Microbiome and Retinal Vascular Diseases

Abstract

The gut microbiome consists of more than a thousand different microbes and their associated genes and microbial metabolites. It influences various host metabolic pathways and is therefore important for homeostasis. In recent years, its influence on health and disease has been extensively researched. In case of a microbiome disequilibrium, called dysbiosis, the gut microbiome is associated with several diseases. Consequent chronic inflammation may lead to or promote inflammatory bowel disease, obesity, diabetes mellitus, atherosclerosis, alcoholic and non-alcoholic liver disease, cirrhosis, hepatocellular carcinoma, and other diseases. The pathogenesis of the three most common retinal vascular diseases, diabetic retinopathy, retinal vein occlusion, and retinal artery occlusion, may also be influenced by an altered microbiome and associated risk factors such as diabetes mellitus, atherosclerosis, hypertension, and obesity. Direct cause–effect relationships remain less well understood. A potential prevention or treatment modality for these diseases could be targeting and modulating the individual's gut microbiome. The gut microbiome consists of more than a thousand different microbes and their associated genes and microbial metabolites. It influences various host metabolic pathways and is therefore important for homeostasis. In recent years, its influence on health and disease has been extensively researched. In case of a microbiome disequilibrium, called dysbiosis, the gut microbiome is associated with several diseases. Consequent chronic inflammation may lead to or promote inflammatory bowel disease, obesity, diabetes mellitus, atherosclerosis, alcoholic and non-alcoholic liver disease, cirrhosis, hepatocellular carcinoma, and other diseases. The pathogenesis of the three most common retinal vascular diseases, diabetic retinopathy, retinal vein occlusion, and retinal artery occlusion, may also be influenced by an altered microbiome and associated risk factors such as diabetes mellitus, atherosclerosis, hypertension, and obesity. Direct cause–effect relationships remain less well understood. A potential prevention or treatment modality for these diseases could be targeting and modulating the individual's gut microbiome. Retinal vascular diseases (RVDs) refer to a range of diseases affecting the blood vessels in the eyes and represent a major part of ophthalmic disease burden in the general population. Diabetic retinopathy (DR) is the most common RVD, followed by retinal vein occlusion (RVO) and retinal artery occlusion (RAO).1Jampol L.M. Glassman A.R. Sun J. Evaluation and care of patients with diabetic retinopathy.N Engl J Med. 2020; 382: 1629-1637Crossref PubMed Scopus (98) Google Scholar,2Leasher J.L. Bourne R.R.A. Flaxman S.R. Jonas J.B. Keeffe J. Naidoo K. Pesudovs K. Price H. White R.A. Wong T.Y. Resnikoff S. Taylor H.R. Vision Loss Expert Group of the Global Burden of Disease StudyGlobal estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 2010.Diabetes Care. 2016; 39: 1643-1649Crossref PubMed Scopus (368) Google Scholar Due to the large number of affected patients and the immense disease burden, it is of medical and economic interest to find measures of improving treatment and ultimately preventing these diseases. Although the three entities DR, RVO, and RAO have different pathophysiologic characteristics, they share common risk factors such as atherosclerosis, arterial hypertension, dyslipidemia, and obesity.3Lin K.Y. Hsih W.H. Lin Y.B. Wen C.Y. Chang T.J. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy.J Diabetes Investig. 2021; 12: 1322-1325Crossref PubMed Scopus (70) Google Scholar, 4The Eye Disease Case-control Study GroupRisk factors for branch retinal vein occlusion.Am J Ophthalmol. 1993; 116: 286-296Abstract Full Text PDF PubMed Scopus (276) Google Scholar, 5Scott I.U. Campochiaro P.A. Newman N.J. Biousse V. Retinal vascular occlusions.Lancet. 2020; 396: 1927-1940Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar In recent years, extensive research has been done to understand the gut microbiome and its impact on health and disease. It influences metabolic processes and the immune system of its host through microbial-derived metabolites. Our gut microbiome consists of microbes including bacteria, archaea, viruses, and eukaryotes, and their microbial products and genes. It comprises more than a thousand different species of bacteria and carries about 150 times more genes than found in the entire human genome. This leads to the assumption that this “essential organ” is of utmost importance for homeostasis and health.6Wang B. Yao M. Lv L. Ling Z. Li L. The human microbiota in health and disease.Engineering. 2017; 3: 71-82Crossref Scopus (471) Google Scholar With the introduction of modern high-throughput sequencing techniques, such as 16S rRNA gene sequencing and whole-metagenome shotgun sequencing, the taxonomic composition of the gut microbiome has been described. On the phylum level, Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia represent the main part of the human gut microbiome.7Rinninella E. Raoul P. Cintoni M. Franceschi F. Miggiano G.A.D. Gasbarrini A. Mele M.C. What is the healthy gut microbiota composition? a changing ecosystem across age, environment, diet, and diseases.Microorganisms. 2019; 7: 14Crossref PubMed Scopus (1400) Google Scholar Associations between an imbalance in the gut microbiome's composition, called dysbiosis, and various diseases such as inflammatory bowel disease, obesity, diabetes mellitus (DM), atherosclerosis, alcoholic and non-alcoholic liver disease, cirrhosis, and hepatocellular carcinoma have been found.6Wang B. Yao M. Lv L. Ling Z. Li L. The human microbiota in health and disease.Engineering. 2017; 3: 71-82Crossref Scopus (471) Google Scholar Under dysbiotic conditions, the equilibrium shifts toward bacteria with pathogenic characteristics. This may lead to the breakdown of the intestinal epithelial barrier and subsequently to translocation of microbes and their products into the systemic circulation. These microbial products may have various effects on tissue and cells in all organs of the body, including the eye. Certain microbial products such as lipopolysaccharides (LPS) lead to inflammation. By contrast, production of microbial metabolites with protective effects, such as short-chain fatty acids (SCFAs) or bile acids (BAs), may be inhibited in case of gut dysbiosis. Furthermore, epigenetic programming through histone acetylation and deacetylation by commensal bacteria, which promotes or represses the expression of certain genes, may have an influence on pathogenesis through overactivation of the immune system leading to chronic low-grade inflammation.8Nayyar A. Gindina S. Barron A. Hu Y. Danias J. Do epigenetic changes caused by commensal microbiota contribute to development of ocular disease? a review of evidence.Hum Genomics. 2020; 14: 11Crossref PubMed Scopus (21) Google Scholar Associations between an altered gut microbiome and the pathogenesis of ophthalmic diseases as well as their risk factors have been suggested.9Karlsson F.H. Fåk F. Nookaew I. Tremaroli V. Fagerberg B. Petranovic D. Bäckhed F. Nielsen J. Symptomatic atherosclerosis is associated with an altered gut metagenome.Nat Commun. 2012; 3: 1245Crossref PubMed Scopus (858) Google Scholar, 10Avery E.G. Bartolomaeus H. Maifeld A. Marko L. Wiig H. Wilck N. Rosshart S.P. Forslund S.K. Müller D.N. The gut microbiome in hypertension: recent advances and future perspectives.Circ Res. 2021; 128: 934-950Crossref PubMed Scopus (56) Google Scholar, 11John G.K. Mullin G.E. The gut microbiome and obesity.Curr Oncol Rep. 2016; 18: 45Crossref PubMed Scopus (198) Google Scholar, 12Zysset-Burri D.C. Morandi S. Herzog E.L. Berger L.E. Zinkernagel M.S. The role of the gut microbiome in eye diseases.Prog Retin Eye Res. 2022; 92: 101117Crossref PubMed Scopus (4) Google Scholar, 13Zinkernagel M.S. Zysset-Burri D.C. Keller I. Berger L.E. Leichtle A.B. Largiadèr C.R. Fiedler G.M. Wolf S. Association of the intestinal microbiome with the development of neovascular age-related macular degeneration.Sci Rep. 2017; 7: 40826Crossref PubMed Scopus (125) Google Scholar, 14Zysset-Burri D.C. Keller I. Berger L.E. Largiadèr C.R. Wittwer M. Wolf S. Zinkernagel M.S. Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration.NPJ Genom Med. 2020; 5: 34Crossref PubMed Scopus (31) Google Scholar, 15Napolitano P. Filippelli M. Davinelli S. Bartollino S. dell'Omo R. Costagliola C. of gut microbiota on eye an Med. 2021; PubMed Scopus Google Scholar The between the gut microbiome and the has been the B. A. M. H. N. Chang E. D. D. sequencing of metabolic pathways in the 2020; Scholar Although the role of the gut microbiome in the pathogenesis of diseases, such as and has been in its influence on other diseases such as remain less D.C. Keller I. Berger L.E. C. Wolf S. Zinkernagel M.S. Retinal artery occlusion is associated with and shifts in the gut microbiome and altered Rep. 2019; PubMed Scopus Google Y. Z. H. S. Z. Z. J. S. and of the gut microbiota in diabetic 2021; PubMed Scopus Google Scholar This review to the the gut microbiome to the most common retinal vascular diseases. The of the three main in the In the between these their risk factors, and the gut microbiome In the the microbial metabolites The the three most common including their and is the most common retinal vascular disease and a major ocular of The of is by The retinal to or blood Although patients in the of the disease more and ultimately in it a disease. This is to the of patients affected by people affected by of which from R. Wong T.Y. C. of diabetic retinopathy, diabetic macular and PubMed Scopus Google Scholar The most important of treatment is for in diabetic patients as well as and of blood it has a on retinopathy and other ocular in the diabetes and of diabetes and Care. Scopus Google Scholar by vascular retinal changes such as and and a of macular is by retinal and of in the to breakdown of the N. P. C. D. N. in diabetic macular review and 3: PubMed Scopus Google Scholar In disease retinal lead to of blood which lead to various such as and retinal This is called is a of retinal of of and S. K. Y. H. Y. S. I. S. Y. H. H. J. M. M. M. N. P. Y. A. inflammation barrier 2017; PubMed Scopus Google Scholar The is in from H. L. J. J. of the retinal and changes diabetic 2019; PubMed Scopus Google Scholar This lead to of such as vascular which is for the of J. The associated with diabetic Res. 2017; PubMed Scopus Google Scholar disease is associated with from these vessels and of the retinal leading to retinal M. A. T.J. R. N. The in and treatment of diabetic Retin Eye Res. 2016; PubMed Scopus Google Scholar retinal of and altered as well as and factors for to for and a for and for obesity, and Due to the large and number of patients affected with and DR, and of with the gut targeting these diseases by of Y. Z. H. S. Z. Z. J. S. and of the gut microbiota in diabetic 2021; PubMed Scopus Google Scholar The most common is It is as a vascular of the on to in the on the affected retinal vein branch retinal impact on and by the a of retinal tissue is about people from the of P. Y. M. Y. I. Global of retinal vein a review and meta-analysis of and risk 2019; PubMed Scopus Google Scholar The most common of is macular a in S. N. L. P. H. Wong T.Y. The of retinal vein from from the and Full Text Full Text PDF PubMed Scopus Google Scholar of macular is the of vascular to vascular and of macular and retinal to of retinal The lead to with M. P. Retinal vein pathogenesis and Full Text Full Text PDF PubMed Scopus Google Scholar retinal to they with of also the of The of treatment and and retinal factors arterial hypertension, dyslipidemia, obesity, atherosclerosis, and I.U. Campochiaro P.A. Newman N.J. Biousse V. Retinal vascular occlusions.Lancet. 2020; 396: 1927-1940Abstract Full Text Full Text PDF PubMed Scopus (63) Google M. P. Retinal vein pathogenesis and Full Text Full Text PDF PubMed Scopus Google Scholar is an important risk for and to be associated with the gut Y. S. Wen F. Diabetes mellitus as a risk for retinal vein a 2020; PubMed Scopus Google J. Li Y. Z. Li S. J. F. of gut microbiota in 2012; PubMed Scopus Google Scholar The most common is RAO with a of about to N. A. B. C. D. J. H. M. of the Group for in the Eye for the treatment of retinal artery and Study Ophthalmol. PubMed Scopus Google Scholar RAO to occlusion of an arterial the Due to the metabolic of the and of vascular RAO leads to a of of retinal and and retinal and breakdown of the metabolic ultimately leading to most RAO caused by large disease such as from to disease also inflammatory be from a such as occlusion of arterial vessels as in Furthermore, a be This could to other diseases affecting the or retinal arterial Retin Eye Res. PubMed Scopus Google Scholar treatment for patients have from a RAO is the of is less than is a treatment I.U. Campochiaro P.A. Newman N.J. Biousse V. Retinal vascular occlusions.Lancet. 2020; 396: 1927-1940Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar In in most of the of the disease be as an A. M.S. of for the a for from the PubMed Scopus Google Scholar risk for vascular also for potential in the a patients risk for a J. N. S. Wolf A. B. R. C. M. B. A. risk factors in retinal artery of a and medical Full Text Full Text PDF PubMed Scopus Google Scholar factors atherosclerosis, hypertension, obesity, dyslipidemia, and or such as these risk factors to be influenced by the gut I.U. Campochiaro P.A. Newman N.J. Biousse V. Retinal vascular occlusions.Lancet. 2020; 396: 1927-1940Abstract Full Text Full Text PDF PubMed Scopus (63) Google G.K. Mullin G.E. The gut microbiome and obesity.Curr Oncol Rep. 2016; 18: 45Crossref PubMed Scopus (198) Google M. P. Retinal vein pathogenesis and Full Text Full Text PDF PubMed Scopus Google Scholar The between the gut microbiome and has been a the influence of the gut microbiome on and D.C. Keller I. Berger L.E. C. Wolf S. Zinkernagel M.S. Retinal artery occlusion is associated with and shifts in the gut microbiome and altered Rep. 2019; PubMed Scopus Google Y. Z. H. S. Z. Z. J. S. and of the gut microbiota in diabetic 2021; PubMed Scopus Google P. Y. J. Yao K. of the gut microbiome and in patients with diabetic 2021; 12: PubMed Scopus Google J. Z. Y. Y. and of gut microbiota in diabetic 2022; PubMed Scopus Google Scholar and the influence of the gut microbiome on The between the gut microbiome and may be by risk factors that between the different of these risk factors and their with the gut microbiome have been the of extensive In the review the associated changes of the gut microbiome in RAO and DR, and the risk factors for with the gut microbiome. In and shifts in the gut microbiome whole-metagenome shotgun sequencing, the gut microbiome of patients with RAO with that of healthy The and the species and in RAO the and the and in D.C. Keller I. Berger L.E. C. Wolf S. Zinkernagel M.S. Retinal artery occlusion is associated with and shifts in the gut microbiome and altered Rep. 2019; PubMed Scopus Google Scholar In to these taxonomic in of the gut microbiome. 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