Manipulation of Gut Microbiota Affects Diet- and Age-Related Retinal Degeneration

Abstract

Purpose : Diet has an important role in risk for age-related eye diseases, including AMD and diabetic retinopathy. Humans that adhere to Western and high glycemic index dietary patterns have increased risk for AMD. We have previously shown that aged mice that consumed high glycemic (HG) diets developed AMD-like retinopathy that could be prevented by a low glycemic (LG) diet. We also showed a role for gut microbiota in mediating protection by a LG diet, which we coined the gut-retina axis. Altered gut microbiota have also been associated with human AMD, but experimental evidence and mechanisms for this association are lacking.

Methods : 12-month male C57BL/6J mice were fed HG and LG diets for 12-months. Gut microbiota were manipulated either by continuous oral antibiotic ablation of commensal bacteria (Ampicillin + Neomycin) or via weekly fecal microbiota transplants from mice consuming opposite diets. Eye health was evaluated using fundus imaging and angiography, immunohistochemical detection of retinal microglial/macrophages, histology, and electron microscopy of the RPE. Bacterial 16S rRNA sequencing was used to determine the fecal microbiome composition.

Results : Mice that consumed HG diets developed multiple retinal lesions, consistent with greater retinal damage scores. There were fewer lesions in mice consuming LG diet, or in HG-fed mice receiving fecal transplants from LG mice. Lesions were associated with infiltration of retinal microglia/macrophages in the choroid and outer retina. Ablation of commensal microbiota was associated with retinal and RPE degeneration in some mice. Microbiome analysis revealed that retinal neuroprotection was associated with increased levels of Akkermansia, a commensal bacteria with known beneficial metabolic functions. HG-fed mice receiving LG fecal microbiota transplants also had improved glycemic control relative to HG-fed mice.

Conclusions : Our studies confirm previously observed roles for commensal gut microbiota in mediating protection against diet-induced AMD. Importantly, these protective effects could be transferred via fecal microbiota transplantation, indicating that microbiome-based therapies have therapeutic potential for AMD. Neuroprotection was associated with improved glycemic control, suggesting that metabolic reprogramming may be a critical component of the gut-retina axis, possibly via modulation of innate immune system function.

This is a 2021 ARVO Annual Meeting abstract.