β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool
Abstract Irinotecan (CPT11)‐induced diarrhea affects 80–90% of cancer patients due to β‐glucuronidase (GUS) converting 7‐ethyl‐10‐hydroxycamptothecin glucuronide (SN38G) to 7‐ethyl‐10‐hydroxycamptothecin (SN38). It remains unclear whether SN38 impacts the homeostasis between gut microbiota and mucos...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411052 |
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| author | Bei Yue Ruiyang Gao Ling Zhao Donghui Liu Cheng Lv Ziyi Wang Fangbin Ai Beibei Zhang Zhilun Yu Xiaolong Geng Hao Wang Kang Wang Kaixian Chen Chenghai Liu Zhengtao Wang Wei Dou |
| author_facet | Bei Yue Ruiyang Gao Ling Zhao Donghui Liu Cheng Lv Ziyi Wang Fangbin Ai Beibei Zhang Zhilun Yu Xiaolong Geng Hao Wang Kang Wang Kaixian Chen Chenghai Liu Zhengtao Wang Wei Dou |
| author_sort | Bei Yue |
| collection | DOAJ |
| description | Abstract Irinotecan (CPT11)‐induced diarrhea affects 80–90% of cancer patients due to β‐glucuronidase (GUS) converting 7‐ethyl‐10‐hydroxycamptothecin glucuronide (SN38G) to 7‐ethyl‐10‐hydroxycamptothecin (SN38). It remains unclear whether SN38 impacts the homeostasis between gut microbiota and mucosal stem cell niche. This study explores the crosstalk between gut microbiota and intestinal stem cells (ISCs) in intestinal mucositis triggered by CPT11 chemotherapy. CPT11‐treated mice exhibited significant colon shortening, inflammatory infiltration, intestinal barrier dysfunction, and ISC impairment, which correlated with gut dysbiosis, enrichment of GUS‐expressing bacteria, and intraluminal SN38 accumulation. In contrast, antidiarrheal (Xianglian pill) treatment alleviated SN38‐induced enterotoxicity and reduced GUS‐expressing bacterial populations. Microbiome profiling of clinical patients and mucositis mice revealed a strong correlation between CPT11/SN38 enterotoxicity and GUS‐expressing bacteria, particularly Lactobacillus reuteri. PLS‐PM modeling further linked L. reuteri to impaired epithelial regeneration, which is validated using a 3D intestinal organoid model. L. reuteri hindered ISC differentiation into secretory lineages within the organoids. Furthermore, L. reuteri colonization in mice exacerbated mucositis and disrupted epithelial differentiation, while its elimination ameliorated colitis symptoms and preserved crypt cell stemness. These findings suggest that selectively targeting GUS‐expressing bacteria, particularly L. reuteri, to protect the regenerative epithelial stem/progenitor pool may serve as an effective strategy for mitigating CPT11‐induced enterotoxicity. |
| format | Article |
| id | doaj-art-dcd61ca4d68c45b8923f2fac9ed0c3ed |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-dcd61ca4d68c45b8923f2fac9ed0c3ed2025-08-20T04:01:01ZengWileyAdvanced Science2198-38442025-07-011226n/an/a10.1002/advs.202411052β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor PoolBei Yue0Ruiyang Gao1Ling Zhao2Donghui Liu3Cheng Lv4Ziyi Wang5Fangbin Ai6Beibei Zhang7Zhilun Yu8Xiaolong Geng9Hao Wang10Kang Wang11Kaixian Chen12Chenghai Liu13Zhengtao Wang14Wei Dou15The MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaSchool of Integrative Medicine Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaCentre for Chinese Herbal Medicine Drug Development Limited Hong Kong Baptist University Hong Kong SAR ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaDepartment of Hepatology Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaThe MOE key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM key Laboratory for New Resources and Quality Evaluation of Chinese Medicines Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaAbstract Irinotecan (CPT11)‐induced diarrhea affects 80–90% of cancer patients due to β‐glucuronidase (GUS) converting 7‐ethyl‐10‐hydroxycamptothecin glucuronide (SN38G) to 7‐ethyl‐10‐hydroxycamptothecin (SN38). It remains unclear whether SN38 impacts the homeostasis between gut microbiota and mucosal stem cell niche. This study explores the crosstalk between gut microbiota and intestinal stem cells (ISCs) in intestinal mucositis triggered by CPT11 chemotherapy. CPT11‐treated mice exhibited significant colon shortening, inflammatory infiltration, intestinal barrier dysfunction, and ISC impairment, which correlated with gut dysbiosis, enrichment of GUS‐expressing bacteria, and intraluminal SN38 accumulation. In contrast, antidiarrheal (Xianglian pill) treatment alleviated SN38‐induced enterotoxicity and reduced GUS‐expressing bacterial populations. Microbiome profiling of clinical patients and mucositis mice revealed a strong correlation between CPT11/SN38 enterotoxicity and GUS‐expressing bacteria, particularly Lactobacillus reuteri. PLS‐PM modeling further linked L. reuteri to impaired epithelial regeneration, which is validated using a 3D intestinal organoid model. L. reuteri hindered ISC differentiation into secretory lineages within the organoids. Furthermore, L. reuteri colonization in mice exacerbated mucositis and disrupted epithelial differentiation, while its elimination ameliorated colitis symptoms and preserved crypt cell stemness. These findings suggest that selectively targeting GUS‐expressing bacteria, particularly L. reuteri, to protect the regenerative epithelial stem/progenitor pool may serve as an effective strategy for mitigating CPT11‐induced enterotoxicity.https://doi.org/10.1002/advs.202411052epithelial regenerationirinotecan‐induced intestinal toxicityGUS‐expressing bacterialactobacillus reuteriXianglian pill |
| spellingShingle | Bei Yue Ruiyang Gao Ling Zhao Donghui Liu Cheng Lv Ziyi Wang Fangbin Ai Beibei Zhang Zhilun Yu Xiaolong Geng Hao Wang Kang Wang Kaixian Chen Chenghai Liu Zhengtao Wang Wei Dou β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool Advanced Science epithelial regeneration irinotecan‐induced intestinal toxicity GUS‐expressing bacteria lactobacillus reuteri Xianglian pill |
| title | β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool |
| title_full | β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool |
| title_fullStr | β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool |
| title_full_unstemmed | β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool |
| title_short | β‐Glucuronidase‐Expressing Lactobacillus reuteri Triggers Irinotecan Enterotoxicity Through Depleting the Regenerative Epithelial Stem/Progenitor Pool |
| title_sort | β glucuronidase expressing lactobacillus reuteri triggers irinotecan enterotoxicity through depleting the regenerative epithelial stem progenitor pool |
| topic | epithelial regeneration irinotecan‐induced intestinal toxicity GUS‐expressing bacteria lactobacillus reuteri Xianglian pill |
| url | https://doi.org/10.1002/advs.202411052 |
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