Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea
Abstract Background Disorder in bile acid (BA) metabolism is known to be an important factor contributing to diarrhea. However, the pathogenesis of BA disorder-induced diarrhea remains unclear. Methods The colonic BA pool and microbiota between health piglets and BA disorder-induced diarrheal piglet...
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BMC
2025-02-01
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| Online Access: | https://doi.org/10.1186/s40168-024-02011-8 |
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| author | Zishen Lin Yue Feng Jinping Wang Zhaoyue Men Xi Ma |
| author_facet | Zishen Lin Yue Feng Jinping Wang Zhaoyue Men Xi Ma |
| author_sort | Zishen Lin |
| collection | DOAJ |
| description | Abstract Background Disorder in bile acid (BA) metabolism is known to be an important factor contributing to diarrhea. However, the pathogenesis of BA disorder-induced diarrhea remains unclear. Methods The colonic BA pool and microbiota between health piglets and BA disorder-induced diarrheal piglets were compared. Fecal microbiota transplantation and various cell experiments further indicated that chenodeoxycholic acid (CDCA) metabolic disorder produced CDCA-3β-glucuronide, which is the main cause of BA disorder diarrhea. Non-targeted metabolomics uncovered the inhibition of the BA glucuronidation by Lactobacillus reuteri (L. reuteri) is through deriving indole-3-carbinol (I3C). In vitro, important gene involved in the reduction of BA disorder induced-diarrhea were screened by RNA transcriptomics sequencing, and activation pathway of FXR-SIRT1-LKB1 to alleviate BA disorder diarrhea and P53-mediated apoptosis were proposed in vitro by multifarious siRNA interference, CO-IP, immunofluorescence, and so on, which mechanism was also verified in a variety of mouse models. Results Here, we reveal for the first time that core microbiota derived I3C represses gut epithelium glucuronidation, particularly 3β-glucuronic CDCA production, which reaction is mediated by host UDP glucuronosyltransferase family 1 member A4 (UGT1A4) and necessary of BA disorder induced diarrhea. Mechanistically, L. reuteri derived I3C activates aryl hydrocarbon receptor to decrease UGT1A4 transcription and CDCA-3β-glucuronide content, thereby upregulating FXR-SIRT1-LKB1 signal. LKB1 binds with P53 based on protein interaction, ultimately resists to apoptosis and diarrhea. Moreover, I3C assists CDCA to attain the ameliorative effects of FXR activation in BA disorder diarrhea, through reversion of abnormal metabolism pathway, improving the outcomes of CDCA supplement. Conclusion These findings uncover the crucial interplay between gut epithelial cells and microbes, highlighting UGT1A4-mediated conversion of CDCA-3β-glucuronide as a key target for ameliorating BA disorder-induced diarrhea. Video Abstract |
| format | Article |
| id | doaj-art-67a71c9657d84173825679e594e8eff4 |
| institution | Kabale University |
| issn | 2049-2618 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj-art-67a71c9657d84173825679e594e8eff42025-02-09T12:46:42ZengBMCMicrobiome2049-26182025-02-0113112610.1186/s40168-024-02011-8Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrheaZishen Lin0Yue Feng1Jinping Wang2Zhaoyue Men3Xi Ma4State Key Laboratory of Animal Nutrition and Feeding, Department of Animal Nutrition and Feed Science, China Agricultural UniversityState Key Laboratory of Animal Nutrition and Feeding, Department of Animal Nutrition and Feed Science, China Agricultural UniversityState Key Laboratory of Animal Nutrition and Feeding, Department of Animal Nutrition and Feed Science, China Agricultural UniversityState Key Laboratory of Animal Nutrition and Feeding, Department of Animal Nutrition and Feed Science, China Agricultural UniversityState Key Laboratory of Animal Nutrition and Feeding, Department of Animal Nutrition and Feed Science, China Agricultural UniversityAbstract Background Disorder in bile acid (BA) metabolism is known to be an important factor contributing to diarrhea. However, the pathogenesis of BA disorder-induced diarrhea remains unclear. Methods The colonic BA pool and microbiota between health piglets and BA disorder-induced diarrheal piglets were compared. Fecal microbiota transplantation and various cell experiments further indicated that chenodeoxycholic acid (CDCA) metabolic disorder produced CDCA-3β-glucuronide, which is the main cause of BA disorder diarrhea. Non-targeted metabolomics uncovered the inhibition of the BA glucuronidation by Lactobacillus reuteri (L. reuteri) is through deriving indole-3-carbinol (I3C). In vitro, important gene involved in the reduction of BA disorder induced-diarrhea were screened by RNA transcriptomics sequencing, and activation pathway of FXR-SIRT1-LKB1 to alleviate BA disorder diarrhea and P53-mediated apoptosis were proposed in vitro by multifarious siRNA interference, CO-IP, immunofluorescence, and so on, which mechanism was also verified in a variety of mouse models. Results Here, we reveal for the first time that core microbiota derived I3C represses gut epithelium glucuronidation, particularly 3β-glucuronic CDCA production, which reaction is mediated by host UDP glucuronosyltransferase family 1 member A4 (UGT1A4) and necessary of BA disorder induced diarrhea. Mechanistically, L. reuteri derived I3C activates aryl hydrocarbon receptor to decrease UGT1A4 transcription and CDCA-3β-glucuronide content, thereby upregulating FXR-SIRT1-LKB1 signal. LKB1 binds with P53 based on protein interaction, ultimately resists to apoptosis and diarrhea. Moreover, I3C assists CDCA to attain the ameliorative effects of FXR activation in BA disorder diarrhea, through reversion of abnormal metabolism pathway, improving the outcomes of CDCA supplement. Conclusion These findings uncover the crucial interplay between gut epithelial cells and microbes, highlighting UGT1A4-mediated conversion of CDCA-3β-glucuronide as a key target for ameliorating BA disorder-induced diarrhea. Video Abstracthttps://doi.org/10.1186/s40168-024-02011-8MicrobiotaBile acid diarrheaChenodeoxycholic acidGlucuronidationLiver kinase B1 |
| spellingShingle | Zishen Lin Yue Feng Jinping Wang Zhaoyue Men Xi Ma Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea Microbiome Microbiota Bile acid diarrhea Chenodeoxycholic acid Glucuronidation Liver kinase B1 |
| title | Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea |
| title_full | Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea |
| title_fullStr | Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea |
| title_full_unstemmed | Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea |
| title_short | Microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea |
| title_sort | microbiota governs host chenodeoxycholic acid glucuronidation to ameliorate bile acid disorder induced diarrhea |
| topic | Microbiota Bile acid diarrhea Chenodeoxycholic acid Glucuronidation Liver kinase B1 |
| url | https://doi.org/10.1186/s40168-024-02011-8 |
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