteria such as C. macginleyi.[19]

Blepharitis

On a genus level, patients with blepharitis have been found to have an increased abundance of Staphylococcus, Corynebacterium, and Enhydrobacter but a decreased abundance of Propionibacterium.[23] Higher abundances of Corynebacterium and Enhydrobacter in blepharitis patients indicate that blepharitis could be induced by pollens, dusts, and soil particles.[23]

Trachoma

Trachoma has been associated with changes in bacteria of the ocular surface microbiome and reduced diversity.[3] An increased abundance of Corynebacterium and Streptococcus in the ocular surface microbiome can be seen in those who had trachoma and subsequent conjunctival scarring.[3] Increased Haemophilus influenzae has also been associated with trachoma, but other studies have found that there is no association.[24][25][3]

Contact Lens-Induced Dysbiosis

Contact lens usage has been associated with dysbiosis of the ocular surface microbiome and an associated increase in abundance of pathogenic organisms.[12][26][27] Those who frequently wear contact lenses typically have higher abundances of Methylobacterium, Lactobacillus, Acinetobacter, and Pseudomonas but lower abundances of Haemophilus, Streptococcus, Staphylococcus, and Corynebacterium, making the ocular surface microbiome more similar to the microbiome of the periorbital skin.[28] Of course, the effects of contact lenses on the ocular surface microbiome can vary by the type of contact lenses.[12] [27]

About one in three contact lens wearers develop irritation and redness, and in rare cases microbial keratitis infections and/or conjunctivitis can develop.[29][30] Those who wear contact lenses, in fact, show lower levels of IgA antibodies in tears against P. aeruginosa, which is an opportunistic pathogen that is typically seen in many cases of microbial keratitis, perhaps leading to an abundance of P. aeruginosa in the ocular surface microbiome.[31]

Stevens Johnson Syndrome

The ocular surface microbiome of patients with Stevens Johnson Syndrome typically have greater bacterial diversity as well as an increased abundance of pathogenic bacteria such as Pseudomonas, Staphylococcus, Streptococcus, Corynebacterium, and Acinetobacter.[32] This dysbiosis may affect chronic inflammations and opportunistic infections.[32]

Diabetes-Induced Dysbiosis and Retinopathy

The ocular surface microbiome of diabetic patients are more diverse than those of healthy eyes.[33] On a genus level, diabetic patients have an increased abundance of Acinetobacter.[33] On a phylum level, there is an increased abundance of Proteobacteria but a decreased abundance of Firmicutes.[33] This change in microbiome could also be potentially attributed to other ocular manifestations associated with diabetes such as dry eye, blepharitis, reduced corneal sensation, and delayed epithelial healing.[33] It has been shown that increased colonization of the conjunctiva can correlate with the severity of diabetic retinopathy.[34] An increase in abundance of coagulase-negative Staphylococcus is associated with the manifestation of diabetic retinopathy.[35]

Table 1: Ocular Manifestations and Associated Dysbiosis of Ocular Surface Microbiome[5][11][14] [21][22][23] [24][25][28][33][35]
Ocular Manifestations Relative Abundance Increase Relative Abundance Decrease
Bacterial Keratitis Genus Level: Streptococcus, Staphylococcus, Paracoccus, Bosea, Gemella, Capnocytophaga, Corynebacterium, Methylobacterium, and Pseudomonas N/A
Fungal Keratitis Phylum Level: Ascomycota Division Level: Basidiomycota
Aqueous Tear-Deficient Dry Eye (ADDE Genus Level: Brevibacterium Genus Level: Pseudomonas
Evaporative/Meibomian Gland Dysfunction Genus Level: Staphylococcus and Sphingomonas

Phylum Level: Firmicutes and Proteobacteria

Genus Level: Corynebacterium

Phylum Level: Actinobacteria

Blepharitis Genus Level: Staphylococcus, Corynebacterium, and Enhydrobacter Genus Level:  Propionibacterium
Trachoma Genus Level: Corynebacterium and Streptococcus N/A
Contact Lens-Induced Dysbiosis Genus Level: Methylobacterium, Lactobacillus, Acinetobacter, and Pseudomonas Genus Level:  Haemophilus, Streptococcus, Staphylococcus, and Corynebacterium
Stevens Johnson Syndrome Genus Level: Pseudomonas, Staphylococcus, Streptococcus, Corynebacterium, and Acinetobacter N/A
Diabetes-Induced Dysbiosis and Retinopathy Genus Level: Acinetobacter and coagulase-negative Staphylococcus

Phylum Level: Proteobacteria

Phylum Level: Firmicutes

Management and Treatment

Several measures can be taken to maintain a healthy ocular surface microbiome. Getting proper sleep can promote the growth of normal ocular surface microbiome.[12][36] It is also recommended that contacts be worn sparingly and not overnight.[12] Appropriate hygienic practices before inserting or removing contacts such as thorough hand washing is important.[12] However, it is also important to avoid the usage of severe chemicals, such as shampoos and face wash, in and around the eyes.[12]

Unfortunately treatments that specifically target dysbiosis of the ocular surface microbiome have not been widely studied. However, one study found that one month of eye-drop probiotic treatment can improve signs and symptoms of patients with vernal keratoconjunctivitis.[37]

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