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The Role of Gut Microbiota in Glaucoma Progression and Other Retinal Diseases

2023; Elsevier BV; Volume: 193; Issue: 11 Linguagem: Inglês

10.1016/j.ajpath.2023.06.015

1525-2191

Julie Chen, Dong Feng Chen, Kin‐Sang Cho,

Gut microbiota and health

As a rapidly growing field, microbiota research offers novel approaches to promoting ocular health and treating major retinal diseases, such as glaucoma. Gut microbiota changes throughout life; however, certain patterns of population changes have been increasingly associated with specific diseases. It has been well established that a disrupted microbiome contributes to central nervous system diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, and glioma, suggesting a prominent role of microbiome in neurodegenerative diseases. This review summarizes the progress in identifying significant changes in the microbial composition of patients with glaucoma by compiling studies on the association between microbiota and disease progression. Of interest is the relationship between increased Firmicutes/Bacteroidetes ratio in patients with primary open-angle glaucoma, increased taurocholic acid, decreased glutathione, and a reduction in retinal ganglion cell survival. Connecting these microbes to specific metabolites sheds light on the pathogenic mechanism and novel treatment strategies. In summary, the current review synthesizes the findings of several studies investigating the effects of shifting bacterial population in retinal diseases, particularly glaucoma, with the aim to identify the current direction of treatment and help direct future endeavors. As a rapidly growing field, microbiota research offers novel approaches to promoting ocular health and treating major retinal diseases, such as glaucoma. Gut microbiota changes throughout life; however, certain patterns of population changes have been increasingly associated with specific diseases. It has been well established that a disrupted microbiome contributes to central nervous system diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, and glioma, suggesting a prominent role of microbiome in neurodegenerative diseases. This review summarizes the progress in identifying significant changes in the microbial composition of patients with glaucoma by compiling studies on the association between microbiota and disease progression. Of interest is the relationship between increased Firmicutes/Bacteroidetes ratio in patients with primary open-angle glaucoma, increased taurocholic acid, decreased glutathione, and a reduction in retinal ganglion cell survival. Connecting these microbes to specific metabolites sheds light on the pathogenic mechanism and novel treatment strategies. In summary, the current review synthesizes the findings of several studies investigating the effects of shifting bacterial population in retinal diseases, particularly glaucoma, with the aim to identify the current direction of treatment and help direct future endeavors. The gut-eye axis represents the ability of gut bacteria to affect eye function.1Trujillo-Vargas C.M. Schaefer L. Alam J. Pflugfelder S.C. Britton R.A. de Paiva C.S. The gut-eye-lacrimal gland-microbiome axis in Sjogren syndrome.Ocul Surf. 2020; 18: 335-344Crossref PubMed Scopus (49) Google Scholar Gut microbiota influence several retinal diseases, including glaucoma.2Napolitano P. Filippelli M. Davinelli S. Bartollino S. dell'Omo R. Costagliola C. Influence of gut microbiota on eye diseases: an overview.Ann Med. 2021; 53: 750-761Crossref PubMed Scopus (25) Google Scholar Regular cues, originating from microbiota, are essential to the normal development of the central nervous system. For instance, brain formation and differentiation during development requires long-distance cell migration, a process influenced by cues from the gut microbiota; dietary components directly interact with the developing brain and impact its function.3Sharon G. Sampson T.R. Geschwind D.H. Mazmanian S.K. The central nervous system and the gut microbiome.Cell. 2016; 167: 915-932Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar Gut microbiota changes in response to external environmental cues. Factors such as age and unhealthy diet cause shifts in the microbiome, altering immune signals and metabolic products, including butyrate and short-chain fatty acids (SCFAs).4Karlsson F. Tremaroli V. Nielsen J. Backhed F. Assessing the human gut microbiota in metabolic diseases.Diabetes. 2013; 62: 3341-3349Crossref PubMed Scopus (318) Google Scholar,5Rashid K. Akhtar-Schaefer I. Langmann T. Microglia in retinal degeneration.Front Immunol. 2019; 10: 1975Crossref PubMed Scopus (186) Google Scholar Immune signal changes play a seminal role in understanding the pathogenesis of glaucoma. Alongside increased intraocular pressure (IOP), higher levels of proinflammatory cytokines and chemokines have been observed in patients with glaucoma.4Karlsson F. Tremaroli V. Nielsen J. Backhed F. Assessing the human gut microbiota in metabolic diseases.Diabetes. 2013; 62: 3341-3349Crossref PubMed Scopus (318) Google Scholar Tracing the metabolites and signals produced by bacteria during glaucoma pathogenesis can help examine the pathways and mechanisms that lead to major retinal disease, providing opportunities for developing novel therapeutic interventions. Establishing the relationship between gut bacteria and retinal eye diseases may lead to novel therapeutic approaches. Probiotics and the introduction of healthy microbiota are some of the methods being explored to prevent or alleviate glaucoma and other retinal diseases.6Parolini C. Effects of fish n-3 PUFAs on intestinal microbiota and immune system.Mar Drugs. 2019; 17: 374Crossref PubMed Scopus (87) Google Scholar An individual's gut microbiota is inherited from the maternal parent and then changes as it is exposed to the surrounding environment. Although the gut microbiota population is expected to fluctuate and change throughout a lifetime, certain disruptions have detrimental impacts on health. The most dramatic changes in microbiota occur during infancy and old age when the immune system is at its weakest, demonstrating a connection between microbiota, the immune system, and aging.7Nagpal R. Mainali R. Ahmadi S. Wang S. Singh R. Kavanagh K. Kitzman D.W. Kushugulova A. Marotta F. Yadav H. Gut microbiome and aging: physiological and mechanistic insights.Nutr Healthy Aging. 2018; 4: 267-285Crossref PubMed Scopus (376) Google Scholar Mouse studies have shown that aging populations have increased Clostridia relative to Bacteriodales and decreased Lactobacillus.8Langille M.G. Meehan C.J. Koenig J.E. Dhanani A.S. Rose R.A. Howlett S.E. Beiko R.G. Microbial shifts in the aging mouse gut.Microbiome. 2014; 2: 50Crossref PubMed Scopus (264) Google Scholar,9Zhang C. Li S. Yang L. Huang P. Li W. Wang S. Zhao G. Zhang M. Pang X. Yan Z. 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Effects of fish n-3 PUFAs on intestinal microbiota and immune system.Mar Drugs. 2019; 17: 374Crossref PubMed Scopus (87) Google Scholar The decreased bacterial diversity and increase in bacterial population found in older adults can trigger immune response and dysregulated para-inflammation,11Chen M. Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration.J Leukoc Biol. 2015; 98: 713-725Crossref PubMed Scopus (220) Google Scholar which is detrimental to retinal health.12Kim S. Jazwinski S.M. The gut microbiota and healthy aging: a mini-review.Gerontology. 2018; 64: 513-520Crossref PubMed Scopus (226) Google Scholar The inflammatory process is a fundamental component underlying several age-related eye diseases, such as glaucoma and age-related macular degeneration (AMD), two of the leading causes of vision loss in elderly individuals. Studying the relationship between eye disease, aging, and shifting microbiota bacterial populations can help better understand disease pathways and uncover novel interventions. Studies of retinal diseases and the influence of microbiota are already underway. The normal human gut microbiota consists primarily of two bacterial phyla, Firmicutes and Bacteroidetes.13Frank D.N. Pace N.R. Gastrointestinal microbiology enters the metagenomics era.Curr Opin Gastroenterol. 2008; 24: 4-10Crossref PubMed Scopus (330) Google Scholar Dysbiosis (disruption in microbiota) of gut microbiome leads to systemic inflammation and induces the onset of many diseases.14Floyd J.L. Grant M.B. The gut-eye axis: lessons learned from murine models.Ophthalmol Ther. 2020; 9: 499-513Crossref PubMed Scopus (44) Google Scholar Inflammation contributes to neurodegeneration in glaucoma.15Rolle T. Ponzetto A. Malinverni L. The role of neuroinflammation in glaucoma: an update on molecular mechanisms and new therapeutic options.Front Neurol. 2020; 11612422PubMed Google Scholar Thus, inflammation caused by dysbiosis and a leaky gut-vessel barrier indicates the potential role of the gut microbiota in retinal disease progression.16Rinninella E. Mele M.C. Merendino N. Cintoni M. Anselmi G. Caporossi A. Gasbarrini A. Minnella A.M. The role of diet, micronutrients and the gut microbiota in age-related macular degeneration: new perspectives from the gut–retina axis.Nutrients. 2018; 10: 1677Crossref PubMed Scopus (101) Google Scholar Increased inflammatory signals are found in glaucomatous eyes.17Pezzino S. Sofia M. Greco L.P. Litrico G. Filippello G. Sarvà I. La Greca G. Latteri S. Microbiome dysbiosis: a pathological mechanism at the intersection of obesity and glaucoma.Int J Mol Sci. 2023; 24: 1166Crossref PubMed Scopus (2) Google Scholar Obesity (linked to gut dysbiosis), and an increased risk of glaucoma, indicate a connection between the microbiome and glaucoma. Further evidence of the role of bacteria in retinal disease is demonstrated by dietary supplantation, which has been proven an effective treatment to slow AMD disease progression.18Age-Related Eye Disease Study Research GroupA randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8.Arch Ophthalmol. 2001; 119: 1417-1436Crossref PubMed Google Scholar Because the retinal pigment epithelium is located in an environment with high oxygen partial pressure, it is especially sensitive to oxidative stress. Thus, the anti-oxidative capability of retinal pigment epithelium is crucial and helps explain the benefits of bacteria that produce antioxidants, especially as this protective capability decreases in aging retinal pigment epithelium cells.19Lim L.S. Mitchell P. Seddon J.M. Holz F.G. Wong T.Y. Age-related macular degeneration.Lancet. 2012; 379: 1728-1738Abstract Full Text Full Text PDF PubMed Scopus (1336) Google Scholar Beneficial bacteria benefit from the production of antioxidants. There is also increasing evidence of a direct relationship between damaged flora and oxidative stress, suggesting that gut dysbiosis leads to age-related retinal degeneration. Gut microbiota can exert a beneficial effect when certain macromolecule intake is decreased. The impact of both high-fat diet and high glucose on microbiota population and the resulting metabolic effects has been extensively studied and established.20Do M.H. Lee E. Oh M.J. Kim Y. Park H.Y. High-glucose or -fructose diet cause changes of the gut microbiota and metabolic disorders in mice without body weight change.Nutrients. 2018; 10: 761Crossref PubMed Scopus (245) Google Scholar Metabolic products produced by gut bacteria as a result of macromolecular breakdown mediate crosstalk between the gut and immune system.21Yoo J.Y. Groer M. Dutra S.V.O. Sarkar A. McSkimming D.I. Gut microbiota and immune system interactions.Microorganisms. 2020; 8: 1587Crossref PubMed Scopus (232) Google Scholar Furthermore, the composition of these metabolites affects bacterial composition. High-fat diet generally leads to increased bacterial Firmicutes and decreased Bacteroidetes. This bacterial population imbalance results in enhanced inflammation.22Murphy E.A. Velazquez K.T. Herbert K.M. Influence of high-fat diet on gut microbiota: a driving force for chronic disease risk.Curr Opin Clin Nutr Metab Care. 2015; 18: 515-520Crossref PubMed Scopus (319) Google Scholar,23Kutsyr O. Noailles A. Martinez-Gil N. Maestre-Carballa L. Martinez-Garcia M. Maneu V. Cuenca N. Lax P. Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation.Proc Natl Acad Sci U S A. 2021; 118e2100566118Crossref PubMed Scopus (12) Google Scholar In a seminal study, mice fed a diet emulating the Western diet presented with an AMD-like disease state. Altering the Western diet, even among older mice, halted the progression of the retinal disease.24Wu J. Cho E. Giovannucci E.L. Rosner B.A. Sastry S.M. Schaumberg D.A. Willett W.C. Dietary intake of alpha-linolenic acid and risk of age-related macular degeneration.Am J Clin Nutr. 2017; 105: 1483-1492Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar A study analyzing microbiota confirmed that mice fed a high glucose diet showed disease-like features in the retina and an increased population of Firmicutes, whereas those fed a low-glucose diet did not develop disease-like symptoms and possessed larger populations of Bacteroidales and Erysipelotrichi.25Rowan S. Jiang S. Korem T. Szymanski J. Chang M.L. Szelog J. Cassalman C. Dasuri K. McGuire C. Nagai R. Du X.L. Brownlee M. Rabbani N. Thornalley P.J. Baleja J.D. Deik A.A. Pierce K.A. Scott J.M. Clish C.B. Smith D.E. Weinberger A. Avnit-Sagi T. Lotan-Pompan M. Segal E. Taylor A. Involvement of a gut-retina axis in protection against dietary glycemia-induced age-related macular degeneration.Proc Natl Acad Sci U S A. 2017; 114: E4472-E4481Crossref PubMed Scopus (158) Google Scholar This finding strengthens the connection between microbiota composition and retinal health, implicating that gut microbiota imbalance contributes to retinal disease development or progression. Examining bacterial populations of interest in AMD may help define their actions in the pathogenesis of glaucoma or other retinal diseases since AMD and glaucoma share similar vascular pathophysiological pathways.26Hu C.C. Ho J.D. Lin H.C. Kao L.T. Association between open-angle glaucoma and neovascular age-related macular degeneration: a case-control study.Eye. 2017; 31: 872-877Crossref PubMed Scopus (18) Google Scholar Changes in metabolite concentration within the blood stemming from microbiota alterations is a promising area of study, where the pathogenesis of glaucoma and AMD, and potentially other retinal diseases, may overlap. Glaucoma, the second leading cause of blindness after cataract in the world, is impacted by altered microbiota.6Parolini C. Effects of fish n-3 PUFAs on intestinal microbiota and immune system.Mar Drugs. 2019; 17: 374Crossref PubMed Scopus (87) Google Scholar,27Weinreb R.N. Aung T. Medeiros F.A. The pathophysiology and treatment of glaucoma: a review.JAMA. 2014; 311: 1901-1911Crossref PubMed Scopus (2175) Google Scholar The hallmarks of glaucoma pathogenesis include progressive degeneration of retinal ganglion cells and their axons which results in irreversible vision loss. It affects >70 million people worldwide.27Weinreb R.N. Aung T. Medeiros F.A. The pathophysiology and treatment of glaucoma: a review.JAMA. 2014; 311: 1901-1911Crossref PubMed Scopus (2175) Google Scholar Mere administration of heat shock protein 27 has been shown to activate T cells, inducing an inflammatory response that leads to neurodegeneration resembling the pathology of glaucoma.28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.J Neurosci. 2008; 28: 12085-12096Crossref PubMed Scopus (178) Google Scholar A seminal study found that germ-free mice could not evoke the heat shock protein–specific CD4+ T-cell responses nor did they develop the glaucomatous neurodegeneration under elevated IOP; however, a milder form of glaucomatous degeneration was detected in altered Schaedler flora Swiss Webster mice that were colonized by eight defined gut bacteria.29Tang Y. Shah S. Cho K.S. Sun X. Chen D.F. Metabolomics in primary open angle glaucoma: a systematic review and meta-analysis.Front Neurosci. 2022; 16835736Crossref Scopus (3) Google Scholar Thus, the presence of a specific microbiota population may be related to the initiation or perpetuation of neurodegenerative T-cell responses. Taken together, these animal studies suggest an association between the presence of microbiota and the progression of neuronal loss in glaucoma. Gut microbiota and their changing composition underlie the presentation as well as the progression of several retinal diseases. Several studies show changes in gut microbiome profiles in animal models of glaucoma or in patients with glaucoma. At the phyla level, Zhang et al30Zhang Y. Zhou X. Lu Y. Gut microbiota and derived metabolomic profiling in glaucoma with progressive neurodegeneration.Front Cell Infect Microbiol. 2022; 12968992Google Scholar showed a significantly higher Firmicutes/Bacteroidetes (F/B) ratio, as well as an increased Verruomicrobia load, in a rat with glaucoma. At the genus level, Romnoutsia, Akkermansia, and Bacteroides were significantly higher in a rat with glaucoma, but Lactobacillus load was higher.30Zhang Y. Zhou X. Lu Y. Gut microbiota and derived metabolomic profiling in glaucoma with progressive neurodegeneration.Front Cell Infect Microbiol. 2022; 12968992Google Scholar The gut microbiome population in humans consists of Firmicutes (65%) and Bacteroidetes (23%) as major bacterial phyla.13Frank D.N. Pace N.R. Gastrointestinal microbiology enters the metagenomics era.Curr Opin Gastroenterol. 2008; 24: 4-10Crossref PubMed Scopus (330) Google Scholar Approximately 5% of gut microbiome composition is reflective of oral microbiome.31Yoon B.W. Lim S.H. Shin J.H. Lee J.W. Lee Y. Seo J.H. Analysis of oral microbiome in glaucoma patients using machine learning prediction models.J Oral Microbiol. 2021; 131962125Crossref PubMed Scopus (5) Google Scholar Dysbiosis of oral microbiome may affect glaucoma progression. A cohort study showed an association between severe periodontal disease and a risk of primary open-angle glaucoma (POAG).32Pasquale L.R. Hyman L. Wiggs J.L. Rosner B.A. Joshipura K. McEvoy M. McPherson Z.E. Danias J. Kang J.H. Prospective study of oral health and risk of primary open-angle glaucoma in men: data from the health professionals follow-up study.Ophthalmology. 2016; 123: 2318-2327Abstract Full Text Full Text PDF PubMed Google Scholar POAG is the most common glaucoma type in America and western Europe and specifically includes the presentation of increased IOP.33Weinreb R.N. Khaw P.T. Primary open-angle glaucoma.Lancet. 2004; 363: 1711-1720Abstract Full Text Full Text PDF PubMed Scopus (1560) Google Scholar,34Shields M.B. Normal-tension glaucoma: is it different from primary open-angle glaucoma?.Curr Opin Ophthalmol. 2008; 19: 85-88Crossref PubMed Scopus (184) Google Scholar Zeng et al35Zeng J. Liu H. Liu X. Ding C. The relationship between Helicobacter pylori infection and open-angle glaucoma: a meta-analysis.Invest Ophthalmol Vis Sci. 2015; 56: 5238-5245Crossref PubMed Scopus (64) Google Scholar reported, in a meta-analysis study, that oral microbiome Helicobacter pylori were associated with POAG and normal-tension glaucoma. Kountouras et al36Kountouras J. Mylopoulos N. Chatzopoulos D. Zavos C. Boura P. Konstas A.G. Venizelos J. Eradication of Helicobacter pylori may be beneficial in the management of chronic open-angle glaucoma.Arch Intern Med. 2002; 162: 1237-1244Crossref PubMed Google Scholar demonstrated that eradication of H. pylori improved IOP and visual field defect in patients with POAG. Nevertheless, the association of H. pylori with glaucoma is still controversial, and a different study was unable to find a significant association between H. pylori and the occurrence of glaucoma.37Kurtz S. Regenbogen M. Goldiner I. Horowitz N. Moshkowitz M. No association between Helicobacter pylori infection or CagA-bearing strains and glaucoma.J Glaucoma. 2008; 17: 223-226Crossref PubMed Scopus (37) Google Scholar In addition, Streptococci load was higher in the saliva of patients with POAG than in the controls. Astafurov et al38Astafurov K. Elhawy E. Ren L. Dong C.Q. Igboin C. Hyman L. Griffen A. Mittag T. Danias J. Oral microbiome link to neurodegeneration in glaucoma.PLoS One. 2014; 9e104416Crossref PubMed Scopus (87) Google Scholar showed that altered commensal microbiome induced changes in cytokine and complement activation. However, independent studies showed that changes in oral microbiome had no correlation to visual field decline.38Astafurov K. Elhawy E. Ren L. Dong C.Q. Igboin C. Hyman L. Griffen A. Mittag T. Danias J. Oral microbiome link to neurodegeneration in glaucoma.PLoS One. 2014; 9e104416Crossref PubMed Scopus (87) Google Scholar,39Polla D. Astafurov K. Hawy E. Hyman L. Hou W. Danias J. A pilot study to evaluate the oral microbiome and dental health in primary open-angle glaucoma.J Glaucoma. 2017; 26: 320-327Crossref PubMed Scopus (22) Google Scholar Further cohort studies of association between oral microbiome profiling and glaucoma are needed. Recent studies report an association between the specific profiles of gut microbiome and neurodegenerative diseases. Yoon et al31Yoon B.W. Lim S.H. Shin J.H. Lee J.W. Lee Y. Seo J.H. Analysis of oral microbiome in glaucoma patients using machine learning prediction models.J Oral Microbiol. 2021; 131962125Crossref PubMed Scopus (5) Google Scholar reported an increased Faecalibacterium load in patients with glaucoma. Faecalibacterium modulates butyrate metabolite in the gut that is correlated to anti-inflammatory effect. Additionally, Faecalibacterium population is reduced in patients with Alzheimer and Parkinson diseases.40Leylabadlo H.E. Ghotaslou R. Feizabadi M.M. Farajnia S. Moaddab S.Y. Ganbarov K. Khodadadi E. Tanomand A. Sheykhsaran E. Yousefi B. Kafil H.S. The critical role of Faecalibacterium prausnitzii in human health: an overview.Microb Pathog. 2020; 149104344Crossref PubMed Scopus (72) Google Scholar Multiple studies demonstrate a link between gut microbiota and neurodegenerative disease, such as Alzheimer disease.41Vogt N.M. Kerby R.L. Dill-McFarland K.A. Harding S.J. Merluzzi A.P. Johnson S.C. Carlsson C.M. Asthana S. Zetterberg H. Blennow K. Bendlin B.B. Rey F.E. Gut microbiome alterations in Alzheimer's disease.Sci Rep. 2017; 713537Crossref Scopus (1055) Google Scholar,42Marizzoni M. Cattaneo A. Mirabelli P. Festari C. Lopizzo N. Nicolosi V. Mombelli E. Mazzelli M. Luongo D. Naviglio D. Coppola L. Salvatore M. Frisoni G.B. Short-chain fatty acids and lipopolysaccharide as mediators between gut dysbiosis and amyloid pathology in Alzheimer's disease.J Alzheimers Dis. 2020; 78: 683-697Crossref PubMed Scopus (150) Google Scholar This further supports a possible association between glaucoma and Alzheimer disease.43Xu X.H. Zou J.Y. Geng W. Wang A.Y. Association between glaucoma and the risk of Alzheimer's disease: a systematic review of observational studies.Acta Ophthalmol. 2019; 97: 665-671Crossref PubMed Scopus (21) Google Scholar, 44Sen S. Saxena R. Tripathi M. Vibha D. Dhiman R. Neurodegeneration in Alzheimer's disease and glaucoma: overlaps and missing links.Eye. 2020; 34: 1546-1553Crossref PubMed Scopus (28) Google Scholar, 45Margeta M.A. Yin Z. Madore C. Pitts K.M. Letcher S.M. Tang J. Jiang S. Gauthier C.D. Silveira S.R. Schroeder C.M. Lad E.M. Proia A.D. Tanzi R.E. Holtzman D.M. Krasemann S. Chen D.F. Butovsky O. Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma.Immunity. 2022; 55: 1627-1644.e7Abstract Full Text Full Text PDF PubMed Google Scholar Recent studies have started to explore correlation between gut microbiota and glaucoma. Normal human gut microbiota consists primarily of two bacterial phyla, Firmicutes and Bacteroidetes.13Frank D.N. Pace N.R. Gastrointestinal microbiology enters the metagenomics era.Curr Opin Gastroenterol. 2008; 24: 4-10Crossref PubMed Scopus (330) Google Scholar Different studies report different changes in the gut microbiota of patients with glaucoma. In 2014, Ma et al46Ma J. Coarfa C. Qin X. Bonnen P.E. Milosavljevic A. Versalovic J. Aagaard K. mtDNA haplogroup and single nucleotide polymorphisms structure human microbiome communities.BMC Genom. 2014; 15: 257Crossref PubMed Google Scholar showed an association between mitochondrial DNA variants m.15784T>C and m.16390G>A and Firmicutes and Proteobacteria phyla, respectively.14Floyd J.L. Grant M.B. The gut-eye axis: lessons learned from murine models.Ophthalmol Ther. 2020; 9: 499-513Crossref PubMed Scopus (44) Google Scholar Collins et al.47Collins D.W. Gudiseva H.V. Trachtman B. Bowman A.S. Sagaser A. Sankar P. Miller-Ellis E. Lehman A. Addis V. O'Brien J.M. Association of primary open-angle glaucoma with mitochondrial variants and haplogroups common in African Americans.Mol Vis. 2016; 22: 454-471PubMed Google Scholar later showed that these variants were enriched in patients with POAG. Recently, Gong et al48Gong H. Zhang S. Li Q. Zuo C. Gao X. Zheng B. Lin M. Gut microbiota compositional profile and serum metabolic phenotype in patients with primary open-angle glaucoma.Exp Eye Res. 2020; 191107921Crossref PubMed Scopus (51) Google Scholar reported increased abundance of family Prevotellaceae, Enterobacteriaceae, and Escherichia coli and decreased loads of Megamonas and Bacteroides plebeius in patients with glaucoma compared with controls. Remarkably, they detected a negative correlation between Megamonas and visual acuity, visual field mean defect, and retinal nerve fiber thickness. In contrast, they observed a positive correlation of Streptococcus with retinal nerve fiber layer thickness and a negative correlation of Faecalibacterium with visual field mean deviation. Recently, Chen et al49Chen S. Wang Y. Liu Y. Li F. Chen Y. Fang X. Wen T. Xu S. Kermany D. Deng S. Dysbiosis of gut microbiome contributes to glaucoma pathogenesis.MedComm Future Med. 2022; 1: e28Crossref Google Scholar analyzed the gut microbiome diversity between patients with POAG and healthy subjects. Family Dysgonamonadaceae was enriched in patients with POAG, whereas Barnesiellaceae was enriched in healthy subjects, suggesting a shift in specific gut bacteria or microbiome patterns that may contribute to neuroinflammation and, hence, the pathogenesis of glaucoma (Table 1).Table 1Population Changes of Microbes in GlaucomaGut microbeChanges in glaucomaFirmicutes28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.J Neurosci. 2008; 28: 12085-12096Crossref PubMed Scopus (178) Google Scholar,44Sen S. Saxena R. Tripathi M. Vibha D. Dhiman R. Neurodegeneration in Alzheimer's disease and glaucoma: overlaps and missing links.Eye. 2020; 34: 1546-1553Crossref PubMed Scopus (28) Google ScholarIncreased in rats with glaucoma and patients with POAGBacteroidetes28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.J Neurosci. 2008; 28: 12085-12096Crossref PubMed Scopus (178) Google Scholar,44Sen S. Saxena R. Tripathi M. Vibha D. Dhiman R. Neurodegeneration in Alzheimer's disease and glaucoma: overlaps and missing links.Eye. 2020; 34: 1546-1553Crossref PubMed Scopus (28) Google ScholarDecreased in rats with glaucoma and patients with POAGVerruomicrobia28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.J Neurosci. 2008; 28: 12085-12096Crossref PubMed Scopus (178) Google ScholarIncreased in rats with glaucomaRomnoutsia28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.J Neurosci. 2008; 28: 12085-12096Crossref PubMed Scopus (178) Google ScholarIncreased in rats with glaucomaAkkermansia28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.J Neurosci. 2008; 28: 12085-12096Crossref PubMed Scopus (178) Google ScholarIncreased in rats with glaucomaBacteroides28Wax M.B. Tezel G. Yang J. Peng G. Patil R.V. Agarwal N. Sappington R.M. Calkins D.J. Induced autoimmunity to h