Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export
Abstract Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron‐mediated, pathogenic anemia‐inflammation crosstalk is regulated in the gut rem...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202306571 |
| _version_ | 1797242655698059264 |
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| author | Peng Xiao Xuechun Cai Zhou Zhang Ke Guo Yuehai Ke Ziwei Hu Zhangfa Song Yuening Zhao Lingya Yao Manlu Shen Jingyun Li Youling Huang Lingna Ye Lingjie Huang Yu Zhang Rongbei Liu Mengque Xu Xutao Xu Yuan Zhao Qian Cao |
| author_facet | Peng Xiao Xuechun Cai Zhou Zhang Ke Guo Yuehai Ke Ziwei Hu Zhangfa Song Yuening Zhao Lingya Yao Manlu Shen Jingyun Li Youling Huang Lingna Ye Lingjie Huang Yu Zhang Rongbei Liu Mengque Xu Xutao Xu Yuan Zhao Qian Cao |
| author_sort | Peng Xiao |
| collection | DOAJ |
| description | Abstract Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron‐mediated, pathogenic anemia‐inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short‐chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis‐induced anemia but also reduces TNF‐α production in macrophages. Consistently, macrophage‐conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti‐TNF‐α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation. |
| first_indexed | 2024-04-24T18:42:41Z |
| format | Article |
| id | doaj.art-003b80915b1d47c790f4a3b20aedd369 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T18:42:41Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-003b80915b1d47c790f4a3b20aedd3692024-03-27T09:39:53ZengWileyAdvanced Science2198-38442024-03-011112n/an/a10.1002/advs.202306571Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron ExportPeng Xiao0Xuechun Cai1Zhou Zhang2Ke Guo3Yuehai Ke4Ziwei Hu5Zhangfa Song6Yuening Zhao7Lingya Yao8Manlu Shen9Jingyun Li10Youling Huang11Lingna Ye12Lingjie Huang13Yu Zhang14Rongbei Liu15Mengque Xu16Xutao Xu17Yuan Zhao18Qian Cao19Department of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Pathology and Pathophysiology Zhejiang University School of Medicine Hangzhou Zhejiang 310058 ChinaDepartment of Pathology and Pathophysiology Zhejiang University School of Medicine Hangzhou Zhejiang 310058 ChinaDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Colorectal Surgery, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Gastroenterology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaAbstract Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron‐mediated, pathogenic anemia‐inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short‐chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis‐induced anemia but also reduces TNF‐α production in macrophages. Consistently, macrophage‐conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti‐TNF‐α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.https://doi.org/10.1002/advs.202306571anemiabutyrateferroportininflammatory bowel diseasemacrophages |
| spellingShingle | Peng Xiao Xuechun Cai Zhou Zhang Ke Guo Yuehai Ke Ziwei Hu Zhangfa Song Yuening Zhao Lingya Yao Manlu Shen Jingyun Li Youling Huang Lingna Ye Lingjie Huang Yu Zhang Rongbei Liu Mengque Xu Xutao Xu Yuan Zhao Qian Cao Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export Advanced Science anemia butyrate ferroportin inflammatory bowel disease macrophages |
| title | Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export |
| title_full | Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export |
| title_fullStr | Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export |
| title_full_unstemmed | Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export |
| title_short | Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export |
| title_sort | butyrate prevents the pathogenic anemia inflammation circuit by facilitating macrophage iron export |
| topic | anemia butyrate ferroportin inflammatory bowel disease macrophages |
| url | https://doi.org/10.1002/advs.202306571 |
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