Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, 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 the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the 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 a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

From Osteoimmunology to Osteomicrobiology: How the Microbiota and the Immune System Regulate Bone

“…Such interventions might include simple dietary modifications that affect the gut microbiota. For example, a low-glycemic diet was found to alter microbiota composition in a way that offered protection against age-related macular degeneration in the mouse, leading to the creation of the term “gut-retina axis” [114]. Perhaps dietary modifications that alter the composition of the microbiota will be found to be useful to prevent bone loss.…”

Plasma branched chain/aromatic amino acids, enriched Mediterranean diet and risk of type 2 diabetes: case-cohort study within the PREDIMED Trial

“…In June 2015, pairs of samples (baseline and first year visits from each participant) were randomly ordered and shipped on dry ice to the Broad Institute (Boston, MA, USA) for the metabolomic analyses. Amino acids, acylcarnitines and other polar plasma metabolites were profiled using liquid chromatography tandem mass spectrometry (LC-MS/MS) as previously described [18–20]. For further details, please refer to the electronic supplementary material (ESM) Methods.…”

Zinc Nutrition and Inflammation in the Aging Retina

“…If retinal parainflammation develops into a chronic retinal malfunction, and constitutes a shift in the normal homeostasis or “balance” to adapt to the new physiological or metabolic conditions of AMD (as occurs in many other chronic inflammatory disease states), the disruption in the interrelationships between nutrition, the microbiome, and host metabolism may be key elements in the disruption of normal homeostasis. The gut microbiome composition may vary according to macro/micronutrient dietary habits, as shown in several studies . The redox state also strongly modulates the gut microbiota .…”