Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway
Introduction: Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome. Objectives: To assess if the endogenous metabolic pro...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
|
| Series: | Journal of Advanced Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224003035 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850261251421110272 |
|---|---|
| author | Zhipeng Wang Zhijun Liu Lili Cui Jianguo Sun Chen Bu Mao Tang Mingming Li Shouhong Gao Wansheng Chen Xia Tao |
| author_facet | Zhipeng Wang Zhijun Liu Lili Cui Jianguo Sun Chen Bu Mao Tang Mingming Li Shouhong Gao Wansheng Chen Xia Tao |
| author_sort | Zhipeng Wang |
| collection | DOAJ |
| description | Introduction: Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome. Objectives: To assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms. Methods: Untargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs. Results: The baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway. Conclusions: The disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway. |
| format | Article |
| id | doaj-art-dcc193c337bf4a7dac01d759c3e7f592 |
| institution | OA Journals |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-dcc193c337bf4a7dac01d759c3e7f5922025-08-20T01:55:27ZengElsevierJournal of Advanced Research2090-12322025-06-017259160410.1016/j.jare.2024.07.019Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathwayZhipeng Wang0Zhijun Liu1Lili Cui2Jianguo Sun3Chen Bu4Mao Tang5Mingming Li6Shouhong Gao7Wansheng Chen8Xia Tao9Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China; Research and Development Center of Chinese Medicine Resources and Biotechnology, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China; College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR ChinaDepartment of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China; College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, PR China; Corresponding authors at: Department of Pharmacy, Second Affiliated Hospital of Naval Medical University. No. 415, Fengyang Road, Shanghai 200003, PR China.Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China; Research and Development Center of Chinese Medicine Resources and Biotechnology, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Corresponding authors at: Department of Pharmacy, Second Affiliated Hospital of Naval Medical University. No. 415, Fengyang Road, Shanghai 200003, PR China.Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China; College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, PR China; Corresponding authors at: Department of Pharmacy, Second Affiliated Hospital of Naval Medical University. No. 415, Fengyang Road, Shanghai 200003, PR China.Introduction: Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome. Objectives: To assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms. Methods: Untargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs. Results: The baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway. Conclusions: The disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.http://www.sciencedirect.com/science/article/pii/S2090123224003035CapecitabineDiarrheaMetabolomicsBile acidsWnt/β-catenin pathway |
| spellingShingle | Zhipeng Wang Zhijun Liu Lili Cui Jianguo Sun Chen Bu Mao Tang Mingming Li Shouhong Gao Wansheng Chen Xia Tao Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway Journal of Advanced Research Capecitabine Diarrhea Metabolomics Bile acids Wnt/β-catenin pathway |
| title | Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway |
| title_full | Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway |
| title_fullStr | Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway |
| title_full_unstemmed | Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway |
| title_short | Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway |
| title_sort | disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the wnt β catenin pathway |
| topic | Capecitabine Diarrhea Metabolomics Bile acids Wnt/β-catenin pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003035 |
| work_keys_str_mv | AT zhipengwang disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT zhijunliu disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT lilicui disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT jianguosun disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT chenbu disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT maotang disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT mingmingli disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT shouhonggao disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT wanshengchen disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway AT xiatao disturbanceofbileacidsprofileaggravatesthediarrheainducedbycapecitabinethroughinhibitingthewntbcateninpathway |