Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity.
Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity.
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饮食限制可增加保护性肠道细菌，以挽救甲氨蝶呤引起的致命肠道毒性
DOI：
10.1080/19490976.2020.1714401
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发表时间：
2020-11-09
期刊：
影响因子：
12.2
通讯作者：
Tao S
中科院分区：
文献类型：
--
作者：
Tang D;Zeng T;Wang Y;Cui H;Wu J;Zou B;Tao Z;Zhang L;Garside GB;Tao S
摘要甲氨蝶呤(MTX)是一种典型的化疗药物，广泛应用于多种恶性肿瘤和自身免疫性疾病的治疗，其最突出的并发症是胃肠道毒性，对患者的预后有重要影响。然而，缓解此类并发症的有效方法仍有待探索。在这里，我们表明，30%的饮食限制(DR)2周显着提高了致命剂量的MTX暴露后2个月大的雌性小鼠的存活率。经MTX治疗后，DR可明显减轻肠道炎症，保留基础隐窝内增殖细胞核抗原阳性细胞的数量，保护肠道干细胞的功能。此外，用广谱抗生素消融肠道微生物群完全消除了Dr.16S rRNA基因的保护作用。深度测序分析表明，短期DR显著增加了乳杆菌属，鼠李糖乳杆菌GG灌胃部分模拟了DR对暴露于致死剂量MTX的随机喂养小鼠肠道的拯救作用。综上所述，目前的研究表明，DR可能是一种高效的方法来减轻大剂量MTX治疗后的肠道致死性损伤，其功能是通过增加小鼠肠道保护性微生物区系来实现的。关键词：饮食限制、甲氨蝶呤、肠道微生物区系、肠道干细胞、肠道毒性
ABSTRACT Methotrexate (MTX) is a typical chemotherapeutic drug that is widely used in the treatment of various malignant diseases as well as autoimmune diseases, with gastrointestinal toxicity being its most prominent complication which could have a significant effect on the prognosis of patients. Yet effective ways to alleviate such complications remains to be explored. Here we show that 30% dietary restriction (DR) for 2 weeks dramatically increased the survival rate of 2-month-old female mice after lethal-dose MTX exposure. DR significantly reduced intestinal inflammation, preserved the number of basal crypt PCNA-positive cells, and protected the function of intestinal stem cells (ISCs) after MTX treatment. Furthermore, ablating intestinal microbiota by broad-spectrum antibiotics completely eliminated the protective effect achieved by DR. 16S rRNA gene deep-sequencing analysis revealed that short-term DR significantly increased the Lactobacillus genus, with Lactobacillus rhamnosus GG gavage partially mimicking the rescue effect of DR on the intestines of ad libitum fed mice exposed to lethal-dose MTX. Together, the current study reveals that DR could be a highly effective way to alleviate the lethal injury in the intestine after high-dose MTX treatment, which is functionally mediated by increasing the protective intestinal microbiota taxa in mice. Keywords: Dietary restriction, Methotrexate, Gut microbiota, Intestinal stem cells, intestinal toxicity
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影响因子：
33.7
作者：
Chan, Edwin S. L.;Cronstein, Bruce N.
通讯作者：
Cronstein, Bruce N.
影响因子：
6.2
作者：
Jordan KR;Loman BR;Bailey MT;Pyter LM
通讯作者：
Pyter LM
影响因子：
64.8
作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
通讯作者：
Gregorieff, Alex
DOI：
10.1007/s00018-017-2693-8
发表时间：
2018-01
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Hugenholtz F;de Vos WM
通讯作者：
de Vos WM
影响因子：
2.2
作者：
Huws, S. A.;Edwards, J. E.;Scollan, N. D.
通讯作者：
Scollan, N. D.