Department of Environmental and Occupation Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Am J Physiol Gastrointest Liver Physiol. 2020 Mar 1;318(3):G439-G450. doi: 10.1152/ajpgi.00351.2019. Epub 2020 Jan 21.
Methionine is an essential amino acid needed for a variety of processes in living organisms. Ionizing radiation depletes tissue methionine concentrations and leads to the loss of DNA methylation and decreased synthesis of glutathione. In this study, we aimed to investigate the effects of methionine dietary supplementation in CBA/CaJ mice after exposure to doses ranging from 3 to 8.5 Gy of Cs of total body irradiation. We report that mice fed a methionine-supplemented diet (MSD; 19.5 vs. 6.5 mg/kg in a methionine-adequate diet, MAD) developed acute radiation toxicity at doses as low as 3 Gy. Partial body irradiation performed with hindlimb shielding resulted in a 50% mortality rate in MSD-fed mice exposed to 8.5 Gy, suggesting prevalence of radiation-induced gastrointestinal syndrome in the development of acute radiation toxicity. Analysis of the intestinal microbiome demonstrated shifts in the gut ecology, observed along with the development of leaky gut syndrome and bacterial translocation into the liver. Normal gut physiology impairment was facilitated by alterations in the one-carbon metabolism pathway and was exhibited as decreases in circulating citrulline levels mirrored by decreased intestinal mucosal surface area and the number of surviving crypts. In conclusion, we demonstrate that a relevant excess of methionine dietary intake exacerbates the detrimental effects of exposure to ionizing radiation in the small intestine. Methionine supplementation, instead of an anticipated health-promoting effect, sensitizes mice to gastrointestinal radiation syndrome. Mechanistically, excess of methionine negatively affects intestinal ecology, leading to a cascade of physiological, biochemical, and molecular alterations that impair normal gut response to a clinically relevant genotoxic stressor. These findings speak toward increasing the role of registered dietitians during cancer therapy and the necessity of a solid scientific background behind the sales of dietary supplements and claims regarding their benefits.
蛋氨酸是一种必需氨基酸，需要在生物体的各种过程中使用。电离辐射会耗尽组织中的蛋氨酸浓度，导致 DNA 甲基化丧失和谷胱甘肽合成减少。在这项研究中，我们旨在研究在接受 3 至 8.5Gy 全身照射剂量的 Cs 照射后，CBA/CaJ 小鼠补充蛋氨酸饮食的影响。我们报告说，喂食蛋氨酸补充饮食（MSD；19.5 与蛋氨酸充足饮食中的 6.5mg/kg 相比）的小鼠在低至 3Gy 的剂量下就会出现急性辐射毒性。用后腿屏蔽进行部分身体照射导致喂食 MSD 的小鼠在 8.5Gy 暴露时的死亡率达到 50%，这表明在急性辐射毒性的发展中存在辐射诱导的胃肠道综合征。肠道微生物组分析表明，肠道生态发生了变化，同时观察到肠道通透性增加和细菌易位到肝脏。通过改变一碳代谢途径，正常的肠道生理功能受损，表现为循环瓜氨酸水平降低，同时肠黏膜表面积和存活隐窝数量减少。总之，我们证明了过量的蛋氨酸饮食摄入会加剧小肠暴露于电离辐射的有害影响。蛋氨酸补充，而不是预期的促进健康的效果，使小鼠易患胃肠道辐射综合征。从机制上讲，过量的蛋氨酸会对肠道生态产生负面影响，导致一连串的生理、生化和分子改变，从而损害正常肠道对临床相关遗传毒性应激源的反应。这些发现表明，在癌症治疗期间注册营养师的作用增加，以及在销售膳食补充剂和声称其益处时需要坚实的科学背景。
