Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion
Abstract Background Intestinal ischemia/reperfusion injury (IIRI) is a life-threatening condition caused by multiple organ and system failures induced by dysbiosis and gut leakage. Metformin has demonstrated efficacy in protecting against IIRI, although the precise role of the gut microbiota in the...
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2025-05-01
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| Online Access: | https://doi.org/10.1186/s12916-025-04119-6 |
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| author | Fangyan Wang Xinyu Wang Chaoyi Wang Wangxin Yan Junpeng Xu Zhengyang Song Mingli Su Jingjing Zeng Qiannian Han Gaoyi Ruan Eryao Zhang Wantie Wang |
| author_facet | Fangyan Wang Xinyu Wang Chaoyi Wang Wangxin Yan Junpeng Xu Zhengyang Song Mingli Su Jingjing Zeng Qiannian Han Gaoyi Ruan Eryao Zhang Wantie Wang |
| author_sort | Fangyan Wang |
| collection | DOAJ |
| description | Abstract Background Intestinal ischemia/reperfusion injury (IIRI) is a life-threatening condition caused by multiple organ and system failures induced by dysbiosis and gut leakage. Metformin has demonstrated efficacy in protecting against IIRI, although the precise role of the gut microbiota in the underlying mechanism is still ambiguous. Methods This study examined intestinal barrier function and ferroptosis-related parameters in mice with IIRI following treatment with metformin. Additionally, dirty cages and antibiotics were utilized to investigate the impact of the microbiota on the effects of metformin. The analysis included an assessment of the microbial composition of metformin-treated mice and the biosynthetic activity of specific metabolites. Results Metformin effectively reduced gut leakage induced by IIRI, as evidenced by decreased intestinal permeability and increased Occludin, ZO-1, Claudin-1, and MUC-1 expression. A decrease in the expression of the pro-ferroptotic proteins ACSL4, TFR1, and VDAC2/3 and a decrease in dihydroethidium (DHE) fluorescence, iron, malondialdehyde (MDA), and myeloperoxidase (MPO) were further observed in metformin-treated mice. In contrast, the damage to the GPX4/GSH system caused by IIRI was reversed after metformin treatment, as shown by increases in GPX4, SLC7A11, and GSH. The antiferroptotic effects of metformin were phenocopied by its fecal microbiota but were eliminated by antibiotic intake. 16S rRNA analysis revealed that the metformin-modulated gut microbiota was characterized by increased Lactobacillus murinus, which expressed higher levels of GshF that contributed to the mitigation of IIRI. Conclusions Murine gut microbiota mediated the anti-ferroptotic effect of metformin on IIRI, and the resulting increase in microbial GSH synthesis could serve as a critical pathway for anti-IIRI. |
| format | Article |
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| institution | OA Journals |
| issn | 1741-7015 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | BMC Medicine |
| spelling | doaj-art-e5ed601e1d1f48e58ff0dd49b91732452025-08-20T01:51:32ZengBMCBMC Medicine1741-70152025-05-0123111410.1186/s12916-025-04119-6Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusionFangyan Wang0Xinyu Wang1Chaoyi Wang2Wangxin Yan3Junpeng Xu4Zhengyang Song5Mingli Su6Jingjing Zeng7Qiannian Han8Gaoyi Ruan9Eryao Zhang10Wantie Wang11Institute of Microbiota and Host Inflammation-Related Diseases, School of Basic Medical Science, Wenzhou Medical UniversityDepartment of Pathology, First Affiliated Hospital of Baotou Medical College of Inner, Mongolia University of Science & TechnologyDepartment of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Colorectal and Anal Surgery, Wenzhou People’s HospitalInstitute of Microbiota and Host Inflammation-Related Diseases, School of Basic Medical Science, Wenzhou Medical UniversityDepartment of Clinical Laboratory, The First Affiliated Hospital of Henan University of TechnologyDepartment of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityInstitute of Microbiota and Host Inflammation-Related Diseases, School of Basic Medical Science, Wenzhou Medical UniversityInstitute of Microbiota and Host Inflammation-Related Diseases, School of Basic Medical Science, Wenzhou Medical UniversityDepartment of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityInstitute of Microbiota and Host Inflammation-Related Diseases, School of Basic Medical Science, Wenzhou Medical UniversityAbstract Background Intestinal ischemia/reperfusion injury (IIRI) is a life-threatening condition caused by multiple organ and system failures induced by dysbiosis and gut leakage. Metformin has demonstrated efficacy in protecting against IIRI, although the precise role of the gut microbiota in the underlying mechanism is still ambiguous. Methods This study examined intestinal barrier function and ferroptosis-related parameters in mice with IIRI following treatment with metformin. Additionally, dirty cages and antibiotics were utilized to investigate the impact of the microbiota on the effects of metformin. The analysis included an assessment of the microbial composition of metformin-treated mice and the biosynthetic activity of specific metabolites. Results Metformin effectively reduced gut leakage induced by IIRI, as evidenced by decreased intestinal permeability and increased Occludin, ZO-1, Claudin-1, and MUC-1 expression. A decrease in the expression of the pro-ferroptotic proteins ACSL4, TFR1, and VDAC2/3 and a decrease in dihydroethidium (DHE) fluorescence, iron, malondialdehyde (MDA), and myeloperoxidase (MPO) were further observed in metformin-treated mice. In contrast, the damage to the GPX4/GSH system caused by IIRI was reversed after metformin treatment, as shown by increases in GPX4, SLC7A11, and GSH. The antiferroptotic effects of metformin were phenocopied by its fecal microbiota but were eliminated by antibiotic intake. 16S rRNA analysis revealed that the metformin-modulated gut microbiota was characterized by increased Lactobacillus murinus, which expressed higher levels of GshF that contributed to the mitigation of IIRI. Conclusions Murine gut microbiota mediated the anti-ferroptotic effect of metformin on IIRI, and the resulting increase in microbial GSH synthesis could serve as a critical pathway for anti-IIRI.https://doi.org/10.1186/s12916-025-04119-6MetforminIntestinal ischemia/reperfusion injuryFerroptosisGut microbiotaGlutathione |
| spellingShingle | Fangyan Wang Xinyu Wang Chaoyi Wang Wangxin Yan Junpeng Xu Zhengyang Song Mingli Su Jingjing Zeng Qiannian Han Gaoyi Ruan Eryao Zhang Wantie Wang Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion BMC Medicine Metformin Intestinal ischemia/reperfusion injury Ferroptosis Gut microbiota Glutathione |
| title | Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion |
| title_full | Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion |
| title_fullStr | Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion |
| title_full_unstemmed | Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion |
| title_short | Gut microbiota-derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia/reperfusion |
| title_sort | gut microbiota derived glutathione from metformin treatment alleviates intestinal ferroptosis induced by ischemia reperfusion |
| topic | Metformin Intestinal ischemia/reperfusion injury Ferroptosis Gut microbiota Glutathione |
| url | https://doi.org/10.1186/s12916-025-04119-6 |
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