Background: Some experimental reports have proposed an interaction between gut microbiota (GM) and uveitis. However, the exact association between GM and its metabolic pathways and uveitis remains unknown. Methods: Summary data of the GM and its metabolic pathways and uveitis were leveraged from the Dutch Microbiome Project and the GWAS Catalog, respectively. We then conducted Mendelian randomization analysis to explore whether the GM and its metabolic pathways have a corresponding causal relationship with uveitis. To confirm the credibility of the findings, we utilized MR Egger, the MR-PRESSO global test, and the Cochran Q test to detect pleiotropy and heterogeneity. Results : According to the inverse variance weighting method, the species Bacteroides faecis (OR=0.598, 95% CI=0.390-0.919, P=0.019) and the superpathway of sulfate assimilation and cysteine biosynthesis (OR=0.179, 95% CI=0.038-0.843, P=0.029) had beneficial effects on uveitis. In contrast, the genus Sutterellaceae (OR=3.493, 95% CI=1.121-10.879, P=0.030); the species Parabacteroides distasonis (OR=5.932, 95% CI=1.321-26.635, P=0.020), Faecalibacterium prausnitzii (OR=4.838, 95% CI=1.067-21.936, P=0.040), and Bacteroides caccae (OR=3.818, 95% CI=1.010-14.437, P=0.048); and the L1,2-propanediol degradation (OR=2.084, 95% CI=1.098-3.954, P=0.024), galactose degradation I (Leloir pathway) (OR=3.815, 95% CI =1.108-13.135, P=0.033), TCA cycle VI (obligate autotrophs) (OR=2.955, 95% CI=1.015-8.606, P=0.046) and UMP biosynthesis (OR=4.979, 95% CI=1.000-24.782, P=0.049) pathways had adverse effects on uveitis. No pleiotropy or heterogeneity was found. Leave-one-out analysis showed the reliability of above findings. Conclusion: Our analysis revealed a causality between certain GM species and metabolic pathways and uveitis via genetic prediction, which may provide new perspectives into the etiology and therapies of uveitis. Keywords: gut microbiota, metabolic pathways, uveitis, Mendelian randomization, causality

Axenfeld-Rieger syndrome is an autosomal dominant genetic disease characterized by binocular anterior segment development defects and systemic dysplasia. In our study, a Chinese Axenfeld-Rieger syndrome pedigree was analyzed. After obtaining consent from the subjects, ophthalmic examinations were performed, and blood samples were collected. Then, the causative gene was identified by targeted next-generation sequencing, and candidate mutations were verified by Sanger sequencing. Pathogenicity analysis and conservative analysis were performed on the mutant gene to evaluate its pathogenicity, and SWISS-MODEL was used to construct the three-dimensional structure of the FOXC1 region to predict the effect of mutations on the structure of the FOXC1 protein. Optimistically, a novel heterozygous, deleterious variant of the FOXC1 gene, c.246C>A(p.S82R), was successfully identified in this Axenfeld-Rieger syndrome pedigree, which cosegregated with the clinical phenotype. This variant resulted in the mutation of amino acid 82 from serine to arginine. The evolution of serine(s) in different species was highly conserved. This mutation led to a change in the three-dimensional structure of the protein, which was pathogenic. The discovery of these new mutation sites further expands its mutation spectrum. Our understanding of Axenfeld-Rieger syndrome will facilitate the development of methods for the diagnosis, prevention and genetic counseling of this disease.