From background diabetic retinopathy to its proliferative stage. What is the role of gut microbiota in the trajectory of DR? a Mendelian randomization study with mediation analysis
Bibliographic record
Abstract
BACKGROUND: Growing evidence suggests that gut microbiota (GM) plays a role in diabetic retinopathy (DR), but the causal microbial drivers and their stage-dependent roles during DR progression remain poorly characterised. Using genetic causality methods, we aim to depict a longitudinal GM mapping and stage-stratified GM signatures across the DR trajectory, spanning initial background DR (BDR) through non-proliferative form (NPDR), to advanced proliferative stage (PDR). METHODS: GWAS data of 207 GM taxa (from phylum to species) were acquired from the Dutch Microbiome Project (N = 7,824), and DR from FinnGen (over 300,000 individuals). A bidirectional two-sample Mendelian Randomization (TSMR) analysis was conducted to elucidate directional causality between GM and DR. Multiple sensitivity evaluations were performed for pleiotropy, heterogeneity, and stability. Additionally, two-step MR and multivariable MR (MVMR) were performed to dissect causal GM-DR relationships using 1400 candidate circulating metabolite level/ratio data from a Canadian cohort (N = 8,299). RESULTS: <0.05), while family_Clostridiaceae (OR = 1.540, 95%CI: 1.110-2.135), genus_Clostridium (OR = 1.473, 95%CI: 1.086-1.997), and species_Eubacterium_ramulus (OR = 1.382, 95%CI: 1.000-1.911) specifically promoted NPDR. Six causal protective GM taxa, comprising four species, Bifidobacterium_longum (OR = 0.540, 95%CI: 0.370-0.788), Bacteroides_stercoris (OR = 0.633, 95%CI: 0.407-0.986), Ruminococcus_torques (OR = 0.771, 95%CI: 0.627-0.948), Roseburia_hominis (OR = 0.652, 95%CI: 0.501-0.849), and two genera, Escherichia (OR = 0.799, 95%CI: 0.638-0.999) and Flavonifractor (OR = 0.825, 95%CI: 0.685-0.993), mitigate NPDR or PDR risks. Among the 76, 90, and 86 causal DR stage-specific metabolites, the mannose-to-hydroxyproline ratio was the only metabolite universally linked to all DR stages, with the other 31 metabolites influencing dual phases. Mediation analysis validated five metabolites (asparagine, cystine, gamma-glutamylglycine, ximenoylcarnitine (C26:1) levels, and androsterone glucuronide to etiocholanolone glucuronide ratio) as key mediators bridging causal GM-DR links, with considerable mediating proportions of 6.75%, 14.90%, 3.03%, 7.25%, and 11.97%, respectively. CONCLUSION: This study pioneers causal longitudinal mapping of GM dynamics across DR progression through integrated genetic prediction and metabolomic mediation analyses, delineating stage-specific microbial drivers, pan-stage pathogens, and metabolite mediators that collectively orchestrate DR pathogenesis. The identified GM-metabolite-DR axis establishes an actionable roadmap for targeted microbiome modulation and metabolite-based therapeutic strategies, bridging observational associations to mechanistic intervention opportunities.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".