# 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.

## Key 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.