Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU
| Autor: | Stephanie S. Singleton, Vincent Obias, Zhuanhuai Wang, Raja Mazumder, Jon White, Lindsay M. Hopson, Shuyun Rao, Paul P. Lin, Lopa Mishra, Bao-Ngoc Nguyen, Michael Yao, Wilma Jogunoori, Xiaochun Yang, Larry S. Miller |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Colon Colorectal cancer Mutant Azoxymethane Antineoplastic Agents Gut flora Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transforming Growth Factor beta medicine Animals Microbiome Molecular Biology Smad4 Protein biology Dextran Sulfate biology.organism_classification medicine.disease Phenotype digestive system diseases Gastrointestinal Microbiome Mice Inbred C57BL 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer research Molecular Medicine Female Fluorouracil Bacteroides Colorectal Neoplasms Signal Transduction Transforming growth factor |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1867:166179 |
| ISSN: | 0925-4439 |
| Popis: | Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-β signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-β-signaling-deficient mice (Smad4+/− and Smad4+/−Sptbn1+/−), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-β signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers. |
| Databáze: | OpenAIRE |
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