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Publication : Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU.

First Author  Wang Z Year  2021
Journal  Biochim Biophys Acta Mol Basis Dis Volume  1867
Issue  10 Pages  166179
PubMed ID  34082069 Mgi Jnum  J:311108
Mgi Id  MGI:6765805 Doi  10.1016/j.bbadis.2021.166179
Citation  Wang Z, et al. (2021) Mice with dysfunctional TGF-beta signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU. Biochim Biophys Acta Mol Basis Dis 1867(10):166179
abstractText  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-beta 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-beta-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-beta 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-beta signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-beta pathway in the treatment of CRC or other cancers.
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