The concept of “Microbe-gut-eye axis” holds that metabolites of the gut microbiota are involved in the pathogenesis of various eye diseases. The composition and diversity of gut microbiota in diabetic retinopathy (DR) patients are significantly different from those in non-DR patients. Metabolites of the gut microbiota such as lipopolysaccharide, short-chain fatty acid, bile acids and branched-chain amino acid aggravate or attenuate the progression of DR by regulating the release of inflammatory cytokines, mitochondrial function, insulin sensitivity, immune response, and autophagy of retinal cells. Therefore, gut microbiota and their metabolites play a role in the occurrence and development of DR through multiple pathways. The participation of gut microbiota may open up a new way to prevent and treat DR in the future.
Citation： Liu Xinyi, Liu Kun. Research progress of gut microbiota in diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2023, 39(3): 260-264. doi: 10.3760/cma.j.cn511434-20220812-00452 Copy
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- 1. Schloissnig S, Arumugam M, Sunagawa S, et al. Genomic variation landscape of the human gut microbiome[J]. Nature, 2013, 493(7430): 45-50. DOI: 10.1038/nature11711.
- 2. Jandhyala SM, Talukdar R, Subramanyam C, et al. Role of the normal gut microbiota[J]. World J Gastroenterol, 2015, 21(29): 8787-803. DOI: 10.3748/wjg.v21.i29.8787.
- 3. Allayee H, Hazen SL. Contribution of gut bacteria to lipid levels: another metabolic role for microbes?[J]. Circ Res, 2015, 117(9): 750-754. DOI: 10.1161/CIRCRESAHA.115.307409.
- 4. Nemet I, Saha PP, Gupta N, et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors[J]. Cell, 2020, 180(5): 862-877. DOI: 10.1016/j.cell.2020.02.016.
- 5. Tanase DM, Gosav EM, Neculae E, et al. Role of gut microbiota on onset and progression of microvascular complications of type 2 diabetes (T2DM)[J/OL]. Nutrients, 2020, 12(12): 3719[2020-12-02]. https://pubmed.ncbi.nlm.nih.gov/33276482/. DOI: 10.3390/nu12123719.
- 6. Tilg H, Zmora N, Adolph TE, et al. The intestinal microbiota fuelling metabolic inflammation[J]. Nat Rev Immunol, 2020, 20(1): 40-54. DOI: 10.1038/s41577-019-0198-4.
- 7. Scuderi G, Troiani E, Minnella AM. Gut microbiome in retina health: the crucial role of the gut-retina axis[J/OL]. Front Microbiol, 2022, 12: 726792[2022-01-14]. https://pubmed.ncbi.nlm.nih.gov/35095780/. DOI: 10.3389/fmicb.2021.726792.
- 8. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control[J]. Nature, 2013, 498(7452): 99-103. DOI: 10.1038/nature12198.
- 9. Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults[J/OL]. PLoS One, 2010, 5(2): e9085[2010-02-05]. https://pubmed.ncbi.nlm.nih.gov/20140211/. DOI: 10.1371/journal.pone.0009085.
- 10. Wu H, Tremaroli V, Schmidt C, et al. The gut microbiota in prediabetes and diabetes: a population-based cross-sectional study[J]. Cell Metab, 2020, 32(3): 379-390. DOI: 10.1016/j.cmet.2020.06.011.
- 11. Cummings JH, Pomare EW, Branch WJ, et al. Short chain fatty acids in human large intestine, portal, hepatic and venous blood[J]. Gut, 1987, 28(10): 1221-1227. DOI: 10.1136/gut.28.10.1221.
- 12. Peng L, He Z, Chen W, et al. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier[J]. Pediatr Res, 2007, 61(1): 37-41. DOI: 10.1203/01.pdr.0000250014.92242.f3.
- 13. Wang HB, Wang PY, Wang X, et al. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription[J]. Dig Dis Sci, 2012, 57(12): 3126-3135. DOI: 10.1007/s10620-012-2259-4.
- 14. Zhang L, Chu J, Hao W, et al. Gut microbiota and type 2 diabetes mellitus: association, mechanism, and translational applications[J/OL]. Mediators Inflamm, 2021, 2021: 5110276[2021-08-17]. https://pubmed.ncbi.nlm.nih.gov/34447287/. DOI: 10.1155/2021/5110276.
- 15. Matheus VA, Monteiro L, Oliveira RB, et al. Butyrate reduces high-fat diet-induced metabolic alterations, hepatic steatosis and pancreatic beta cell and intestinal barrier dysfunctions in prediabetic mice[J]. Exp Biol Med (Maywood), 2017, 242(12): 1214-1226. DOI: 10.1177/1535370217708188.
- 16. Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2[J]. Diabetes, 2012, 61(2): 364-371. DOI: 10.2337/db11-1019.
- 17. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota[J]. Nature, 2015, 528(7581): 262-266. DOI: 10.1038/nature15766.
- 18. Sun L, Xie C, Wang G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin[J]. Nat Med, 2018, 24(12): 1919-1929. DOI: 10.1038/s41591-018-0222-4.
- 19. Su B, Liu H, Li J, et al. Acarbose treatment affects the serum levels of inflammatory cytokines and the gut content of bifidobacteria in Chinese patients with type 2 diabetes mellitus[J]. J Diabetes, 2015, 7(5): 729-739. DOI: 10.1111/1753-0407.12232.
- 20. Baxter NT, Lesniak NA, Sinani H, et al. The glucoamylase inhibitor acarbose has a diet-dependent and reversible effect on the murine gut microbiome[J/OL]. mSphere, 2019, 4(1): e00528-18[2019-02-06]. https://pubmed.ncbi.nlm.nih.gov/30728281/. DOI: 10.1128/mSphere.00528-18.
- 21. Das T, Jayasudha R, Chakravarthy S, et al. Alterations in the gut bacterial microbiome in people with type 2 diabetes mellitus and diabetic retinopathy[J/OL]. Sci Rep, 2021, 11(1): 2738[2021-02-02]. https://pubmed.ncbi.nlm.nih.gov/33531650/. DOI: 10.1038/s41598-021-82538-0.
- 22. Padakandla SR, Das T, Sai Prashanthi G, et al. Gut mycobiome dysbiosis in rats showing retinal changes indicative of diabetic retinopathy[J/OL]. PLoS One, 2022, 17(4): e0267080[2022-04-19]. https://pubmed.ncbi.nlm.nih.gov/35439275/. DOI: 10.1371/journal.pone.0267080.
- 23. Huang Y, Wang Z, Ma H, et al. Dysbiosis and implication of the gut microbiota in diabetic retinopathy[J/OL]. Front Cell Infect Microbiol, 2021, 11: 646348[2021-03-19]. https://pubmed.ncbi.nlm.nih.gov/33816351/. DOI: 10.3389/fcimb.2021.646348.
- 24. Vagaja NN, Binz N, McLenachan S, et al. Influence of endotoxin-mediated retinal inflammation on phenotype of diabetic retinopathy in Ins2 Akita mice[J]. Br J Ophthalmol, 2013, 97(10): 1343-1350. DOI: 10.1136/bjophthalmol-2013-303201.
- 25. Hao L, Michaelsen TY, Singleton CM, et al. Novel syntrophic bacteria in full-scale anaerobic digesters revealed by genome-centric metatranscriptomics[J]. ISME J, 2020, 14(4): 906-918. DOI: 10.1038/s41396-019-0571-0.
- 26. Beli E, Yan Y, Moldovan L, et al. Restructuring of the gut microbiome by intermittent fasting prevents retinopathy and prolongs survival in db/db mice[J]. Diabetes, 2018, 67(9): 1867-1879. DOI: 10.2337/db18-0158.
- 27. Ye P, Zhang X, Xu Y, et al. Alterations of the gut microbiome and metabolome in patients with proliferative diabetic retinopathy[J/OL]. Front Microbiol, 2021, 12: 667632[2021-09-08]. https://pubmed.ncbi.nlm.nih.gov/34566901/. DOI: 10.3389/fmicb.2021.667632.
- 28. Liu H, Zhang H, Wang X, et al. The family coriobacteriaceae is a potential contributor to the beneficial effects of Roux-en-Y gastric bypass on type 2 diabetes[J]. Surg Obes Relat Dis, 2018, 14(5): 584-593. DOI: 10.1016/j.soard.2018.01.012.
- 29. Scheiman J, Luber JM, Chavkin TA, et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism[J]. Nat Med, 2019, 25(7): 1104-1109. DOI: 10.1038/s41591-019-0485-4.
- 30. Khan R, Sharma A, Ravikumar R, et al. Association between gut microbial abundance and sight-threatening diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2021, 62(7): 19. DOI: 10.1167/iovs.62.7.19.
- 31. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance[J]. Diabetes, 2007, 56(7): 1761-1772. DOI: 10.2337/db06-1491.
- 32. Kokona D, Ebneter A, Escher P, et al. Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation[J]. J Neuroinflammation, 2018, 15(1): 340. DOI: 10.1186/s12974-018-1373-4.
- 33. Hernández C, Ortega F, García-Ramírez M, et al. Lipopolysaccharide-binding protein and soluble CD14 in the vitreous fluid of patients with proliferative diabetic retinopathy[J]. Retina, 2010, 30(2): 345-352. DOI: 10.1097/iae.0b013e3181b7738b.
- 34. Zhou L, Xu Z, Oh Y, et al. Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy[J/OL]. JCI Insight, 2021, 6(23): e93382[2021-12-08]. https://pubmed.ncbi.nlm.nih.gov/34673570/. DOI: 10.1172/jci.insight.93382.
- 35. Cai X, Li J, Wang M, et al. GLP-1 treatment improves diabetic retinopathy by alleviating autophagy through GLP-1R-ERK1/2-HDAC6 signaling pathway[J]. Int J Med Sci, 2017, 14(12): 1203-1212. DOI: 10.7150/ijms.20962.
- 36. Zhou HR, Ma XF, Lin WJ, et al. Neuroprotective role of GLP-1 analog for retinal ganglion cells via PINK1/Parkin-mediated mitophagy in diabetic retinopathy[J/OL]. Front Pharmacol, 2021, 11: 589114[2021-02-12]. https://pubmed.ncbi.nlm.nih.gov/33679385/. DOI: 10.3389/fphar.2020.589114.
- 37. Pathak P, Xie C, Nichols RG, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism[J]. Hepatology, 2018, 68(4): 1574-1588. DOI: 10.1002/hep.29857.
- 38. Zhang MY, Zhu L, Zheng X, et al. TGR5 activation ameliorates mitochondrial homeostasis via regulating the PKCδ/Drp1-HK2 signaling in diabetic retinopathy[J/OL]. Front Cell Dev Biol, 2022, 9: 759421[2022-02-14].https://pubmed.ncbi.nlm.nih.gov/35096809/. DOI: 10.3389/fcell.2021.759421.
- 39. Chung YR, Choi JA, Koh JY, et al. Ursodeoxycholic acid attenuates endoplasmic reticulum stress-related retinal pericyte loss in streptozotocin-induced diabetic mice[J/OL]. J Diabetes Res, 2017, 2017: 1763292[2017-01-03]. https://pubmed.ncbi.nlm.nih.gov/28127564/. DOI: 10.1155/2017/1763292.
- 40. Shiraya T, Araki F, Ueta T, et al. Ursodeoxycholic acid attenuates the retinal vascular abnormalities in anti-PDGFR-β antibody-induced pericyte depletion mouse models[J/OL]. Sci Rep, 2020, 10(1): 977[2020-01-22].https://pubmed.ncbi.nlm.nih.gov/31969665/. DOI: 10.1038/s41598-020-58039-x.
- 41. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance[J]. Cell Metab, 2009, 9(4): 311-326. DOI: 10.1016/j.cmet.2009.02.002.
- 42. Ola MS, Alhomida AS, LaNoue KF. Gabapentin attenuates oxidative stress and apoptosis in the diabetic rat retina[J]. Neurotox Res, 2019, 36(1): 81-90. DOI: 10.1007/s12640-019-00018-w.
- 43. Chen T, Ni Y, Ma X, et al. Branched-chain and aromatic amino acid profiles and diabetes risk in Chinese populations[J/OL]. Sci Rep, 2016, 6: 20594[2016-02-05]. https://pubmed.ncbi.nlm.nih.gov/26846565/. DOI: 10.1038/srep20594.
- 44. Liu W, Wang C, Xia Y, et al. Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy[J]. Acta Diabetol, 2021, 58(2): 221-229. DOI: 10.1007/s00592-020-01610-9.
- 45. Heianza Y, Sun D, Li X, et al. Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost Trial[J]. Gut, 2019, 68(2): 263-270. DOI: 10.1136/gutjnl-2018-316155.
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