Comments to the Editor concerning the paper entitled “The microbiome and ophthalmic disease” by Baim et al.

Baim et al.¹ in their informative narrative review demonstrated the existing piece of evidence linking microbiome and ocular disease. Apart from other pathogens, Helicobacter pylori (Hp) was associated with primary open angle glaucoma (POAG) and diverse interesting mechanisms were suggested, which could interpret its potential virulence.

Since both Hp infection (Hp-I) and glaucoma appear to be large worldwide health burdens (Hp-I affects approximately half of the world population² and there were around 4.4 billion individuals with Hp-I worldwide in 2015; glaucoma is the second leading cause of irreversible blindness, and there are 64.3 million individuals with glaucoma globally³), we wish to add further relevant information regarding the Hp-I involvement in the pathophysiology of glaucoma and other ocular pathologies. Specifically, beyond its very well-documented involvement to gastric ulcer and adenocarcinoma, Hp appears to have pleiotropic extra-gastric effects.^2,4 Among others, emerging evidence supports the association between Hp and central nervous system pathologies and particularly Alzheimer’s disease (AD). Likewise, Hp-I has been implicated in the pathogenesis of glaucoma and accumulating data support this causative hypothesis.^5–8 The latter is known bibliographically as “ocular AD,” since both modalities share common pathophysiologic mechanisms.²

As soon as 2001, our research team revealed, by using the gold standard of histologic substantiation, a high Hp-I prevalence in patients with POAG and pseudoexfoliation glaucoma (PEG).⁹ Later on, we reported¹⁰ a positive effect on POAG progression after Hp eradication with accompanying reduction in intraocular pressure and improvement of visual field parameters, study also mentioned by the authors.¹ It is important to note that the majority of our glaucoma patients, particularly the subgroup of patients in whom the Hp eradication treatment was unsuccessful, exhibited chronic atrophic gastritis.^9,10 In this respect, relative studies reported that Hp-related chronic atrophic gastritis or atrophic gastritis per se results in malabsorption of vitamin B-12 and folate, which leads to the failure of methylation by 5-methyl-tetrahydrofolic acid and, thus, to homocysteine (Hcy) accumulation. Subsequently, elevated Hcy concentrations can trigger endothelial dysfunction and vascular oxidative injury involved in the pathophysiology of neurodegenerative disorders including dementia, AD and glaucoma.^11–13 Endothelial injury and vascular dysregulation play a role in glaucomatous optic nerve atrophy pathogenesis, and hyperhomocysteinemia is a risk factor for endothelial dysfunction and is associated with both POAG and PEG.¹³ Moreover, augmented Hcy concentrations observed in the plasma and aqueous humor of POAG patients can induce oxidative stress damage in human trabecular meshwork cells, thereby signifying that Hcy could be a potential treatment target in POAG patients.¹⁴

Likewise, we showed that specific Hp-immunoglobulin G antibody concentration in the aqueous humor of POAG and PEG patients was increased, and there was a correlation of this concentration to the degree of vertical cupping, possibly reflecting the severity of glaucomatous damage.¹⁵ Additionally, we detected, for the first time, Hp microorganisms in iris and trabeculum of POAG patients.¹⁶ Relevant data from different countries including Korea, Turkey, China, Iran and India, using serology or the ¹³C-urea breath test, support a causative relationship.⁸ However, as mentioned by the authors,¹ the Hp involvement in glaucoma pathogenesis remains controversial with wide variability of diagnostic criteria among existing studies as well as Israel groups reporting no significant association with either pathogenic or non-pathogenic strains of this organism, by using serology.¹⁷ Nevertheless, concerns have arisen regarding the methodology, selection of patient groups, and claims considered by the aforementioned Israel series,¹⁸ and thus further research is needed.

Apart from hyperhomocysteinemia, Hp-I might affect the pathophysiology of POAG by several additional mechanisms. For example, Hp-I can induce nitric oxide synthase (iNOS) expression and nitric oxide (NO) overproduction derived from iNOS; NO is a rapidly diffusing gas and in sufficient concentrations is a potent neurotoxin that may facilitate the apoptotic death of retinal ganglion cells in the pathophysiology of glaucomatous optic neuropathy.⁷ Abnormalities in regulation of apoptosis appear to influence the pathophysiology of both Hp-I and glaucoma. Two major pathways of apoptosis that include Fas/Fas ligand (Fas or membrane death receptor)-mediated and mitochondria-dependent signaling for cell degradation appear to play crucial roles in the pathogenesis of glaucoma and Hp-induced pathologies, thereby suggesting an apoptotic link in the pathophysiology of both diseases.¹⁹ Moreover, Hp-I might induce blood–brain barrier (BBB)/blood–ocular barrier (BOB) breakdown by releasing the several inflammatory mediators, thereby contributing to the pathogenesis of glaucoma and other neuropathies. For example, Hp could indirectly signal brain through the production and distant action of TNF-α; the latter is involved in BBB disruption through matrix metalloproteinases’ upregulation.²⁰ Moreover, Hp-induced vacuolating cytotoxin A exhibits chemotactic activities to the bone marrow-derived mast cells (BMD-MCs) and induces BMD-MCs to produce proinflammatory cytokines involved in the BBB disruption. In this respect, TNF-α alone, or in combination with other cytokines, induces permeability of the blood–retinal barrier (BRB)²¹ and BRB breakdown is implicated in ophthalmic diseases including POAG;²² BRB permeability renders circulating mediators, such as endothelin-1 (ET-1), a potent constrictor of arterioles and venules, direct access to optic nerve head and to adjacent retinal tissue, thereby resulting in vasoconstriction observed in the peri-papillary retinal vessel in glaucoma patients.^7,23 In this respect, increased ET-1 and NO are associated with Hp-I and ET-1-produced vasoconstriction of the anterior optic nerve vessels and NO modulation of vascular tone in the ophthalmic artery might promote glaucomatous damage;⁷ ET-1 and NO are significantly raised in the aqueous humor of patients with POAG, thereby possibly involving in POAG pathophysiology.²⁴

Furthermore, circulating antibodies against Hp might also invade the aqueous circulation due to aforementioned BOB/BRB disruption, thus potentially being implicated in glaucomatous and neuropathy pathophysiology; once serum-specific antibodies of glaucoma patients enter the brain, they are known to have deadly properties against retinal cells.¹⁵ Moreover, circulating monocytes with defective autophagy may ingest Hp, which later replicates in autophagic vesicles and reaches the central nervous system through disrupted aforementioned barriers (the so-called Trojan horse theory) and might lead to POAG and related pathologies like AD. Finally, once oral cavity serves as Hp reservoir, the microorganism might reach the ophthalmic tissues and brain through nasal cavity and the so-called olfactory pathway, causing thus POAG and neurodegenerative pathologies.^2,8

Of particular interest is the evidence, that an increasing number of ocular pathologies, beyond POAG are associated with Hp-I. Central serous chorioretinitis and blepharitis belong to this category, and evidence is significantly strengthened by relevant positive systematic reviews with meta-analysis.^25–27 In this respect, Hp may reach the eye through the aforementioned nasal cavity, possibly causing, apart from blepharitis, and dacryostenosis (DS).²⁸ Relative evidence indicates that ascending nasal inflammation or descending ocular inflammation play a role in DS development; ascending agents (i.e. pepsin) of gastroesophageal reflux (GER) may induce local swelling of the nasolacrimal duct mucosa, which might progress to fibrosis and chronic inflammation ultimately resulting in the occurrence of DS; and deficiency of trefoil factor family (TFF) peptides that regulate the human lacrimal system, may also contribute to DS development. Moreover, although other antimicrobial peptides (defensins) appear to exhibit therapeutic effects in dacryocystitis, caution is needed since defensins are also known for their ability to induce fibrin formation and cell proliferation, critical elements in DS; in particular, human-beta defensin (HBD)-2 is detected in the lacrimal passage in the presence of bacterial dacryocystitis,²⁸ and the detection of Hp in lacrimal secretions by PCR indicates the existence of a number of mechanisms for Hp transmission to lacrimal secretions.²⁹ Our own data reveal that: Hp-I is involved in GER disease pathophysiology³⁰ and the ophthalmic tissue Hp bacteria,¹⁶ beyond other eye pathologies, could also induce DS, by releasing diverse proinflammatory cytokines, thereby contributing to the descending ocular inflammatory process. Furthermore, Hp significantly upregulates HBD-2 expression, which, as a proinflammatory agent, is implicated in Hp-related inflammatory disorders and decreases TFF protein expression causing damage, and thus further contributing to DS pathophysiology.²⁸

Taken all together, it seems that Hp has “gained ground” over the last years, as independent data from different research teams and countries suggest a causative role with mechanistic interpretations, rather than a random coincidence–coexistence. However, further large-scale studies are required, before a consensus regarding ophthalmic pathologies and Hp can be reached.

Authors’ contributions

MD and JK conceived the idea and drafted the article. SAP, AP and PK critically revised the article for important intellectual content.

DECLARATION OF CONFLICTING INTERESTS

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

FUNDING

The author(s) received no financial support for the research, authorship, and/or publication of this article.