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Oral Metformin Inhibits Choroidal Neovascularization by Modulating the Gut-Retina Axis.

Jason Y Zhang1, Jason Xiao1, Bingqing Xie2

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Investigative Ophthalmology & Visual Science
|December 18, 2023
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Metformin reduces choroidal neovascularization (CNV) by altering the gut microbiome, suggesting a novel therapeutic approach for age-related macular degeneration (AMD). This study highlights the gut microbiome

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Area of Science:

  • Ophthalmology
  • Microbiology
  • Pharmacology

Background:

  • Emerging evidence suggests metformin may prevent age-related macular degeneration (AMD).
  • The mechanisms behind metformin's anti-aging effects are not fully understood, with the gut microbiome being a proposed pathway.
  • Choroidal neovascularization (CNV) is a hallmark of advanced neovascular AMD.

Purpose of the Study:

  • To investigate the effects of oral metformin on laser-induced CNV.
  • To analyze the impact of metformin on the retinal pigment epithelium (RPE)/choroid transcriptome.
  • To examine metformin's influence on the gut microbiota composition and function.

Main Methods:

  • Male mice received oral metformin or vehicle, followed by laser-induced CNV.
  • CNV size and immune cell infiltration were assessed via immunostaining.
  • RNA sequencing of RPE/choroid, 16S rRNA sequencing, shotgun metagenomics, and metabolite analysis of fecal samples were performed. Studies were repeated in germ-free and microbiota-transplanted mice.

Main Results:

  • Metformin treatment significantly reduced CNV size and macrophage/microglial infiltration.
  • Gene expression analysis revealed downregulation of pro-angiogenic factors in metformin-treated mice.
  • Metformin altered the gut microbiome composition, increasing beneficial bacteria (Bifidobacterium, Akkermansia) and key metabolites (butyrate, succinate, cholic acid). Metformin's effect on CNV was dependent on the presence of a gut microbiome.

Conclusions:

  • Oral metformin suppresses CNV, a key lesion in advanced neovascular AMD.
  • These effects are mediated through modulation of the gut microbiome.
  • Metformin's impact on the gut microbiome suggests a potential therapeutic strategy for AMD.