Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways
Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared wi...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/6/3424 |
| _version_ | 1797240693814460416 |
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| author | Qiuxia Lin Binbin Zhang Manyun Dai Yan Cheng Fei Li |
| author_facet | Qiuxia Lin Binbin Zhang Manyun Dai Yan Cheng Fei Li |
| author_sort | Qiuxia Lin |
| collection | DOAJ |
| description | Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-β-muricholic acid (T-β-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression. |
| first_indexed | 2024-04-24T18:11:30Z |
| format | Article |
| id | doaj.art-8c236d7650b948c7ba258ef5b8d5a3c2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:30Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8c236d7650b948c7ba258ef5b8d5a3c22024-03-27T13:46:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256342410.3390/ijms25063424Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling PathwaysQiuxia Lin0Binbin Zhang1Manyun Dai2Yan Cheng3Fei Li4Laboratory of Hepatointestinal Diseases and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaLaboratory of Hepatointestinal Diseases and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Gastroenterology & Hepatology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, ChinaLaboratory of Hepatointestinal Diseases and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaLaboratory of Hepatointestinal Diseases and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaAspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-β-muricholic acid (T-β-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression.https://www.mdpi.com/1422-0067/25/6/3424aspirinintestinal injuryFXRendothelin 1bile acid |
| spellingShingle | Qiuxia Lin Binbin Zhang Manyun Dai Yan Cheng Fei Li Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways International Journal of Molecular Sciences aspirin intestinal injury FXR endothelin 1 bile acid |
| title | Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways |
| title_full | Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways |
| title_fullStr | Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways |
| title_full_unstemmed | Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways |
| title_short | Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways |
| title_sort | aspirin caused intestinal damage through fxr and et 1 signaling pathways |
| topic | aspirin intestinal injury FXR endothelin 1 bile acid |
| url | https://www.mdpi.com/1422-0067/25/6/3424 |
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