Western diets and gut dysbiosis are implicated in choroidal transcriptional dysregulation and neovascularization

Abstract

Purpose : Western-style (WD) diets, enriched in fats and sugars and gut dysbiosis have been identified as modulators of age-related macular degeneration (AMD). However, a causal relationship between WD-induced gut dysbiosis and AMD features has not been established. In this study, we assess the interactions of WD and the gut microbiome organ with CNV features and CNV transcriptomic signatures using germ-free (GF), gnotobiotic animal models and fecal microbial transplantation (FMT).

Methods : Mice were raised either under sterile GF conditions or standard conditions (specific pathogen free; SPF) and fed either normal diet (ND) or WD pellets ad libitum. A subset of SPF mice underwent antibiotic therapy to ablate the gut microbiome. A subset of GF ND mice underwent FMT with the fecal microbiome of either SPF ND or SPF WD mice. In a subset of mice, at 16 weeks, laser photocoagulation was performed to induce choroidal neovascularization. Following sacrifice, globes were dissected and cryopreserved. Choroidal flatmounts were stained and imaged for lectin and IBA-1, and remaining choroidal tissue was used for RNA-seq and differential gene expression analysis.

Results : We observed significant WD-induced gut dysbiosis, with WD mice being enriched for Firmicutes and Verrucomicrobia and relatively depleted of Bacteroidota. WD mice had broad choroidal transcriptional dysregulation, with hundreds of differentially expressed genes (DEGs) and with enrichment of AMD-related pathways including angiogenesis (e.g., Egfl7, Slc9a3r2) or tissue remodeling (e.g., Adam15, C1qtnf5). SPF WD mice had 54.2% greater CNV and 7.99% greater macrophage infiltration than did the ND mice. For GF mice or SPF mice that underwent antibiotic treatment, CNV lesion sizes for WD groups decreased (27.5% and 34.5%, respectively) and more closely resembled the ND groups. Notably, for GF mice on ND that underwent FMT with the microbiota of SPF ND or WD mice, their CNV lesion sizes most closely resembled that of the SPF ND or WD mice, respectively, suggesting that the gut microbiome mediates WD’s effects on CNV features.

Conclusions : In mice, WD are associated with choroidal transcriptional dysregulation and alter the gut microbiome, with this diet-induced gut dysbiosis playing a causative role in increasing CNV and macrophage infiltration upon laser photocoagulation.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.