Interaction of Metabolome and Microbiome Contributes to Dietary Glycemia-induced Age-related Macular Degeneration in Aged C57BL/6J Mice

Abstract

Purpose : High dietary glycemia in aged C57BL/6J mice leads to Age-related Macular Degeneration (AMD)-like features associated with metabolic changes and accumulation of advanced glycation end-products. These effects are prevented by change to a lower glycemia diet. We sought to determine metabolites and microbiota that are associated with retina pathology and to determine their relationship to diet and each other.

Methods : 1-year old mice were fed diets for one year and fecal, urine, and plasma samples were collected. Retina pathology was assessed via funduscopy, histology, and electron microscopy. 16S rRNA sequencing was performed from three time points to determine the gut microbiome. ¹H-NMR metabolomics was performed from urine samples. Plasma metabolomics was accomplished by LC-MS/MS.

Results : Mice fed a high glycemia diet developed AMD-like features including loss of photoreceptors, accumulation of lipofuscin and phagosomes in the RPE, and accumulation of advanced glycation-endproducts in the retina and RPE. Several metabolites and metabolic pathways were associated with retina pathology in both urine and plasma samples. These pathways pointed toward carbohydrate metabolism, citric acid cycle, DHA-derived lipids, and metabolites affected by microbiota. Several metabolites interacted synergistically or additively with the diet. Significant differences in microbiota were detected between mice fed high and low glycemia diets, with higher abundance of the Bacteroidetes phylum associated with the low glycemia diet. Certain bacterial taxa were associated with retinal pathology, including multiple members of the Clostridiales order and the Lachnospiraceae family, as well as an Actinobacteria phylum member. Specific microbiota associated with metabolites that were associated with retinal pathology, indicative of an inter-related network of metabolite-microbiota interactions.

Conclusions : Chronic consumption of a high glycemia diet induces AMD-like retinal degeneration, which can be prevented by lowering dietary glycemia. Our identification of metabolites, metabolic pathways, and interactions with the gut microbiota point to new potential pathways by which the diet affects the risk for AMD, and points to new opportunities to prevent AMD.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.