Gut Microbiota Signatures and Potential Mediators in the Trajectory of Age-related Macular Degeneration: A Phased Atlas by Genetic Inference

TL;DR

This study maps gut microbiota changes linked to age-related macular degeneration (AMD) stages and identifies potential microbial and biochemical targets for intervention.

Contribution

The first phased atlas of gut microbiota signatures across AMD stages, using genetic inference to identify causal and mediating factors.

Findings

12-9 genetically predicted causal gut taxa were identified across different AMD stages.

g.Ruminococcaceae and s.Ruminococcaceae_bacterium_D16 were shared across three AMD stages.

Firmicutes showed stage-specific duality, and under-studied Actinobacteria and Verrucomicrobia were linked to AMD for the first time.

Abstract

To depict an atlas of stage-stratified gut microbiota (GM) signatures and intermediatory metabolites, inflammatory proteins, and immune cell traits, governing the AMD trajectory.

We deployed bidirectional two-sample Mendelian randomization (TSMR) integrating GWAS data of 207 GM taxa from the Dutch Microbiome Project (N = 7,738), and multiple AMD stages/subtypes, including 'Macular degeneration (senile) of retina', 'Early AMD', 'Disease progression to GA/CNV', 'Dry AMD includes GA', and 'Wet AMD', encapsulating the disease trajectory (N > 410,000), complemented by multivariable MR (MVMR) mediation analysis of 1,400 circulating metabolites, 731 immune cell traits, and 91 inflammatory proteins.

We identified 12/8/5/2/9/8 genetically predicted causal GM taxa of various AMD stages/subtypes as a stage-stratified GM signature across the AMD trajectory, among which g.Ruminococcaceae and s.Ruminococcaceae_bacterium_D16 were the sole shared GM taxa in triple AMD stages, while s.Bacteroides eggerthii, c.Gammaproteobacteria, s.Dorea and s.Ruminococcus_obeum influence dual AMD stages. Bidirectional analysis revealed that f.Streptococcaceae, g.Erysipelotrichaceae_noname, g.Streptococcus, s.Streptococcus_thermophilus, g.Ruminococcaceae_noname, and s.Ruminococcaceae_bacterium_D16 exhibited genetically reciprocal causation with AMD. We also proposed that Firmicutes may exhibit stage-specific duality depending on their constituent members and AMD stages. Several understudied GM from p.Actinobacteria and p.Verrucomicrobia have been implicated as AMD-associated taxa for the first time. Key metabolites, immune cell traits, and inflammatory proteins were established as significant mediators of GM-AMD links.

This first phased atlas uncovers GM effects over the AMD course, identifying potential microbial and biochemical targets for intervening in disease development.

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