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Despite its low incidence, ON can lead to severe, irreversible visual impairment. Emerging evidence suggests the gut microbiota (GM) may influence ON through complex immune and metabolic pathways, yet the mechanisms remain underexplored. This study employed a multi-omics Mendelian randomization (MR) approach to assess the causal relationships between GM taxa and ON. We analyzed data from extensive genetic and metabolic profiling, examining the causal effect between 473 GM taxa, 731 immune cells\/traits, 1400 metabolites, vitamin B6, and ON. Our methodology involved two-sample MR analysis to establish causality and mediation analysis to explore the mechanisms between GM and ON and potential therapeutic strategies. We identified 27 GM taxa with a direct causal relationship to ON risk. Further analysis highlighted three GM taxa with particularly strong associations. Mediation analysis revealed specific metabolic and immune pathways through which these taxa exert their effects, including notable interactions with vitamin B6 metabolism, which appeared to mediate some of these relationships. We found that vitamin B6 could be a potential therapeutic method by acting on GM in ON. This study advances our understanding of the complex etiology of ON and highlights the potential of GM as a target for therapeutic strategies. The significant role of vitamin B6 suggests new avenues for prevention and treatment, emphasizing the need for further research into diet-based interventions.<\/jats:p>","DOI":"10.1007\/s12035-025-04923-4","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T23:39:46Z","timestamp":1744328386000},"page":"10499-10510","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multi-omics Mendelian Randomization Reveals Immunometabolic Signatures of the Gut Microbiota in Optic Neuritis and the Potential Therapeutic Role of Vitamin B6"],"prefix":"10.1007","volume":"62","author":[{"given":"Jingzhi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehao","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"issue":"1","key":"4923_CR1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S1474-4422(22)00187-9","volume":"22","author":"JL Bennett","year":"2023","unstructured":"Bennett JL, Costello F, Chen JJ et al (2023) Optic neuritis and autoimmune optic neuropathies: advances in diagnosis and treatment. 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