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Mendelian randomization analysis revealed a gut microbiota-eye axis in acute anterior uveitis

Eye volume 39, pages 1562–1570 (2025) Cite this article

Subjects

Abstract

Background

Observational studies suggest that gut microbiome (GM) may contribute to acute anterior uveitis (AAU) development, but causality remains unclear. This study was conducted to test whether specific GM taxa were causally associated with AAU.

Methods

The GM data were obtained from the DMP, which included 7738 individuals’ faecal samples and an analysis of host genotype-taxa abundance associations. The AAU data were derived from the FinnGen Consortium (8624 cases and 473,095 controls). We primarily employed the inverse-variance weighted method, complemented by supplementary sensitivity analyses.

Results

Higher abundance of Lachnospiraceae noname (OR = 0.86, 95% CI 0.81–0.91, P = 5.7 × 10-8), Alistipes finegoldii (OR = 0.87, 95% CI 0.78–0.96, P = 0.008), Erysipelotrichaceae (OR = 0.90, 95% CI 0.81–0.99, P = 0.037), Erysipelotrichia (OR = 0.90, 95% CI 0.81–0.99, P = 0.037), Erysipelotrichales (OR = 0.90, 95% CI 0.81–0.99, P = 0.037), and Bacteroides ovatus (OR = 0.93, 95% CI 0.87–1.00, P = 0.039) predicted a lower AAU risk. Conversely, higher abundance of Bifidobacterium catenulatum (OR = 1.06, 95% CI: 1.02–1.10, P = 0.005), Bacteroides coprocola (OR = 1.11, 95% CI: 1.02–1.21, P = 0.014), Parabacteroides unclassified (OR = 1.12, 95% CI 1.03–1.22, P = 0.010), and Prevotella (OR = 1.15, 95% CI: 1.01–1.29, P = 0.029) predicted a higher AAU risk. The results also showed a reverse causation from AAU to Bifidobacterium catenulatum (OR = 1.39, 95% CI: 1.03–1.86, P = 0.005).

Conclusion

This study suggests that specific GM is causally associated with AAU risk, warranting more mechanistic validation and clinical trials.

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Fig. 1
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Fig. 2: The overview of bidirectional causal relationships between gut microbiota and acute anterior uveitis (AAU).
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Fig. 3
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Fig. 4: Scatterplots for Mendelian Randomization (MR) analyses of the causal effect of gut microbiota on acute anterior uveitis.
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Fig. 5: Bidirectional Mendelian Randomization (MR) analyses examining the relationship between Bifidobacterium catenulatum and acute anterior uveitis (AAU).
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Data availability

Summary statistics of gut microbiome GWAS were obtained from the GWAS Catalog https://www.ebi.ac.uk/gwas/publications/35115690, and acute anterior uveitis GWAS summary statistics were retrieved from the FinnGen database https://www.finngen.fi/en/access_results.

References

  1. Tsirouki T, Dastiridou A, Symeonidis C, Tounakaki O, Brazitikou I, Kalogeropoulos C, et al. A focus on the epidemiology of uveitis. Ocul Immunol Inflamm. 2018;26:2–16.

    PubMed  Google Scholar 

  2. Goodchild C, O’Rourke M, Haroon M, FitzGerald O, Murphy CC. 5-year longitudinal study of clinical and patient-reported outcomes in acute anterior uveitis. Eye. 2021;35:651–8.

    PubMed  Google Scholar 

  3. Zhuang Z, Wang Y, Zhu G, Gu Y, Mao L, Hong M, et al. Imbalance of Th17/Treg cells in pathogenesis of patients with human leukocyte antigen B27 associated acute anterior uveitis. Sci Rep. 2017;7:40414.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Huang XF, Brown MA. Progress in the genetics of uveitis. Genes Immun. 2022;23:57–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Foster CS, Kothari S, Anesi SD, Vitale AT, Chu D, Metzinger JL, et al. The ocular immunology and uveitis foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016;61:1–17.

    PubMed  Google Scholar 

  6. Lin P, Suhler EB, Rosenbaum JT. The future of uveitis treatment. Ophthalmology 2014;121:365–76.

    PubMed  Google Scholar 

  7. Dick AD, Rosenbaum JT, Al-Dhibi HA, Belfort R Jr., Brézin AP, Chee SP, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitiS (FOCUS) initiative. Ophthalmology 2018;125:757–73.

    PubMed  Google Scholar 

  8. Huang X, Ye Z, Cao Q, Su G, Wang Q, Deng J, et al. Gut microbiota composition and fecal metabolic phenotype in patients with acute anterior uveitis. Investig Ophthalmol Vis Sci. 2018;59:1523–31.

    CAS  Google Scholar 

  9. Essex M, Rios Rodriguez V, Rademacher J, Proft F, Löber U, Markó L, et al. Shared and distinct gut microbiota in spondyloarthritis, acute anterior uveitis, and Crohn’s disease. Arthritis Rheumatol. 2024;76:48–58.

    PubMed  Google Scholar 

  10. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans. Cell 2016;164:337–40.

    CAS  PubMed  Google Scholar 

  11. Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023;23:38–54.

    CAS  PubMed  Google Scholar 

  12. Wang Q, Yi S, Su G, Du Z, Pan S, Huang X, et al. Changes in the gut microbiome contribute to the development of behcet’s disease via adjuvant effects. Front Cell Dev Biol. 2021;9:716760.

    PubMed  PubMed Central  Google Scholar 

  13. Pingault JB, O’Reilly PF, Schoeler T, Ploubidis GB, Rijsdijk F, Dudbridge F. Using genetic data to strengthen causal inference in observational research. Nat Rev Genet. 2018;19:566–80.

    CAS  PubMed  Google Scholar 

  14. Plotnikov D, Guggenheim JA. Mendelian randomisation and the goal of inferring causation from observational studies in the vision sciences. Ophthalmic Physiol Opt. 2019;39:11–25.

    PubMed  Google Scholar 

  15. Hong JB, Chen YX, Su ZY, Chen XY, Lai YN, Yang JH. Causal association of juvenile idiopathic arthritis or JIA-associated uveitis and gut microbiota: a bidirectional two-sample Mendelian randomisation study. Front Immunol. 2024;15:1356414.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Morris AH, Bohannan BJM. Estimates of microbiome heritability across hosts. Nat Microbiol. 2024;9:3110–9.

    CAS  PubMed  Google Scholar 

  17. Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement. JAMA 2021;326:1614–21.

    PubMed  Google Scholar 

  18. Lopera-Maya EA, Kurilshikov A, van der Graaf A, Hu S, Andreu-Sánchez S, Chen L, et al. Effect of host genetics on the gut microbiome in 7738 participants of the Dutch Microbiome Project. Nat Genet. 2022;54:143–51.

    CAS  PubMed  Google Scholar 

  19. Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K, Donner KM, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 2023;613:508–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sanna S, van Zuydam NR, Mahajan A, Kurilshikov A, Vich Vila A, Võsa U, et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet. 2019;51:600–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu X, Tong X, Zou Y, Lin X, Zhao H, Tian L, et al. Mendelian randomization analyses support causal relationships between blood metabolites and the gut microbiome. Nat Genet. 2022;54:52–61.

    CAS  PubMed  Google Scholar 

  22. Mi Y, Zhu Q, Zheng X, Wan M. The protective role of water intake in age-related eye diseases: insights from a Mendelian randomization study. Food Funct. 2024;15:5147–57.

    CAS  PubMed  Google Scholar 

  23. Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics 2019;35:4851–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bowden J, Spiller W, Del Greco MF, Sheehan N, Thompson J, Minelli C, et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. Int J Epidemiol. 2018;47:2100.

    PubMed  PubMed Central  Google Scholar 

  25. Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40:755–64.

    PubMed  Google Scholar 

  26. Mi Y, Chen K, Lin S, Tong L, Zhou J, Wan M. Lactobacillaceae-mediated eye-brain-gut axis regulates high myopia-related anxiety: from the perspective of predictive, preventive, and personalized medicine. EPMA J. 2024;15:573–85.

    PubMed  Google Scholar 

  27. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017;13:e1007081.

    PubMed  PubMed Central  Google Scholar 

  28. Panagiotou OA, Ioannidis JP. What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. Int J Epidemiol. 2012;41:273–86.

    PubMed  Google Scholar 

  29. Slob EAW, Burgess S. A comparison of robust Mendelian randomization methods using summary data. Genet Epidemiol. 2020;44:313–29.

    PubMed  PubMed Central  Google Scholar 

  30. Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res. 2019;4:186.

    PubMed  Google Scholar 

  31. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–89.

    PubMed  PubMed Central  Google Scholar 

  32. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40:304–14.

    PubMed  PubMed Central  Google Scholar 

  33. Burgess S, Zuber V, Gkatzionis A, Foley CN. Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid. Int J Epidemiol. 2018;47:1242–54.

    PubMed  PubMed Central  Google Scholar 

  34. Xue H, Shen X, Pan W. Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects. Am J Hum Genet. 2021;108:1251–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Burgess S, Bowden J, Fall T, Ingelsson E, Thompson SG. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology 2017;28:30–42.

    PubMed  Google Scholar 

  37. Greco MF, Minelli C, Sheehan NA, Thompson JR. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med. 2015;34:2926–40.

    Google Scholar 

  38. Wang Q, Wu S, Ye X, Tan S, Huang F, Su G, et al. Gut microbial signatures and their functions in Behcet’s uveitis and Vogt-Koyanagi-Harada disease. J Autoimmun. 2023;137:103055.

    CAS  PubMed  Google Scholar 

  39. Zhong Z, Su G, Yang P. Risk factors, clinical features and treatment of Behçet’s disease uveitis. Prog Retin Eye Res. 2023;97:101216.

    PubMed  Google Scholar 

  40. Liu C, Wang X, Cao X. IL-10: a key regulator and potential therapeutic target in uveitis. Cell Immunol. 2024;405-406:104885.

    CAS  PubMed  Google Scholar 

  41. Burrello C, Garavaglia F, Cribiù FM, Ercoli G, Lopez G, Troisi J, et al. Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat Commun. 2018;9:5184.

    PubMed  PubMed Central  Google Scholar 

  42. Robinson PC, Claushuis TA, Cortes A, Martin TM, Evans DM, Leo P, et al. Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol. 2015;67:140–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen W, Zhao B, Jiang R, Zhang R, Wang Y, Wu H, et al. Cytokine expression profile in aqueous humor and sera of patients with acute anterior uveitis. Curr Mol Med. 2015;15:543–9.

    CAS  PubMed  Google Scholar 

  44. Vacca M, Celano G, Calabrese FM, Portincasa P, Gobbetti M, De Angelis M. The controversial role of human gut lachnospiraceae. Microorganisms. 2020;8:573.

  45. Lin P. Importance of the intestinal microbiota in ocular inflammatory diseases: a review. Clin Exp Ophthalmol. 2019;47:418–22.

    PubMed  Google Scholar 

  46. Huang YF, Zhang WM, Wei ZS, Huang H, Mo QY, Shi DL, et al. Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: a bidirectional Mendelian randomization study. Front Immunol. 2023;14:1136169.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yi M, Zheng X, Niu M, Zhu S, Ge H, Wu K. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21:28.

    PubMed  PubMed Central  Google Scholar 

  48. Li Y, Hong M, Huang X, Zhong L, Gu Y. Wang D, et al. PD-1 polymorphisms are associated with susceptibility of acute anterior uveitis in chinese population. DNA Cell Biol. 2019;38:121–8.

    CAS  PubMed  Google Scholar 

  49. Yang C, Mogno I, Contijoch EJ, Borgerding JN, Aggarwala V, Li Z, et al. Fecal IgA levels are determined by strain-level differences in bacteroides ovatus and are modifiable by gut microbiota manipulation. Cell Host Microbe. 2020;27:467–75.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ihekweazu FD, Engevik MA, Ruan W, Shi Z, Fultz R, Engevik KA, et al. Bacteroides ovatus promotes IL-22 production and reduces trinitrobenzene sulfonic acid-driven colonic inflammation. Am J Pathol. 2021;191:704–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sprenkels SH, Uksila J, Vainionpää R, Toivanen P, Feltkamp TE. IgA antibodies in HLA-B27 associated acute anterior uveitis and ankylosing spondylitis. Clin Rheumatol. 1996;15:52–6.

    PubMed  Google Scholar 

  52. Huang JC, Schleisman M, Choi D, Mitchell C, Watson L, Asquith M, et al. Preliminary Report on Interleukin-22, GM-CSF, and IL-17F in the Pathogenesis of Acute Anterior Uveitis. Ocul Immunol Inflamm. 2021;29:558–65.

    CAS  PubMed  Google Scholar 

  53. O’Toole PW, Marchesi JR, Hill C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol. 2017;2:17057.

    PubMed  Google Scholar 

  54. Wu PH, Tseng YF, Liu W, Chuang YS, Tai CJ, Tung CW, et al. Exploring the relationship between gut microbiome composition and blood indole-3-acetic acid in hemodialysis patients. Biomedicines 2024;12:148.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ye Z, Wu C, Zhang N, Du L, Cao Q, Huang X, et al. Altered gut microbiome composition in patients with Vogt-Koyanagi-Harada disease. Gut Microbes. 2020;11:539–55.

    PubMed  PubMed Central  Google Scholar 

  56. Ye Z, Zhang N, Wu C, Zhang X, Wang Q, Huang X, et al. A metagenomic study of the gut microbiome in Behcet’s disease. Microbiome 2018;6:135.

    PubMed  PubMed Central  Google Scholar 

  57. Lin P, Bach M, Asquith M, Lee AY, Akileswaran L, Stauffer P, et al. HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats. PLoS One. 2014;9:e105684.

    PubMed  PubMed Central  Google Scholar 

  58. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2013;2:e01202.

    PubMed  PubMed Central  Google Scholar 

  59. Tett A, Pasolli E, Masetti G, Ercolini D, Segata N. Prevotella diversity, niches and interactions with the human host. Nat Rev Microbiol. 2021;19:585–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Servin AL. Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens. FEMS Microbiol Rev. 2004;28:405–40.

    CAS  PubMed  Google Scholar 

  61. Kim J, Choi SH, Kim YJ, Jeong HJ, Ryu JS, Lee HJ, et al. Clinical effect of IRT-5 probiotics on immune modulation of autoimmunity or alloimmunity in the eye. Nutrients. 2017;9:166.

  62. Westfall S, Caracci F, Zhao D, Wu QL, Frolinger T, Simon J, et al. Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors. Brain Behav Immun. 2021;91:350–68.

    CAS  PubMed  Google Scholar 

  63. Shen X, Du J, Guan W, Zhao Y. The balance of intestinal Foxp3+ regulatory T cells and Th17 cells and its biological significance. Expert Rev Clin Immunol. 2014;10:353–62.

    CAS  PubMed  Google Scholar 

  64. van der Houwen TB, van Laar JAM, Kappen JH, van Hagen PM, de Zoete MR, van Muijlwijk GH, et al. Behçet’s disease under microbiotic surveillance? A combined analysis of two cohorts of behçet’s disease patients. Front Immunol. 2020;11:1192.

    PubMed  PubMed Central  Google Scholar 

  65. Shimizu J, Kubota T, Takada E, Takai K, Fujiwara N, Arimitsu N, et al. Bifidobacteria abundance-featured gut microbiota compositional change in patients with Behcet’s disease. PLoS ONE. 2016;11:e0153746.

    PubMed  PubMed Central  Google Scholar 

  66. Hall N, Douglas VP, Ivanov A, Ross C, Elze T, Kempen JH, et al. The epidemiology and risk factors for the progression of sympathetic ophthalmia in the United States: an IRIS registry analysis. Am J Ophthalmol. 2024;258:208–16.

    CAS  PubMed  Google Scholar 

  67. Wang Q, Ma J, Gong Y, Zhu L, Tang H, Ye X, et al. Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet’s uveitis. Cell Discov. 2024;10:47.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all participants and investigators from the Dutch Microbiome Project and FinnGen study.

Funding

This work was supported by a grant from the Wenzhou Science & Technology Bureau (Grant No. Y20210997).

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Author notes

  1. These authors contributed equally: Yuze Mi, Lu Chen.

Authors and Affiliations

  1. National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China

    Yuze Mi, Lu Chen, Na Liao & Minghui Wan

  2. State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China

    Yuze Mi, Lu Chen, Na Liao & Minghui Wan

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  1. Yuze Mi
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  2. Lu Chen
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  3. Na Liao
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Contributions

YM conceptualized and designed the study. YM performed the data analysis, while LC validated the analytical findings. YM NL and MW drafted and substantially revised the manuscript. All authors reviewed and approved the final version of the manuscript for publication.

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Correspondence to Na Liao or Minghui Wan.

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Mi, Y., Chen, L., Liao, N. et al. Mendelian randomization analysis revealed a gut microbiota-eye axis in acute anterior uveitis. Eye 39, 1562–1570 (2025). https://doi.org/10.1038/s41433-025-03715-3

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