Beneficial Effects of Micronutrient Supplementation in Restoring the Altered Microbiota and Gut-Retina Axis in Patients with Neovascular Age-Related Macular Degeneration-A Randomized Clinical Trial

Abstract

Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly and is characterized by a multifactorial etiology. Emerging evidence points to the potential involvement of the gut-retina axis in AMD pathogenesis, prompting exploration into novel therapeutic strategies. This study aims to investigate the effects of some micronutrients (such as lutein and zeaxanthin) and saffron (as a supplement)-known for their anti-inflammatory properties-on ophthalmological and microbial parameters in neovascular AMD (nAMD) patients. Methods: Thirty naive nAMD patients were randomized to receive daily micronutrient supplementation alongside anti-VEGF (vascular endothelial growth factor) therapy, or anti-VEGF treatment alone, over a 6-month period, with comparisons made to a healthy control (HC) group (N = 15). Ophthalmological assessments, biochemical measurements, and stool samples were obtained before and after treatment. Gut microbiota (GM) characterization was performed using 16S rRNA sequencing, while short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), and long-chain fatty acids (LCFAs) were analyzed with a gas chromatography-mass spectrometry protocol. Results: Compared to HC, nAMD patients exhibited reduced GM alpha diversity, altered taxonomic composition, and decreased total SCFA levels, in addition to elevated levels of proinflammatory octanoic and nonanoic acids. Micronutrient supplementation was associated with improved visual acuity relative to the group treated with anti-VEGF alone, along with a decrease in the total amount of MCFAs, which are metabolites known to have adverse ocular effects. Conclusions: In conclusion, despite certain limitations-such as the limited sample size and the low taxonomic resolution of 16S rRNA sequencing-this study highlights compositional and functional imbalances in the GM of nAMD patients and demonstrates that micronutrient supplementation may help restore the gut-retina axis. These findings suggest the therapeutic potential of micronutrients in enhancing ocular outcomes for nAMD patients, underscoring the complex interaction between GM and ocular health.

Keywords: gut microbiota; gut–retina axis; lutein; nAMD; saffron; short-chain fatty acids; zeaxanthin.

Figure 1

Principal coordinate analysis (PCoA) computed using Hellinger distance on transformed genera abundances of stool samples among HC and nAMD patients.

Figure 2

Box plots showing fecal alpha diversity indices (observed ASV richness, Shannon index, and Pielou’s evenness) between HC and nAMD patients.

Figure 3

Boxplot displaying the results of differential abundances analysis between HC and nAMD patients. The Y-axis, reporting the percent abundance of each taxon, is scaled to improve the readability of lower abundances. All results have an adjusted. p < 0.05.

Figure 4

Bar plots representing the significant fecal acid abundances among HC and nAMD patients. Analyses were assessed using the Mann–Whitney test, and p-values less than 0.05 were considered statistically significant. The asterisks (*) represent p-values; * p < 0.05, *** p < 0.001.

Figure 5

Visual acuity measurements of nAMD patients assigned to intervention (A) or control (B) groups.

Figure 6

OCT of nAMD patients assigned to intervention (A) and control (B) groups. Analyses were assessed using the Mann–Whitney test, and p-values less than 0.05 were considered statistically significant. The asterisks (*) represent p-values; ** p < 0.01.

Figure 7

Bar plots representing the significant fecal acid abundances in nAMD patients pre- and post-micronutrient supplementation. Analyses were assessed using the Mann–Whitney test, and p-values less than 0.05 were considered statistically significant. The asterisks (*) represent p-values; * p < 0.05, ** p < 0.01.