Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital, viale dei Cappuccini n.1, 71013, San Giovanni Rotondo, FG, Italy.
Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
Cancer Chemother Pharmacol. 2018 Apr;81(4):773-782. doi: 10.1007/s00280-018-3549-0. Epub 2018 Feb 22.
Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-related death. We aimed to evaluate whether gemcitabine treatment shapes the gut microbiota in a model of PDAC xenografted mice.
Pancreatic cancer xenograft mice were subjected to gemcitabine injection once per week for 3 weeks to assess the tumor volume as compared to control mice injected with normal saline solution. The composition of fecal microbiota, the activation of NF-kB pathway in cancer tissues and the serum metabolomics were further analyzed.
Gemcitabine considerably decreases the proportion of Gram- positive Firmicutes (from about 39 to 17%) and the Gram- negative Bacteroidetes (from 38 to 17%) which are the two dominant phyla in the gut of tumor-bearing control mice. This downshift was replaced by an increase of Proteobacteria (Escherichia coli and Aeromonas hydrophila) from 15 up to 32% and Verrucomicrobia (Akkermansia muciniphila) from 5 to 33% in the gut of drug-receiving mice. An overall increase in inflammation-associated bacteria was observed upon gemcitabine. Consistently, activation of the NF-kB canonical pathway was found in cancer tissues from gemcitabine-treated mice. Serum metabolomics revealed a significant decrease of the purine compounds inosine and xanthine, and a decreasing trend for their metabolically-related molecule hypoxanthine.
Understanding chemotherapy side effects may explain the lack of activity or the chemoresistant processes and it may help to set up strategies to improve the effectiveness of therapy.
胰腺导管腺癌（PDAC）是癌症相关死亡的第四大原因。我们旨在评估吉西他滨治疗是否会在 PDAC 异种移植小鼠模型中改变肠道微生物群。
对胰腺癌异种移植小鼠进行每周一次的吉西他滨注射，共 3 周，以评估肿瘤体积与注射生理盐水的对照小鼠相比。进一步分析粪便微生物群的组成、癌症组织中 NF-kB 通路的激活和血清代谢组学。
吉西他滨显著降低了革兰氏阳性菌Firmicutes（从约 39%降至 17%）和革兰氏阴性菌Bacteroidetes（从 38%降至 17%）的比例，这两种菌是肿瘤对照小鼠肠道中的两个主要菌群。这种下降被药物接受小鼠肠道中 Proteobacteria（大肠杆菌和嗜水气单胞菌）从 15%增加到 32%和 Verrucomicrobia（阿克曼氏菌粘液菌）从 5%增加到 33%所取代。在用吉西他滨治疗的小鼠中，观察到与炎症相关的细菌总体增加。一致地，在接受吉西他滨治疗的小鼠的癌症组织中发现 NF-kB 经典途径的激活。血清代谢组学显示嘌呤化合物肌苷和黄嘌呤显著减少，其代谢相关分子次黄嘌呤呈下降趋势。
了解化疗的副作用可以解释缺乏活性或化疗耐药的过程，并可能有助于制定改善治疗效果的策略。
