Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma.

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.

Microbial Dynamics in Ophthalmic Health: Exploring the Interplay between Human Microbiota and Glaucoma Pathogenesis.

The human microbiome has a crucial role in the homeostasis and health of the host. These microorganisms along with their genes are involved in various processes, among these are neurological signaling, the maturation of the immune system, and the inhibition of opportunistic pathogens. In this sense, it has been shown that a healthy ocular microbiota acts as a barrier against the entry of pathogens, contributing to the prevention of infections. In recent years, a relationship has been suggested between microbiota dysbiosis and the development of neurodegenerative diseases. In patients with glaucoma, it has been observed that the microbiota of the ocular surface, intraocular cavity, oral cavity, stomach, and gut differ from those observed in healthy patients, which may suggest a role in pathology development, although the evidence remains limited. The mechanisms involved in the relationship of the human microbiome and this neurodegenerative disease remain largely unknown. For this reason, the present review aims to show a broad overview of the influence of the structure and composition of the human oral and gut microbiota and relate its dysbiosis to neurodegenerative diseases, especially glaucoma.

Validation of 16S rRNA Gene Sequencing of the Periocular Microbiome and Lack of Alteration by Topical Eyedrops.

Purpose: Genomic techniques for characterizing the ocular microbiome require further validation. We compared the microbiome of patients' eyelids through both conventional culture and 16S rRNA analysis and analyzed the impact of eyedrop use on microbiome diversity. Methods: Ninety-eight patients followed for management of glaucoma or suspicion of glaucoma had eyelid swabs performed with Isohelix MS Mini DNA Swabs (98 participants) and ESwabs (49 participants) for 16S rRNA analysis and conventional culture, respectively. The effect of preservative-containing eyedrops on the microbiomes detected using these two techniques were analyzed and compared across techniques. Results: Forty-five of the 50 (non-unique) genera (90%) identified by conventional culture were also identified by each individual's 16S rRNA analysis within the top 14 most abundant organisms present based on operational taxonomic unit. All conventional cultures performed had at least one or more genera also identified by each participant's 16S rRNA analysis. There was no difference in the conventional culture positivity rate or proportion of participants with a particular genus present on conventional culture based on whether preservative-containing eyedrops were regularly used. Similarly, in eyes using versus not using eyedrops, no differences were observed in the proportions of participants with a particular genus present or the Shannon index as determined by 16S rRNA analysis. Conclusions: 16S rRNA analysis correlates well with conventional culture results for the eyelid microbiome, with results from neither technique demonstrating an association of microbiome composition and eyedrop use. The clinical relevance of the large numbers of microbes detected via 16S rRNA analysis requires further study. Translational Relevance: 16S rRNA analysis of the periocular microbiome is consistent with conventional culture and enables further study of physiologic and pathologic ocular processes possibly related to microbiome diversity.

Mycoplasma infection and ocular surface diseases: a nationwide cohort study.

Whether patients with Mycoplasma infection have an increased risk of ocular surface ulcers. Using a nation-wide database, we identified patients with a new diagnosis of Mycoplasma infection between 1997 and 2013, and compared them with age-, sex-, and index year-matched subjects without the infection. Cox proportional regression was performed to compare the risk of corneal diseases between the two cohorts. The incidence of corneal diseases was significantly higher in the 4223 patients with Mycoplasma infection than in the 16,892 patients without (7.28 vs. 5.94 per 1000 person-years, P < 0.01). The adjusted hazard ratio for the risk of corneal diseases in the study cohort was 1.21 times higher (95% CI 1.02-1.44) than that in the comparison cohort. Mycoplasma infection might be a predisposing factor for patients with keratitis.

T Cell-Mediated Autoimmunity in Glaucoma Neurodegeneration.

Glaucoma as the leading neurodegenerative disease leads to blindness in 3.6 million people aged 50 years and older worldwide. For many decades, glaucoma therapy has primarily focused on controlling intraocular pressure (IOP) and sound evidence supports its role in delaying the progress of retinal ganglial cell (RGC) damage and protecting patients from vision loss. Meanwhile, accumulating data point to the immune-mediated attack of the neural retina as the underlying pathological process behind glaucoma that may come independent of raised IOP. Recently, some scholars have suggested autoimmune aspects in glaucoma, with autoreactive T cells mediating the chief pathogenic process. This autoimmune process, as well as the pathological features of glaucoma, largely overlaps with other neurodegenerative diseases in the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In addition, immune modulation therapy, which is regarded as a potential solution for glaucoma, has been boosted in trials in some CNS neurodegenerative diseases. Thus, novel insights into the T cell-mediated immunity and treatment in CNS neurodegenerative diseases may serve as valuable inspirations for ophthalmologists. This review focuses on the role of T cell-mediated immunity in the pathogenesis of glaucoma and discusses potential applications of relevant findings of CNS neurodegenerative diseases in future glaucoma research.

The role of commensal microflora-induced T cell responses in glaucoma neurodegeneration.

Over the last decade, new evidence has become increasingly more compelling that commensal microflora profoundly influences the maturation and function of resident immune cells in host physiology. The concept of gut-retina axis is actively being explored. Studies have revealed a critical role of commensal microbes linked with neuronal stress, immune responses, and neurodegeneration in the retina. Microbial dysbiosis changes the blood-retina barrier permeability and modulates T cell-mediated autoimmunity to contribute to the pathogenesis of retinal diseases, such as glaucoma. Heat shock proteins (HSPs), which are evolutionarily conserved, are thought to function both as neuroprotectant and pathogenic antigens of T cells contributing to cell protection and tissue damage, respectively. Activated microglia recruit and interact with T cells during this process. Glaucoma, characterized by the progressive loss of retinal ganglion cells, is the leading cause of irreversible blindness. With nearly 70 million people suffering glaucoma worldwide, which doubles the number of patients with Alzheimer's disease, it represents the most frequent neurodegenerative disease of the central nervous system (CNS). Thus, understanding the mechanism of neurodegeneration in glaucoma and its association with the function of commensal microflora may help unveil the secrets of many neurodegenerative disorders in the CNS and develop novel therapeutic interventions.

Impact of nitric oxide's bidirectional role on glaucoma: focus on Helicobacter pylori-related nitrosative stress.

Nitric oxide (NO), a small molecule generated ubiquitously, targets a plethora of tissues to regulate both physiological and pathophysiological functions. NO overproduction, stimulated by microenvironmental conditions, is the main component that dysregulates the tight balance between its beneficial and damaging roles in ocular homeostasis. Considering the protective functions of NO against glaucoma, its endogenous release facilitates aqueous humor drainage and regulates ocular blood flow, maintaining a normal intraocular pressure. NO overproduction generates free radicals, such as peroxynitrite, which induce a vicious circle of vascular disharmony and dysregulation, transient ischemia, nitrosative stress, neuronal degeneration, and permanent glaucomatic injury. Helicobacter pylori (Hp) is considered a burdening factor of glaucoma. NO overproduction and possible systematic dispersion in Hp infection (Hp-I) could suggest a potential pathophysiological bridge between these conditions. In this review, we aim to elucidate the role of NO in glaucoma with respect to Hp-I, with the aim to stimulate further studies.

[The Efficiency of In-Depth Glaucoma Examination within the Framework of Dispensarization of Individuals with Chronic Infectious Diseases].

In Russia, the population aged 60 years and older is the fastest increasing group. This is the reason of augmenting interest to screening programs permitting to timely detect chronic disease, to proceed with treatment and to stabilize condition of patient. At the same time, screening programs require permanent analysis and development that became a foundation for the actual study. The purpose of the study is to evaluate the medical organizational aspects of the second stage (in-depth) of dispensarization exemplified by glaucoma. The retrospective analysis of 392 out-patient records of patients on suspicion of glaucoma was carried out. The questionnaire for ophthalmologists, consisting of 35 questions, was developed. The anonymous questionnaire survey of 62 ophthalmologists was carried out. The analysis of results of survey established that the most significant problem of dispensarization was shortage of time on reception of patient. This problem was resolved through both partial implementation of all needed examinations (21%) and referring all patients to specialized medical centers. All scheduled manipulations are not implemented by 87% of respondents. All respondents mentioned basically needed equipment as available. The extremely low quality of in-depth examination results in redistribution of load to the specialized medical centers and to increasing of waiting time period from establishment of diagnosis to beginning of treatment of disease. It is necessary to provide continuity of medical care during the second stage of dispensarization by the way of implementation of general scheme of out-patient record and notation of particular methods of examination. These measures will both decrease load on specialized medical centers and permit apply resources more efficiently and reduce time period from suspicion of disease to establishment of diagnosis and beginning of treatment of glaucoma.

Newborn Glaucoma: Do not Forget Infections.

Intrauterine infections can affect various structures of the developing fetal eye. Rubella infection results in congenital cataracts, keratopathy, retinopathy and less commonly, glaucoma. Ophthalmic manifestations of intrauterine cytomegalovirus (CMV) infection have been reported to be chorioretinitis, optic nerve colobomas, and corneal opacities, but have not been implicated in congenital cataract or congenital glaucoma. Concurrent infection with both rubella and CMV virus has not been reported. We report concurrent rubella and CMV infection in a baby born with corneal opacification, severe congenital glaucoma, and congenital cataract. It is important to recognize these babies early and investigate for intrauterine infections rather than assume they are all primary congenital glaucoma. Involvement of the cornea, glaucoma, and cataract make management of these babies a major challenge requiring a multidisciplinary team approach.

The Role of Microbiota in Retinal Disease.

The ten years since the first publications on the human microbiome project have brought enormous attention and insight into the role of the human microbiome in health and disease. Connections between populations of microbiota and ocular disease are now being established, and increased accessibility to microbiome research and insights into other diseases is expected to yield enormous information in the coming years. With the characterization of the ocular microbiome, important insights have already been made regarding corneal and conjunctival tissues. Roles for non-ocular microbiomes in complex retinal diseases are now being evaluated. For example, the gut microbiome has been implicated in the pathogenesis of uveitis. This short review will summarize the few studies linking gut or oral microbiota to diabetic retinopathy (DR), glaucoma, and age-related macular degeneration (AMD). We will also conjecture where the most significant findings still remain to be elucidated. Finally, we will propose the gut-retina axis, related but distinct from the gut-brain axis.

Aspergillus spp. panophthalmitis with intralenticular invasion in dogs: report of two cases.

This case series describes the ocular, clinical and histologic manifestations of disseminated Aspergillosis in two dogs. Two dogs presented for severe unilateral panophthalmitis and secondary glaucoma with positive Aspergillus spp. titers. Case 1 showed no clinicopathologic systemic symptoms of fungal dissemination, however, case 2 was affected with acute renal failure. The affected eye of case 1 did not respond to medical therapy and was enucleated for comfort. The affected eye of case 2 responded to aggressive topical and systemic medical therapies, however, the patient was euthanized for acute renal failure. Globes were collected for histologic evaluation at the time of death. Histology of both revealed panophthalmitis with presence of significant intraocular hemorrhage, multifocal fungal granulomas, retinal and optic nerve changes consistent with secondary glaucoma, rupture of the anterior lens capsule, and fungal invasion and colonization of the intralenticular space. These cases represent a unique and devastating ocular manifestation of disseminated Aspergillosis. Cases presenting with uveitis and secondary glaucoma of unknown origin, especially with confirmed or suspected lens capsular rupture, should have serologic testing for this infectious agent.

Oral microbiome link to neurodegeneration in glaucoma.

BACKGROUND: Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. METHODS: Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. FINDINGS: Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. CONCLUSIONS: The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.

Postoperative infection in penetrating versus non-penetrating glaucoma surgery.

The aim of glaucoma surgery is to lower the intraocular pressure in order to reduce the risk of further glaucomatous progression, particularly in cases refractory to topical therapy. Although effective in reducing intraocular pressure, these procedures are not without complications, with endophthalmitis being one of the most serious. A PubMed review of the literature was performed for trabeculectomy, glaucoma drainage device procedures (Ahmed, Baerveldt and Molteno implants) and non-penetrating glaucoma surgery (deep sclerectomy and viscocanalostomy) for reports of postoperative infection, including blebitis and endophthalmitis. The literature on infections relating to non-penetrating glaucoma surgery is sparse compared with penetrating surgery, but this may be a reflection of the relatively shorter follow-up duration and comparatively smaller body of data available on non-penetrating procedures. Overall, there is not enough evidence, in terms of well-constructed randomised clinical trials with sufficiently large sample sizes and long follow-up durations, to be able to make informed comparisons of the risk of postoperative endophthalmitis and infection between the various glaucoma operations. This review article summarises the incidences of endophthalmitis from the literature and discusses the major risk factors for postoperative infection.

Glaucoma and Helicobacter pylori infection: correlations and controversies.

A possible association between Helicobacter pylori infection and eye diseases, including Sjögren syndrome, blepharitis, central serous chorioretinopathy and uveitis, has been proposed. Glaucoma is the second leading cause of blindness in the world, after cataracts, and the leading cause of irreversible blindness, but many aspects of its pathogenesis remain unknown. H pylori infection may influence the pathophysiology of glaucoma by releasing various proinflammatory and vasoactive substances, as well as by influencing the apoptotic process, parameters that may also exert their own effects in the induction and/or progression of glaucomatous neuropathy. It is difficult to understand how H pylori infection can be linked to such varied pathologies. Systemic H pylori-induced oxidative damage may be the mechanism which links oxidative stress, H pylori infection and the damage to the trabecular meshwork and optical nerve head that results in glaucoma.

Secondary glaucoma associated with bilateral Aspergillus niger endophthalmitis in an HIV-positive patient: case report.

Aspergillus endophthalmitis is usually related to systemic or local dissemination in immunosuppressed subjects. The authors report a rare case of severe bilateral glaucoma secondary to an intraocular infection with Aspergillus niger, in the absence of any detectable focus of aspergillosis, in an HIV-infected patient. There were no confirming signs of injection drug use, and the agent was isolated after inoculation in experimental animals. This case shows that Aspergillus endophthalmitis should be considered in non-injecting drug users and HIV-infected patients even in the absence of systemic aspergillosis.