Effects of High-Fat Diet and Gut-Dysbiosis on Gut-Retina Axis Pathways

Abstract

Purpose : Emerging data show that the gut-microbiome plays a role in retinal physiology and several retinal diseases such as: age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and diabetic retinopathy (DR. Our team has described the retinal pathways of the gut-retina axis in retinal homeostasis under regular diet conditions. The gut microbiome is significantly affected by diet and, in particular, a diet rich in fats or high-fat diet (HFD). The HFD modifies the composition and diversity of the gut microbiota; a condition referred to as gut-dysbiosis. The retinal pathways of the gut-retina axis in HFD-induced gut dysbiosis conditions remain unknown. The purpose of this study is to delineate how HFD-induced gut dysbiosis modulates the gut-retina axis pathways by comparing the transcriptome of mice with HFD-induced gut dysbiosis with germ-free (GF) mice that have no microbiome fed on regular diet (ND).

Methods : We compared the retinal gene expression and biologic pathways of C57Bl/6J mice fed on 23% HFD for 8 weeks and GF mice age and gender matched fed on ND (4 per group). RNA-sequencing (RNA-seq) was performed on whole retinas using a base paired-end method on the NovaSEQ600 platform. We then identified Differentially Expressed Genes (DEGs) (P-value<0.01) and performed a functional enrichment network analysis using Toppgene to elucidate the biologic pathways affected.

Results : We identified 538 DEGs with a p-value <0.01. Some of the DEGs identified were the regulatory associated Protein of MTOR Complex 1 (Rptor), peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Alpha (PPARGC1A) and activating Transcription Factor 2 (ATF2); all of which have been implicated in retinal diseases like AMD and DR. The enrichment network analysis showed numerous signaling and metabolic pathways affected including the phototransduction cascade, the Related Orphan Receptor A (RORA) and the mitochondrial biogenesis activation pathways.

Conclusions : Our data shows that several pathways of the gut-retina axis are affected in HFD-induced gut dysbiosis conditions. Further studies delineating the effects and interactions of diet and gut microbiome on retinal physiology are needed to reveal the relationship to retinal disease pathogenesis.

This is a 2021 ARVO Annual Meeting abstract.