Purchase this article with an account.
Jason Xiao, Bingqing Xie, David Dao, Asadolah Movahedan, Mark D'Souza, Hugo Adrian Barba, Betty Theriault, Melanie Spedale, Eugene Chang, Dinanath Sulakhe, Dimitra Skondra; High-fat diet modulates the retinal pigment epithelium and choroid transcriptome in the absence of gut microbiota. Invest. Ophthalmol. Vis. Sci. 2022;63(7):282 – F0327.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Diet and the gut microbiome are implicated in age-related macular degeneration (AMD). Our team has shown that high-fat diets (HFDs) induce gut dysbiosis, exacerbate laser-induced choroidal neovascularization, and alter retinal transcription in the absence of microbiome. However, the diet-microbiome-transcriptome associations within the choroid/retinal pigment epithelium (RPE) remain unknown. Here, we study how HFDs alter choroid/RPE gene expression and related biological pathways in the absence of microbiome using germ-free (GF) mice.
RNA was extracted from choroid/RPE tissue (4 mice/group) of 15-weeks old GF C57BL/6J male mice fed normal diet or HFD (23% saturated fat for 8 weeks). RNA was sequenced via paired-end method on NovaSeq6000. Differentially expressed genes (DEGs) were identified (adjusted p-value <0.05) and incorporated in functional enrichment analysis using Toppgene (FDR BH <0.05, logFC >1.5).
After correction of raw data, 1044 DEGs were identified from 24,784 genes. In the GF-HFD cohort, 912 DEGs were upregulated and 132 were downregulated. HFD affected genes involved in inflammation, angiogenesis, immunity, and extracellular matrix (ECM) interactions in the RPE/choroid according to Gene Ontology enrichment. HFD increased expression of Vegfc, Angpt1, Angpt2, Pdgfc, and Pdgfd, which function in concert to regulate angiogenesis and vascular remodeling, and are active targets in clinical trials of AMD. In addition, HFD affected inflammatory and immune-related genes. Some of the most significant DEGs clustered around natural killer T (NKT) cells, including NKT receptors (Cd244a), binding partners (Cd48), cytotoxic effectors (Gzma and Prf1), activators (Cxcl10), and growth factors (IL12b). HFD also upregulated C1qb, C2, C4b, and Cfh of the complement cascade. Finally, ECM components, including collagens Col8a1 and Col10a1, as well as enzymes such as Adamts9, were impacted, all of which correlate with AMD.
This study provides novel data that HFDs alter choroid/RPE biology at the transcriptional level in the absence of gut microbiota. We use the framework of AMD pathogenesis to highlight significant differences in gene expression and pathways, including angiogenesis, inflammation, complement cascade, and ECM interactions. Further studies will help delineate the complex relationships between diet, gut microbiota, and AMD pathobiology.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
This PDF is available to Subscribers Only