Abstract Text: Investigating the relationship between alterations in the gut microbiota in age-related macular degeneration (AMD) can uncover a completely novel mechanism of this blinding eye disease. A cross-sectional case-control study of advanced AMD patients and age-similar healthy control subjects from a university practice was performed. We used 16S rRNA gene sequencing to characterize gut bacterial differences and flow-cytometry-based bacterial cell sorting taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) to show that high IgA coating uniquely identifies colitogenic intestinal bacteria. We analyzed 85 advanced AMD and 49 healthy control subjects. An intestinal dysbiosis in advanced AMD was demonstrated at the phyla and genus levels (e.g. increased differential abundance of Proteobacteria-Gammaproteobacteria and reduction in Firmicutes-Clostridia [p < 0.05]). Increased genetic risk score in AMD subjects was associated with decreased gut bacterial alpha diversity (Spearman’s r=-0.3, p=0.0086 value), whereas AREDS (2) supplementation significantly increased alpha diversity. The percentage of IgA-bound gut bacteria was significantly increased in ARMS2 homozygous risk allele patients (23.7%, p=0.008) compared to non-risk allele AMD subjects. AMD and control subjects showed differences in IgA coating indices for Prevotella and Ruminococceae genera. Metabolite pathways represented by the gut bacteria that were differentially abundant in AMD vs. control subjects included lipid metabolism and carotenoid biosynthesis pathways that are known to be important in AMD pathogenesis. AREDS supplementation and genetic risk are crucial determinants of intestinal microbial alterations in advanced AMD and may point to novel therapeutic targets to treat this blinding condition.
