Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway
Abstract Background Gut microbiota has emerged as a promising therapeutic target for neurodegenerative disorders through regulation of neuroinflammatory responses, while its role in optic nerve degeneration remains incompletely characterized. This study elucidates the neuroprotective role of gut mic...
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BMC
2025-07-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03505-4 |
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| author | Ning Wang Chengyang Sun Yijie Yang Dandan Zhang Lulu Huang Chenrui Xu Minghan Wang Mengmeng Xu Tongtong Yan Yue Wu Li Xu Yahan Ju Hao Sun Wenyi Guo |
| author_facet | Ning Wang Chengyang Sun Yijie Yang Dandan Zhang Lulu Huang Chenrui Xu Minghan Wang Mengmeng Xu Tongtong Yan Yue Wu Li Xu Yahan Ju Hao Sun Wenyi Guo |
| author_sort | Ning Wang |
| collection | DOAJ |
| description | Abstract Background Gut microbiota has emerged as a promising therapeutic target for neurodegenerative disorders through regulation of neuroinflammatory responses, while its role in optic nerve degeneration remains incompletely characterized. This study elucidates the neuroprotective role of gut microbiota derived tryptophan metabolites in glaucoma through gut-eye communication and inhibition of microglia-mediated neuroinflammation. Methods Gut microbiota profiling (16 S rRNA sequencing) and serum indoleacetic acid (IAA) quantification were performed in glaucoma patients versus controls. Microbiota–metabolite relationships were further validated through fecal microbiota transplantation (FMT). The neuroprotective and anti-neuroinflammatory effect of Bacteroides fragilis (B. fragilis) and IAA was assessed in both microbead-induced ocular hypertension mice model and in vitro BV-2 microglial cell inflammation model via immunofluorescence, qPCR, Western blot and mice behavioral assays. To explore the underlying mechanisms, retinal transcriptomics and microglia-neuron co-cultures were also employed. Result Glaucoma patients exhibited gut dysbiosis characterized by depleted tryptophan-metabolizing bacteria (B. fragilis, Bacteroides thetaiotaomicron, Anaerostipes hadrus) and reduced serum IAA levels. Mice receiving FMT from glaucoma patients exhibited lower systemic IAA levels. In in vivo and in vitro models, B. fragilis or IAA restored AhR activation, suppressed inflammation by inhibiting microglial activation and the release of pro-inflammatory mediators throughout the retina, reduced retinal ganglion cells (RGCs) loss and preserved visual function. Mechanistically, IAA attenuated RAGE/NF-κB pathway activation via AhR-dependent signaling, conferring neuroprotection. Conclusion Our study proposes a novel AhR-mediated gut microbiota-eye axis in glaucoma pathogenesis and demonstrates that IAA serves as an effective neuroprotective strategy with clinical potential for managing RGCs neurodegeneration. |
| format | Article |
| id | doaj-art-4bc4d479f47247e3b0e6ff6487a25cd2 |
| institution | DOAJ |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-4bc4d479f47247e3b0e6ff6487a25cd22025-08-20T03:05:11ZengBMCJournal of Neuroinflammation1742-20942025-07-0122112210.1186/s12974-025-03505-4Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathwayNing Wang0Chengyang Sun1Yijie Yang2Dandan Zhang3Lulu Huang4Chenrui Xu5Minghan Wang6Mengmeng Xu7Tongtong Yan8Yue Wu9Li Xu10Yahan Ju11Hao Sun12Wenyi Guo13Department of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineDepartment of Ophthalmology, Shanghai 9th People’s Hospital, Shanghai Jiaotong University School of MedicineAbstract Background Gut microbiota has emerged as a promising therapeutic target for neurodegenerative disorders through regulation of neuroinflammatory responses, while its role in optic nerve degeneration remains incompletely characterized. This study elucidates the neuroprotective role of gut microbiota derived tryptophan metabolites in glaucoma through gut-eye communication and inhibition of microglia-mediated neuroinflammation. Methods Gut microbiota profiling (16 S rRNA sequencing) and serum indoleacetic acid (IAA) quantification were performed in glaucoma patients versus controls. Microbiota–metabolite relationships were further validated through fecal microbiota transplantation (FMT). The neuroprotective and anti-neuroinflammatory effect of Bacteroides fragilis (B. fragilis) and IAA was assessed in both microbead-induced ocular hypertension mice model and in vitro BV-2 microglial cell inflammation model via immunofluorescence, qPCR, Western blot and mice behavioral assays. To explore the underlying mechanisms, retinal transcriptomics and microglia-neuron co-cultures were also employed. Result Glaucoma patients exhibited gut dysbiosis characterized by depleted tryptophan-metabolizing bacteria (B. fragilis, Bacteroides thetaiotaomicron, Anaerostipes hadrus) and reduced serum IAA levels. Mice receiving FMT from glaucoma patients exhibited lower systemic IAA levels. In in vivo and in vitro models, B. fragilis or IAA restored AhR activation, suppressed inflammation by inhibiting microglial activation and the release of pro-inflammatory mediators throughout the retina, reduced retinal ganglion cells (RGCs) loss and preserved visual function. Mechanistically, IAA attenuated RAGE/NF-κB pathway activation via AhR-dependent signaling, conferring neuroprotection. Conclusion Our study proposes a novel AhR-mediated gut microbiota-eye axis in glaucoma pathogenesis and demonstrates that IAA serves as an effective neuroprotective strategy with clinical potential for managing RGCs neurodegeneration.https://doi.org/10.1186/s12974-025-03505-4Gut microbiota-eye axisGlaucomaNeuroinflammationTryptophan metabolitesAhRMicroglia |
| spellingShingle | Ning Wang Chengyang Sun Yijie Yang Dandan Zhang Lulu Huang Chenrui Xu Minghan Wang Mengmeng Xu Tongtong Yan Yue Wu Li Xu Yahan Ju Hao Sun Wenyi Guo Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway Journal of Neuroinflammation Gut microbiota-eye axis Glaucoma Neuroinflammation Tryptophan metabolites AhR Microglia |
| title | Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway |
| title_full | Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway |
| title_fullStr | Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway |
| title_full_unstemmed | Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway |
| title_short | Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway |
| title_sort | gut microbiota derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr rage pathway |
| topic | Gut microbiota-eye axis Glaucoma Neuroinflammation Tryptophan metabolites AhR Microglia |
| url | https://doi.org/10.1186/s12974-025-03505-4 |
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