Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.
Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.
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DOI：
10.1016/j.cell.2017.03.040
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发表时间：
2017-04-20
期刊：
影响因子：
64.5
通讯作者：
Cabreiro F
中科院分区：
文献类型：
--
作者：
Scott TA;Quintaneiro LM;Norvaisas P;Lui PP;Wilson MP;Leung KY;Herrera-Dominguez L;Sudiwala S;Pessia A;Clayton PT;Bryson K;Velagapudi V;Mills PB;Typas A;Greene NDE;Cabreiro F
氟尿嘧啶是结直肠癌的一线治疗药物，但其疗效在患者之间差异很大。我们质疑肠道微生物（一种已知的个体间变异性来源）是否影响药物疗效。结合两个易于处理的遗传模型，细菌大肠杆菌和线虫秀丽隐杆线虫，我们进行了三向高通量筛选，揭示了宿主-微生物-药物相互作用的复杂性。我们报告说，微生物可以通过涉及细菌维生素B6，B 9和核糖核苷酸代谢的代谢药物相互转化来支持或抑制氟嘧啶的作用。此外，细菌脱氧核苷酸池的干扰放大了5-FU诱导的宿主细胞自噬和细胞死亡，这是由核苷二磷酸激酶ndk-1调节的作用。我们的数据表明，氟嘧啶对宿主代谢的影响是双向细菌介导的，这有助于药物疗效。这些发现强调了操纵肠道微生物群以确保宿主代谢健康和治疗疾病的潜在治疗能力。药物-微生物-宿主高通量筛选揭示癌症药物的新机制微生物整合营养和药物线索调节宿主中的治疗功效宿主和微生物之间存在癌症前药的核糖核苷酸共代谢不平衡的细菌脱氧核苷酸协同5-FU诱导的自噬细胞死亡涉及宿主-微生物-宿主的三向高通量筛选药物相互作用表明，某些药物的有益影响可能是由于肠道微生物组成的药物依赖性改变的影响，而不是治疗药物本身的直接作用。
Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease. Drug-microbe-host high-throughput screens reveal new mechanisms for cancer drugs Microbes integrate nutritional and drug cues regulating treatment efficacy in the host Ribonucleotide co-metabolism of cancer pro-drugs exists between host and microbe Imbalanced bacterial deoxynucleotides synergize 5-FU-induced autophagic cell death A three-way high-throughput screen involving host-microbe-drug interactions reveals that the beneficial impact of some drugs can be due to effects of drug-dependent alterations by gut microbe composition rather than direct action of the therapeutic itself.