Cheema Amrita K, Maier Irene, Dowdy Tyrone, Wang Yiwen, Singh Rajbir, Ruegger Paul M, Borneman James, Fornace Albert J, Schiestl Robert H
Department of Oncology, Georgetown University Medical Center, Washington, D.C., United States of America.
Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, D.C., United States of America.
PLoS One. 2016 Apr 13;11(4):e0151190. doi: 10.1371/journal.pone.0151190. eCollection 2016.
Intestinal microbiota play a significant role in nutrient metabolism, modulation of the immune system, obesity, and possibly in carcinogenesis, although the underlying mechanisms resulting in disease or impacts on longevity caused by different intestinal microbiota are mostly unknown. Herein we use isogenic Atm-deficient and wild type mice as models to interrogate changes in the metabolic profiles of urine and feces of these mice, which are differing in their intestinal microbiota. Using high resolution mass spectrometry approach we show that the composition of intestinal microbiota modulates specific metabolic perturbations resulting in a possible alleviation of a glycolytic phenotype. Metabolites including 3-methylbutyrolactone, kyneurenic acid and 3-methyladenine known to be onco-protective are elevated in Atm-deficient and wild type mice with restricted intestinal microbiota. Thus our approach has broad applicability to study the direct influence of gut microbiome on host metabolism and resultant phenotype. These results for the first time suggest a possible correlation of metabolic alterations and carcinogenesis, modulated by intestinal microbiota in A-T mice.
肠道微生物群在营养代谢、免疫系统调节、肥胖以及可能的致癌过程中发挥着重要作用，尽管导致疾病的潜在机制或不同肠道微生物群对寿命的影响大多尚不清楚。在此，我们使用同基因的Atm缺陷型和野生型小鼠作为模型，来研究这些肠道微生物群不同的小鼠尿液和粪便代谢谱的变化。使用高分辨率质谱方法，我们表明肠道微生物群的组成调节特定的代谢扰动，从而可能缓解糖酵解表型。在肠道微生物群受限的Atm缺陷型和野生型小鼠中，已知具有抗癌保护作用的代谢物，如3-甲基丁内酯、犬尿酸和3-甲基腺嘌呤有所升高。因此，我们的方法在研究肠道微生物群对宿主代谢和最终表型的直接影响方面具有广泛的适用性。这些结果首次表明，在共济失调毛细血管扩张症（A-T）小鼠中，代谢改变与致癌作用之间可能存在由肠道微生物群调节的相关性。
