About 200 million people worldwide are afflicted by age-related macular degeneration (AMD), a leading cause of blindness. As populations skew older, numbers are predicted to grow.
Although treatments do exist for this complex disease, some patients show poor response. Researchers are now exploring the involvement of the intestinal microbiome in AMD, potentially offering a new avenue for management.
This blog will address the evidence for the “gut-eye axis” along with possible microbiota-related therapeutic approaches to AMD.
AMD, in brief
Age-related macular degeneration (AMD) affects one in eight people 60 years of age or older and is the most common cause of irreversible blindness in older persons in developed countries. The eye’s macula contains a dense population of light-detecting cells called photoreceptors. These cells transmit signals to the brain, where they are interpreted as images. The macula is located within the retina, the light-sensitive tissue at the back of the eye.
AMD’s complex origins involve cellular, biochemical, and molecular processes influenced by various factors like genetics and the environment. While the exact cause remains unclear, research suggests that lipid metabolism, extracellular matrix biology, complement cascade activation, oxidative stress, inflammation, and immune responses play a role in the disease’s development.
The aging process drives a low-grade inflammation (inflammaging) that is a significant risk factor in AMD and other diseases. Aging weakens the retina’s normally robust physical and immune protections, making it more susceptible to oxidative stress, hyperglycemia, and increased intraocular pressure.
Immunosenescence (altered immune function in aging) may result in various symptoms in AMD, including the buildup of drusen (fat and protein deposits) beneath the retinal pigment epithelium and geographic atrophy. The existence of many large drusen is an early sign of AMD.
AMD varieties are categorized as exudative (wet) and non-exudative (dry). The primary treatment for advanced wet AMD is the injection of anti-vascular endothelial growth factor drugs directly into the eye. However, some patients may experience disease relapse or show no response to this treatment. No effective treatments are available for the dry form.
In addition to aging, many other factors such as genetics, lifestyle (smoking), diet (high-fat, high-glucose, high fructose), environment (light exposure), and dysbiosis of the intestinal microbiome may contribute to the risk and progression of AMD.
AMD and the gut microbiome
Recent research shows that the gut microbiota can influence inflammation—including low-grade—and immunity in the eye, a relationship designated as the gut-eye axis. Gut dysbiosis leads to increased gut permeability, elevated circulation of bacterial products, microbial metabolites and inflammatory mediators that result in immune dysregulation at distant anatomic sites including the retina.
Different gut microbiota in AMD
Dysbiosis of the gut microbiome is associated with AMD, as reported in the following studies.
For example, a 2017 study found that alterations in the gut microbiome were linked to AMD. They found the genera Anaerotruncus and Oscillibacter as well as Ruminococcus torques and Eubacterium ventriosum were higher in patients with AMD. These are associated with glutamate degradation and increased arginine biosynthesis pathways, both of which are linked to poor or degenerative retinal function. In addition, bacteria controlling fatty acid elongation were lacking; long-chain polyunsaturated fatty acids appear to impact retinal function and therefore may contribute to AMD.
Another study also found that intestinal microbiota was different in patients with AMD compared to healthy controls. A lower concentration of Firmicutes and higher levels of Proteobacteria and Bacteroidota were observed in the AMD group.
The significance of these differences may lie partly in the ability of bacteria to produce metabolites such as short-chain fatty acids. Firmicutes produce SCFAs such as butyrate which help regulate gut permeability, reduce inflammation, and restrict pathogen growth by lowering pH. Immune cells in the retina may be modulated by the altered translocation of gut metabolites due to increased gut permeability. In addition, a recent study in a mouse model found that intra-peritoneal injected SCFAs were detected in the eye and reduced intraocular inflammation induced by lipopolysaccharides.
Dietary factors could represent a link between the alteration of gut microbiota and AMD.
Both micro- and macronutrient optimization may modulate the gut microbiome, lowering the risk of low-grade inflammation which contributes to AMD progression.
Many studies (Age-Related Eye Disease Study (AREDS and AREDS 2) have shown the beneficial role of micronutrients. Regarding macronutrients, a low-glycemic diet may reverse age-related macular degeneration features, associated with a high-glycemic diet according to a 2017 study in mice. In addition, a pattern of eating, known as the “Western Diet” (higher intake of red and processed meats, high-fat dairy products, etc.), was associated with increased AMD risk in a study of 4,088 participants. Moreover, gut microbiota associated with obesity drove retinal tissue pathology in a recent study.
AMD and probiotics
Microbiome modulation may be a new therapeutic target for AMD. Lactic acid bacteria are commonly consumed to enhance the intestinal barrier and immune function. Researchers have tested this concept in animals.
In a 2023 study in a rat model of dry AMD (slower progression compared to wet AMD), a combined treatment of a specific strain of Limosilactobacillus fermentum combined with an extract of anthocyanin (a flavonoid plant pigment) could alleviate retinal damage, better than the plant pigment alone.
In another mice study, one strain of Lacticaseibacillus paracasei has been observed to suppress retinal inflammation by reducing cytokine-producing macrophages and the loss of age-related retinal cells in mice. Moreover, further study in mice showed that the same strain of Lacticaseibacillus paracasei suppressed inflammation on photoreceptor cells, suggesting a preventive effect against degenerative retinal diseases.
Nevertheless, the relevance of these studies to the human condition is limited due to the absence of a murine model that accurately represents all aspects of AMD in humans.
Researchers are investigating the relationship between the intestinal microbiome and age-related macular degeneration (AMD) to explore new treatment options. Dysbiosis of the gut microbiome, characterized by an imbalance in gut bacteria, has been associated with AMD and its progression. Studies have shown that specific gut bacteria and their metabolites may play a role in retinal function and inflammation, and interventions with probiotics have shown potential in alleviating retinal damage and suppressing inflammation in animal models of AMD. Further studies are needed to determine the impact of gut microbiota on the apparently complex pathogenesis of human AMD.
Age-Related Eye Disease Study 2 Research Group. “Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial.” JAMA vol. 309,19 (2013): 2005-15. doi:10.1001/jama.2013.4997
Age-Related Eye Disease Study Research Group. “A 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.” Archives of ophthalmology (Chicago, Ill. : 1960) vol. 119,10 (2001): 1417-36. doi:10.1001/archopht.119.10.1417
Andriessen, Elisabeth Mma et al. “Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization.” EMBO molecular medicine vol. 8,12 1366-1379. 1 Dec. 2016, doi:10.15252/emmm.201606531
Blaak, E E et al. “Short chain fatty acids in human gut and metabolic health.” Beneficial microbes vol. 11,5 (2020): 411-455. doi:10.3920/BM2020.0057
Bui, Bang V et al. “Glutamate metabolic pathways and retinal function.” Journal of neurochemistry vol. 111,2 (2009): 589-99. doi:10.1111/j.1471-4159.2009.06354.x
Chen, Nu et al. “Short chain fatty acids inhibit endotoxin-induced uveitis and inflammatory responses of retinal astrocytes.” Experimental eye research vol. 206 (2021): 108520. doi:10.1016/j.exer.2021.108520
Chiu, Chung-Jung et al. “The relationship of major American dietary patterns to age-related macular degeneration.” American journal of ophthalmology vol. 158,1 (2014): 118-127.e1. doi:10.1016/j.ajo.2014.04.016
Floyd, Jason L, and Maria B Grant. “The Gut-Eye Axis: Lessons Learned from Murine Models.” Ophthalmology and therapy vol. 9,3 (2020): 499-513. doi:10.1007/s40123-020-00278-2
Khoo, Hock Eng et al. “Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits.” Food & nutrition research vol. 61,1 1361779. 13 Aug. 2017, doi:10.1080/16546628.2017.1361779
Liu, Aihua et al. “Long-chain and very long-chain polyunsaturated fatty acids in ocular aging and age-related macular degeneration.” Journal of lipid research vol. 51,11 (2010): 3217-29. doi:10.1194/jlr.M007518
Mangiola, F et al. “Gut microbiota and aging.” European review for medical and pharmacological sciences vol. 22,21 (2018): 7404-7413. doi:10.26355/eurrev_201811_16280
Morita, Yuji et al. “Lactobacillus paracasei KW3110 Prevents Blue Light-Induced Inflammation and Degeneration in the Retina.” Nutrients vol. 10,12 1991. 15 Dec. 2018, doi:10.3390/nu10121991
Morita, Yuji et al. “Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice.” Aging vol. 10,10 (2018): 2723-2740. doi:10.18632/aging.101583
Nadeem, Urooba et al. “Gut microbiome and retinal diseases: an updated review.” Current opinion in ophthalmology vol. 33,3 (2022): 195-201. doi:10.1097/ICU.0000000000000836
Nussenblatt, Robert B, and Frederick Ferris 3rd. “Age-related macular degeneration and the immune response: implications for therapy.” American journal of ophthalmology vol. 144,4 (2007): 618-26. doi:10.1016/j.ajo.2007.06.025
Rinninella, Emanuele, et al. “The Role of Diet, Micronutrients and the Gut Microbiota in Age-Related Macular Degeneration: New Perspectives from the Gut–Retina Axis.” Nutrients, vol. 10, no. 11, Nov. 2018, p. 1677. Crossref, https://doi.org/10.3390/nu10111677.
Rowan, Sheldon et al. “Involvement of a gut-retina axis in protection against dietary glycemia-induced age-related macular degeneration.” Proceedings of the National Academy of Sciences of the United States of America vol. 114,22 (2017): E4472-E4481. doi:10.1073/pnas.1702302114
Scuderi, Gianluca et al. “Gut Microbiome in Retina Health: The Crucial Role of the Gut-Retina Axis.” Frontiers in microbiology vol. 12 726792. 14 Jan. 2022, doi:10.3389/fmicb.2021.726792
Serban, Dragos et al. “Gut Microbiota Dysbiosis in Diabetic Retinopathy-Current Knowledge and Future Therapeutic Targets.” Life (Basel, Switzerland) vol. 13,4 968. 7 Apr. 2023, doi:10.3390/life13040968
Tadayoni, Ramin et al. “Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration.” Ophthalmologica. Journal international d’ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde vol. 244,2 (2021): 93-101. doi:10.1159/000513048
Vyawahare, Hrishikesh, and Pranaykumar Shinde. “Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment.” Cureus vol. 14,9 e29583. 26 Sep. 2022, doi:10.7759/cureus.29583
Xing, Yan et al. “Combination of Lactobacillus fermentum NS9 and aronia anthocyanidin extract alleviates sodium iodate-induced retina degeneration.” Scientific reports vol. 13,1 8380. 24 May. 2023, doi:10.1038/s41598-023-34219-3
Zhang, Yuanyuan et al. “Alterations of the intestinal microbiota in age-related macular degeneration.” Frontiers in microbiology vol. 14 1069325. 5 Apr. 2023, doi:10.3389/fmicb.2023.1069325
Zinkernagel, Martin S et al. “Association of the Intestinal Microbiome with the Development of Neovascular Age-Related Macular Degeneration.” Scientific reports vol. 7 40826. 17 Jan. 2017, doi:10.1038/srep40826