Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Proceedings
Publication Acceptance Date: 4/20/2017
Publication Date: 5/9/2017
Citation: Rowan, S., Jiang, S., Korem, T., Szymanski, J., Chang, M., Szelog, J., Cassalman, C., Dasuri, K., McGuire, C., Nagai, R., Du, X., Brownlee, M., Rabbani, N., Thornalley, P.J., Baleja, J.D., Deik, 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. 2017. Involvement of a gut-retina axis in protection against dietary glycemia induced age-related macular degeneration. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.1702302114. Interpretive Summary: Age-related Macular Degeneration (AMD) is the leading cause of blindness in the United States and affects millions of people. It is caused by the death of light-sensing cells in the part of our eye that we use for most of our central color vision. While there are disease contributions from our genes, environment, age, and diet, it is easier to change diet than other factors. We know from clinical studies in humans and experimental studies in mice the kinds of foods in the diet that are important in disease risk for AMD; foods that break down rapidly into sugar are worse for you than foods that take longer to break down into sugar - this is known as the glycemic index. We used middle-aged mice that were normal and healthy and fed them either high glycemic index diets (HG) or low glycemic index diets (LG) for a year until they were of advanced age and determined the consequences on their eyes, their metabolism, and the microorganisms within their guts (gut microbiota.) Mice fed a HG diet developed many AMD disease features, were obese and hyperglycemic, and showed evidence of advanced metabolic stress. In contrast, mice fed an LG diet were lean and healthy. If we altered the diet mid-way through the study from HG to LG, we completely prevented the AMD disease and associated metabolic problems, suggesting that dietary change late in life could still be helpful for preventing AMD in individuals at high risk due to their poor diets. By analyzing hundreds of circulating metabolites in the blood and urine, we identified a molecular signature of AMD as well as a mechanism by which LG diets protect against AMD. The protective mechanism appears to involve changes in the gut microbiota, which lead to activation of protective pathways to the eye. We refer to this signal as the gut-retina axis. Our findings not only advance our understanding of AMD disease mechanism, but offer a real-life dietary intervention that should benefit millions of Americans at risk of losing vision to AMD as they age.
Technical Abstract: Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial cell (RPE) dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns on risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect of isocaloric diets that differ only in the type of dietary carbohydrate on AMD in a new wildtype aged mouse model. Consuming a high glycemia (HG) diet resulted in many AMD features (AMDf) including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consuming the lower glycemia (LG) did not. Critically, switching from HG to LG diet late in life arrested or reversed AMDf. LG diets limited accumulation of advanced glycation end products (AGEs), long-chain polyunsaturated lipids and their peroxidation end-products, and increased C3-carnitine in retina, plasma or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet and we identified microbiota in the Clostridiales order as being associated with AMDf and HG diet, whereas protection from AMDf was associated with Bacteroidales order and LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet- and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest that simple dietary intervention may be useful in patients to arrest AMD.