June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
High-fat diet modulates the retinal pigment epithelium and choroid transcriptome in the absence of gut microbiota
Author Affiliations & Notes
  • Jason Xiao
    University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
  • Bingqing Xie
    Center for Research Informatics, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
    Department of Medicine, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • David Dao
    Department of Ophthalmology and Visual Science, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
  • Asadolah Movahedan
    Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, Connecticut, United States
  • Mark D'Souza
    Center for Research Informatics, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • Hugo Adrian Barba
    Department of Ophthalmology and Visual Science, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
  • Betty Theriault
    Department of Surgery, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • Melanie Spedale
    Animal Resources Center, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • Eugene Chang
    Department of Medicine, Microbiome Medicine Program, Knapp Center for Biomedical Discovery, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • Dinanath Sulakhe
    Department of Medicine, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • Dimitra Skondra
    Department of Ophthalmology and Visual Science, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
  • Footnotes
    Commercial Relationships   Jason Xiao None; Bingqing Xie None; David Dao None; Asadolah Movahedan None; Mark D'Souza None; Hugo Barba None; Betty Theriault None; Melanie Spedale None; Eugene Chang None; Dinanath Sulakhe None; Dimitra Skondra Allergan, Biogen, Alimera Science, Focuscope, Neurodiem, LaGrippe Research, Code C (Consultant/Contractor)
  • Footnotes
    Support  1. BrightFocus Foundation “Role of high fat diet and gut microbiome in macular degeneration” (Dimitra Skondra, M2018042) 2. NIDDK P30 (Eugene B. Chang, DK42086) 3. The University of Chicago Women’s Board (Dimitra Skondra) 4. Illinois Society for the Prevention of Blindness (Dimitra Skondra, FP067271-01-PR and Jason Xiao, FP105447)
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 282 – F0327. doi:
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    • Get Citation

      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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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.

Methods : 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).

Results : 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.

Conclusions : 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.

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