Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA.
Biochim Biophys Acta Mol Basis Dis. 2021 Oct 1;1867(10):166179. doi: 10.1016/j.bbadis.2021.166179. Epub 2021 May 31.
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 Smad4Sptbn1), 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.
新兴数据显示，年轻男性和女性的结直肠癌（CRC）发病率上升，且往往对化疗有抗药性。一个潜在的风险因素是微生物组的改变。在这里，我们研究了 TGF-β 信号对肠道微生物组的作用以及在小鼠中用氧化偶氮甲烷和葡聚糖硫酸钠诱导 CRC 时化疗的疗效。我们使用了两种 TGF-β 信号缺陷型小鼠（Smad4 和 Smad4Sptbn1），它们具有相似的 CRC 表型，并且肠道微生物组也有相似的改变。使用这些小鼠，我们评估了肠道微生物组，并确定了功能失调的 TGF-β 信号对 CRC 诱导后对化疗药物 5-氟尿嘧啶（5FU）反应的影响。通过 shotgun 宏基因组测序，我们确定了患有 CRC 的小鼠的肠道微生物组组成，并发现突变体中有益的拟杆菌属和副拟杆菌属的数量比野生型（WT）小鼠减少。此外，患有 CRC 的突变体小鼠对 5FU 具有抗性。虽然 CRC 小鼠中 E. boltae、B.dorei、Lachnoclostridium sp.和 Mordavella sp.的丰度显著降低，但这些物种仅在 WT 小鼠用 5FU 治疗后才恢复到基础水平，这表明由于 TGF-β 信号受损而导致的肠道微生物组改变削弱了对 5FU 的反应。这些发现可能对抑制 TGF-β 通路在 CRC 或其他癌症的治疗中有重要意义。
