From the Human Blood Metabolome to an Interventional Murine CNV Model: Unveiling Saccharin's Protective Effect on Neovascular AMD

Abstract

Purpose : As nutrition stands as a pivotal risk factor for age-related macular degeneration (AMD), it has transformed with the growing consumption of artificial sweeteners (AS). Given the current uncertainties surrounding the effects of AS on the human body, this study probes the potential link between AS metabolite levels in the bloodstream and clinical markers of neovascular AMD (nAMD). Within this framework, the research emphasizes the potential role of saccharin in retinal diseases, especially its impact on anomalous angiogenesis and choroidal neovascularization (CNV).

Methods : This study involved a cross-sectional analysis of 46 nAMD patients receiving anti-VEGF intravitreal treatment. They were grouped based on CNV activity control. Blood levels of six artificial sweeteners (acesulfame, aspartate, erythritol, saccharin, sorbitol, xylitol) were measured using LC-MS/MS mass spectrometry to explore associations with nAMD traits. Additionally, an interventional study using a murine CNV model was conducted. This involved oral saccharin administration to mice and subsequent evaluation through imaging techniques and gene expression analysis.

Results : Saccharin significantly impacted nAMD, with higher blood levels correlating with controlled CNV activity (0.33 ± 0.11 non-controlled vs. 5.17 ± 2.76 controlled; p=0.004) and less subretinal hyperreflective material (odds ratio: 9.03, p=0.015). In the murine CNV model, saccharin-treated mice had fewer leaky scars (14.2 kpx2 ± 13.9 kpx2 control vs. 8.5 px2 ± 6.2 px2 saccharin; p=0.0125) and less bleeding. Histologically, there was a decrease in fibrosis (0.001 mm3 ± 0.0072 mm3 control vs. 0.00025 mm3 ± 0.0001 mm3 saccharin; p=0.035) and a 40% reduction in monocyte presence (15.88 ± 10.75 control vs. 10.33 ± 5.688 saccharin; p=0.063). Additionally, inflammatory markers and VEGFR-1-related genes, including VEGFb, were significantly lower in saccharin-treated samples (1.035 ± 0.3264 control vs. 0.62 ± 0.1483 saccharin; p=0.016).

Conclusions : Saccharin showcased potential protective benefits for nAMD patients undergoing intravitreal anti-VEGF therapy. It played a vital role in regulating pathological aberrations and scar tissue formation. The murine model results provided additional support to this view, emphasizing saccharin's potential in modulating and minimizing VEGFR-1-mediated immune responses.

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