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While pathogens of the eye have been studied for a very long time, the existence of resident microbes on the surface of healthy eyes has gained interest only recently. It appears that commensal microbes are a normal feature of the healthy eye, whose role and properties are currently the subject of extensive research. This review provides an overview of studies that have used 16s rRNA gene sequencing and whole metagenome shotgun sequencing to characterize microbial communities associated with the healthy ocular surface from kingdom to genus level. Bacteria are the primary colonizers of the healthy ocular surface, with three predominant phyla: , and , regardless of the host, environment, and method used. Refining the microbial classification to the genus level reveals a highly variable distribution from one individual and study to another. Factors accounting for this variability are intriguing - it is currently unknown to what extent this is attributable to the individuals and their environment and how much is artifactual. Clearly, it is technically challenging to accurately describe the microorganisms of the ocular surface because their abundance is relatively low, thus, permitting substantial contaminations. More research is needed, including better experimental standards to prevent biases, and the exploration of the ocular surface microbiome's role in a spectrum of healthy to pathological states. Outcomes from such research include the opportunity for therapeutic interventions targeting the microbiome.

The term ocular microbiota refers to all types of commensal and pathogenic microorganisms present on or in the eye. The ocular surface is continuously exposed to the environment and harbors various commensals. Commensal microbes have been demonstrated to regulate host metabolism, development of immune system, and host defense against pathogen invasion. An unbalanced microbiota could lead to pathogenic microbial overgrowth and cause local or systemic inflammation. The specific antigens that irritate the deleterious immune responses in various inflammatory eye diseases remain obscure, while recent evidence implies a microbial etiology of these illnesses. The purpose of this review is to provide an overview of the literature on ocular microbiota and the role of commensal microbes in several eye diseases. In addition, this review will also discuss the interaction between microbial pathogens and host factors involved in intraocular inflammation, and evaluate therapeutic potential of targeting ocular microbiota to treat intraocular inflammation.

Although dry eye disease (DED) is one of the most common ocular surface diseases worldwide, its pathogenesis is incompletely understood, and treatment options are limited. There is growing evidence that complex interactions between the ocular surface microbiome (OSM) and tear fluid constituents, potentially leading to inflammatory processes, are associated with ocular surface diseases such as DED. In this study, we aimed to find unique compositional and functional features of the OSM associated with human and microbial tear proteins in patients with DED. Applying whole-metagenome shotgun sequencing of forty lid and conjunctival swabs, we identified 229 taxa, with Actinobacteria and Proteobacteria being the most abundant phyla and Propionibacterium acnes the dominating species in the cohort. When DED patients were compared to controls, the species Corynebacterium tuberculostearicum was more abundant in conjunctival samples, whereas the family Propionibacteriaceae was more abundant in lid samples. Functional analysis showed that genes of L-lysine biosynthesis, tetrapyrrole biosynthesis, 5-aminoimidazole ribonucleotide biosynthesis, and the super pathway of L-threonine biosynthesis were enriched in conjunctival samples of controls. The relative abundances of Acinetobacter johnsonii correlated with seven human tear proteins, including mucin-16. The three most abundant microbial tear proteins were the chaperone protein DnaK, the arsenical resistance protein ArsH, and helicase. Compositional and functional features of the OSM and the tear proteome are altered in patients with DED. Ultimately, this may help to design novel interventional therapeutics to target DED.

PurposeTo compare ocular surface microbiome and its antibiotic sensitivity in vernal keratoconjunctivitis (VKC) with normal ocular surface.MethodsIn this case-control study, thirty patients each with clinical diagnosis of VKC and age-matched controls with normal ocular surface were enrolled. Tear film samples were collected from each group and subjected to microbial evaluation with microscopy, conventional culture methods, and polymerase chain reaction (PCR). Microbial diversity and antibiotic sensitivity patterns were analyzed.ResultsMost patients (67%) belonged to severe grades (3 and 4) of VKC, and allergic history could be elicited in 20%. On culture, bacteria were isolated in 50% of VKC patients and 47% of control group. Staphylococcus species were identified in 70% VKC group and 57% control group. S. aureus growth was seen in 52% and 21% of VKC patients and controls, respectively. S. pneumoniae was isolated only in controls (29%) (p<0.05). Confluent colonies (≥10 colonies/μl) were seen in 70% of VKC patients and 14% of controls (p<0.05). Fluoroquinolone resistance was more among higher grades of VKC (50%) (p<0.01) and was observed in 46% of VKC patients and 23% of control group (p<0.01). Both groups were negative for HSV-1 DNA and fungal growth.ConclusionStaphylococcus, the most common ocular surface flora, was predominant in VKC patients. Microbial analysis revealed similar microbial diversity in both groups. However, bacterial load was higher in VKC. Increased fluoroquinolone resistance was observed in VKC patients with more resistance among higher grades. Fungi and HSV-1 were not seen in VKC or normal ocular surface.

Purpose: The pathogenesis of dry eye concomitant with autoimmune disease is different from that of dry eye without autoimmune disease. The aim of this study was to explore differences in the microbiota diversity and composition in dry eye with and without autoimmune disease.Methods: Swab samples from the inferior fornix of the conjunctival sac were obtained from dry eye patients without autoimmune disease (n = 49, dry eye group) and from those with autoimmune disease (n = 38, immdry eye group). Isolated bacterial DNAs from swabs were analyzed with 16S rRNA amplicon sequencing.Results: Analysis of the alpha diversity revealed no significant differences between subjects in the dry eye and immdry eye groups. Those in the immdry eye group had a distinct microbial composition compared with those in the dry eye group. The combination of the genera Corynebacterium and Pelomonas distinguished subjects in the immdry eye group from those in the dry eye group, with an area under the curve of 0.73 (95% CI = 0.62–0.84). For the same bacteria, the correlations between microbe abundance and the ocular surface parameters were different in the two groups. In addition, the functions of the microbial communities were altered in the two groups.Conclusions: Our study demonstrates changes in the composition and function of the ocular microbiome between subjects in the immdry eye and dry eye groups, which suggests that the potential pathogenesis is different.

Although glaucoma is a leading cause of irreversible blindness worldwide, its pathogenesis is incompletely understood, and intraocular pressure (IOP) is the only modifiable risk factor to target the disease. Several associations between the gut microbiome and glaucoma, including the IOP, have been suggested. There is growing evidence that interactions between microbes on the ocular surface, termed the ocular surface microbiome (OSM), and tear proteins, collectively called the tear proteome, may also play a role in ocular diseases such as glaucoma. This study aimed to find characteristic features of the OSM and tear proteins in patients with glaucoma. The whole-metagenome shotgun sequencing of 32 conjunctival swabs identified Actinobacteria, Firmicutes, and Proteobacteria as the dominant phyla in the cohort. The species Corynebacterium mastitidis was only found in healthy controls, and their conjunctival microbiomes may be enriched in genes of the phospholipase pathway compared to glaucoma patients. Despite these minor differences in the OSM, patients showed an enrichment of many tear proteins associated with the immune system compared to controls. In contrast to the OSM, this emphasizes the role of the proteome, with a potential involvement of immunological processes in glaucoma. These findings may contribute to the design of new therapeutic approaches targeting glaucoma and other associated diseases.

Purpose: The low microbial abundance on the ocular surface results in challenges in the characterization of its microbiome. The purpose of this study was to reveal factors introducing bias in the pipeline from sample collection to data analysis of low-abundant microbiomes.Methods: Lower conjunctiva and lower lid swabs were collected from six participants using either standard cotton or flocked nylon swabs. Microbial DNA was isolated with two different kits (with or without prior host DNA depletion and mechanical lysis), followed by whole-metagenome shotgun sequencing with a high sequencing depth set at 60 million reads per sample. The relative microbial compositions were generated using the two different tools MetaPhlan3 and Kraken2.Results: The total amount of extracted DNA was increased by using nylon flocked swabs on the lower conjunctiva. In total, 269 microbial species were detected. The most abundant bacterial phyla were Actinobacteria, Firmicutes and Proteobacteria. Depending on the DNA extraction kit and tool used for profiling, the microbial composition and the relative abundance of viruses varied.Conclusion: The microbial composition on the ocular surface is not dependent on the swab type, but on the DNA extraction method and profiling tool. These factors have to be considered in further studies about the ocular surface microbiome and other sparsely colonized microbiomes in order to improve data reproducibility. Understanding challenges and biases in the characterization of the ocular surface microbiome may set the basis for microbiome-altering interventions for treatment of ocular surface associated diseases.

The ocular surface microbiome consists of microorganisms that play an important role in maintaining homeostasis and preventing disease from invading pathogens. Commensal microbes on the ocular surface interact with cells and molecules of the ocular surface immune system to promote immune tolerance to the normal flora of the ocular surface and facilitate immune protection against invading pathogenic microbes, which allows for a disease-free ocular surface. Various factors can impact the composition, distribution, and diversity of the ocular surface microbiome, including age, gender, disease state, antibiotic treatment, and contact lens use. In addition, there is no cohesive consensus on the species that make up the ocular surface microbes. There is, however, thorough research present on other similar mucosal membranes, such as the gut and oral mucosa, that share similarities with the ocular mucosa. Exploring the relationship of different mucosae allows us to explore treatment options for common ocular diseases such as dry eye syndrome. This review highlights studies that define the ocular surface microbiome, its diversity and composition, host–immune interactions at the ocular surface, factors that cause dysbiosis of the ocular surface microbiome, the impact of dysbiosis on the ocular surface microbiome, and microbiome-based therapy.

[...]the gut microbiome reportedly influences diseases in these organs, but it can also affect disorders in organs outside the digestive tract, such as neurological disorders [e.g., Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (Dinan and Dinan, 2022)] in addition to the success of therapy for several types of cancer (Lu et al., 2022). For dry eye and cicatricial keratoconjunctivitis, quality and/or quantity of tear fluid, is altered, while eyelid findings affect the ocular surface in blepharitis. [...]it is not difficult to imagine that these conditions may affect the OSM in these diseases. [...]the application of NGS technologies in ophthalmology is far from routine but its increasing use has the potential to contribute to the elucidation of pathogenesis, development of new treatment methods and response to treatment, not only for ocular surface diseases, but also for ocular diseases where there is interaction between host microbiome(s) and their metabolites.

Background The ocular surface microbiome (OSM) in patients with meibomian gland dysfunction (MGD) differs from that of healthy individuals. However, the precise role of OSM in MGD remains unknown. Therefore, we aimed to investigate the mechanism of OSM in the inflammation of MGD and the effects of topical sodium butyrate (SB) treatment in ApoE −/− mice. Methods ApoE −/− ( n  = 36) and wild-type C57BL/6J ( n  = 16) mice served as MGD models and healthy controls, respectively. MGD mice were treated with safety-confirmed concentrations of SB (1, 5, and 10 mM) and PBS for 3 weeks. OSM was analyzed by 16S rRNA gene sequencing (V3–V4). The slit-lamp biomicroscopy, tear cytokines, histopathology (oil red O/PAS/TUNEL staining), and TLR4/MyD88/NF-κB signaling (RT-qPCR, immunohistochemistry, and Western blotting) were evaluated. Results Five-month-old ApoE −/− mice exhibited typical clinical and histological features of MGD. These mice exhibited elevated tear levels of inflammatory cytokines and activation of the TLR4/NF-κB signaling pathway in the MGs and conjunctivae. Treatment with SB improved the corneal fluorescein staining score of MGD. The ApoE −/− mice demonstrated dysbiosis of OSM, characterized by an increase in Proteobacteria and a decrease in Bacteroidota . Additionally, the relative abundance of Muribacter and Muribacter muris increased in ApoE −/− mice, while that of Staphylococcus and Staphylococcus lentus decreased, and these alterations were restored by SB treatment. SB also reduced the expression of the TLR4/NF-κB p65 signaling pathway, inflammatory cytokines, and apoptosis in MGs and conjunctival tissues. Conclusion ApoE −/− mice exhibited characteristic features of MGD, accompanied by dysbiosis of OSM. Topical administration of SB modulated the OSM and reduced MGD-associated inflammation. 3uDHCn4-anMbfB6kqnAFHJ Video Abstract