Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer
FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectivenes...
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Elsevier
2025-03-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000611 |
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| author | Qian Fang Xiaoying Hou Limei Fan Yufei Deng Xiaoxuan Li Hongyun Zhang Haiping Wang Zhengqi Fu Binlian Sun Xiji Shu Hongzhi Du Yuchen Liu |
| author_facet | Qian Fang Xiaoying Hou Limei Fan Yufei Deng Xiaoxuan Li Hongyun Zhang Haiping Wang Zhengqi Fu Binlian Sun Xiji Shu Hongzhi Du Yuchen Liu |
| author_sort | Qian Fang |
| collection | DOAJ |
| description | FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX in vitro, however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX’s therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX’s anti-colon cancer effects in vivo. Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment. |
| format | Article |
| id | doaj-art-29a92dd8a7c64198bd12d219442e1b33 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-29a92dd8a7c64198bd12d219442e1b332025-02-07T04:46:53ZengElsevierPharmacological Research1096-11862025-03-01213107636Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancerQian Fang0Xiaoying Hou1Limei Fan2Yufei Deng3Xiaoxuan Li4Hongyun Zhang5Haiping Wang6Zhengqi Fu7Binlian Sun8Xiji Shu9Hongzhi Du10Yuchen Liu11Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaCancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, ChinaHubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, ChinaCancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China; Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan 430065, China; Corresponding author at: Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan 430065, China.Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China; Corresponding author at: Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China.FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX in vitro, however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX’s therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX’s anti-colon cancer effects in vivo. Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment.http://www.sciencedirect.com/science/article/pii/S1043661825000611Colon cancerFOLFOXDeoxycholic AcidUgt1a6bEnterohepatic circulation |
| spellingShingle | Qian Fang Xiaoying Hou Limei Fan Yufei Deng Xiaoxuan Li Hongyun Zhang Haiping Wang Zhengqi Fu Binlian Sun Xiji Shu Hongzhi Du Yuchen Liu Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer Pharmacological Research Colon cancer FOLFOX Deoxycholic Acid Ugt1a6b Enterohepatic circulation |
| title | Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer |
| title_full | Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer |
| title_fullStr | Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer |
| title_full_unstemmed | Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer |
| title_short | Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer |
| title_sort | gut microbiota derived dca enhances folfox efficacy via ugt1a6b mediated enterohepatic circulation in colon cancer |
| topic | Colon cancer FOLFOX Deoxycholic Acid Ugt1a6b Enterohepatic circulation |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000611 |
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