Abstract
Purpose :
Diet may affect age-related macular degeneration (AMD) progression, but the mechanism and therapeutic window remain unknown. We hypothesized that switching to Mediterranean diet (MedD) or high-fat diet (HFD) after laser induction modulates choroidal neovascularization (CNV) in a preclinical model of neovascular AMD (nAMD). Furthermore, we hypothesized that CNV response correlates with distinct gut microbiome and metabolite profiles.
Methods :
Male C57Bl/6J mice at 12-weeks of age underwent laser-induced CNV. Mice were fed a normal diet (ND) until 5 days post-laser and allocated to ND, HFD, or MedD (n=11 mice per group, 4 lesions per eye). After 21 days, choroidal flatmounts were stained for Iba1 and Isolectin B4 and analyzed in ImageJ. 16S rRNA sequencing of fecal DNA was analyzed in QIIME2. Fecal metabolomics were assayed with panels for short-chain fatty acids (SCFAs), small metabolites, and bile acids (BAs).
Results :
MedD (7,185 ± 6,129 µm2) decreased CNV size compared to ND (10,258 ± 9429 µm2, p=0.044) or HFD (14,939 ± 9213 µm2, p<0.001). Within lesions, MedD Iba1 intensity (38.8 ± 5.7) was smaller than ND (46.7 ± 10.2, p<0.001) or HFD (56.5 ± 6.0, p<0.001). Number of Iba1+ microglia around lesions did not differ. Groups easily separated by principle component analysis of microbiome beta-diversities. ND (FDR=0.003) and MedD (FDR=0.083) were enriched with phylum Bacteroidetes relative to HFD. HFD increased order Clostridiales (FDR<0.01), whereas MedD decreased Negativicutes relative to ND (FDR=0.003). Compared to HFD, ND and MedD had decreased family Clostridiaceae 1 (FDR<0.001) and genera Clostridium sensu stricto (FDR<0.001) and Clostridium XlVb (FDR<0.01). MedD increased abundance of genus Butyrvibrio relative to ND and HFD (FDR<0.001). Among SCFAs, acetate and propionate levels were significantly elevated in ND and MedD compared to HFD; ND also increased butyrate. MedD raised levels of glycine, proline, and valerate compared to ND or HFD, and HFD increased palmitate levels. HFD and MedD demonstrated increased BA levels of chenodeoxycholic, ursodeoxycholic, tauroursodeoxycholic, and 3-oxolithocholic acid.
Conclusions :
Switching to MedD or HFD after CNV-induction modulates severity of nAMD-like features. Each diet induces a distinct gut microbiome composition and metabolomic profile, demonstrating potential for AMD intervention along the gut-retina axis.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.