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
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 ma...
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BMC
2025-08-01
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| Series: | Diabetology & Metabolic Syndrome |
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| Online Access: | https://doi.org/10.1186/s13098-025-01813-6 |
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| author | Yifan Zhou Jialong Dong Zhenyu Wang Chen Huang Xiaotong Yu Xinjun Wang Bo Yang Yuechen Wu Qing Peng |
| author_facet | Yifan Zhou Jialong Dong Zhenyu Wang Chen Huang Xiaotong Yu Xinjun Wang Bo Yang Yuechen Wu Qing Peng |
| author_sort | Yifan Zhou |
| collection | DOAJ |
| description | 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 We identified 11 causal GM taxa (1 family, 3 genera, and 7 species) during the progression of DR. Notably, species_Bacteroides_dorei and species_Dorea_longicatena demonstrated pan-stage pathogenicity (BDR and PDR, all OR>1, P IVW <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. |
| format | Article |
| id | doaj-art-dc168b4d79034d68ab89a624461fbef7 |
| institution | Kabale University |
| issn | 1758-5996 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj-art-dc168b4d79034d68ab89a624461fbef72025-08-24T11:41:45ZengBMCDiabetology & Metabolic Syndrome1758-59962025-08-0117111110.1186/s13098-025-01813-6From 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 analysisYifan Zhou0Jialong Dong1Zhenyu Wang2Chen Huang3Xiaotong Yu4Xinjun Wang5Bo Yang6Yuechen Wu7Qing Peng8Department of Ophthalmology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityDepartment of Ophthalmology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityBeijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology and Visual Science Key Lab, Capital Medical UniversityCenter of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third HospitalCenter of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third HospitalAffiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical UniversitySchool of Medicine, Tongji UniversityDepartment of Traditional Chinese Medicine, Shanghai Fourth People’s Hospital Affiliated to Tongji UniversityDepartment of Ophthalmology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityAbstract 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 We identified 11 causal GM taxa (1 family, 3 genera, and 7 species) during the progression of DR. Notably, species_Bacteroides_dorei and species_Dorea_longicatena demonstrated pan-stage pathogenicity (BDR and PDR, all OR>1, P IVW <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.https://doi.org/10.1186/s13098-025-01813-6Gut-eye axisCirculating metabolitesMendelian randomization studyMediation analysisGenome-wide association studies (GWAS) |
| spellingShingle | Yifan Zhou Jialong Dong Zhenyu Wang Chen Huang Xiaotong Yu Xinjun Wang Bo Yang Yuechen Wu Qing Peng 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 Diabetology & Metabolic Syndrome Gut-eye axis Circulating metabolites Mendelian randomization study Mediation analysis Genome-wide association studies (GWAS) |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Gut-eye axis Circulating metabolites Mendelian randomization study Mediation analysis Genome-wide association studies (GWAS) |
| url | https://doi.org/10.1186/s13098-025-01813-6 |
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