Fenugreek, gut microbiota, and resiliency to Western diet

胡芦巴(Trigonella foenum-graecum)在世界许多地区用于治疗糖尿病、心血管疾病 疾病和抑郁症。虽然这些行动的机制(S)尚不清楚，但它正在变得越来越多 明确肠道微生物区系是动态平衡的关键因素，也是饮食中真正的首过代谢的中介 化合物。此外，胡芦巴种子的高蛋白质和纤维含量特别适合于改良 肠道细菌，并抵消高脂肪/低纤维西式饮食的反生物效应。事实上，来自我们的数据 实验室表明，胡芦巴显著改变了肠道微生物种群，并逆转了关键的西方饮食-- 引起肠道微生物区系的变化。基于这些观察，我们提出了以下假设： 胡芦巴通过改变肠道微生物区系诱导生理弹性 我们的假设是基于胡芦巴抵消饮食诱导的肠道生物失调的能力，以及数据显示 胡芦巴形状的微生物群可以复制胡芦巴的特定效果。虽然这些数据支持一个角色 对于肠道细菌对胡芦巴的有益反应，需要关键数据来确认和确定机制 胡芦巴-微生物群的相互作用推动了生理效益。首先，肠道微生物区系对 胡芦巴的有益情况需要建立起来。此外，胡芦巴-微生物区系的相互作用是否会改变 肠道代谢组直接通过揭开/产生否则无法获得的植物化学物质； 或者间接地通过改变西方饮食的新陈代谢来解决。最后，对肠道和肠道组织的鉴定 需要基于血液的代谢物来调节胡芦巴的生理弹性，以加速 翻译这些发现。为了满足这些需求，我们设计了一种独特的实验方法 结合常规和无菌小鼠，适应性微生物组移植范例，以及一系列 在硅胶分析中的尖端技术，用于识别微生物组衍生的胡芦巴代谢物 生理弹性。特定目标1常规饲养和无菌小鼠以确定肠道 微生物区系塑造了胡芦巴的有益效果。AIM 2将使用微生物组移植来确定 特定的微生物区系对于胡芦巴的有益作用既是必要的也是充分的，并将决定 如果胡芦巴-微生物群的相互作用通过揭开/产生其他- 难以获取的植物植物化学物质；或通过改变西方饮食的新陈代谢间接产生的。目标3将确定 血液和肠道中预测神经行为和代谢损伤的确切代谢物 使用验证队列和最先进的生物信息学工具。这些代谢物的鉴定，以及 共生菌负责它们的生产，可以带头制定安全有效的 在当今的现代环境中保护健康的战略。此外，提高了对如何 肠道微生物区系平衡不利和有益饮食元素的相互作用可以被利用来 促进所有患者的生理弹性，而不考虑饮食。

Fenugreek (Trigonella foenum-graecum) is used in many parts of the world for diabetes, cardiovascular disease, and depression. While the mechanism(s) of these actions is not known, it is becoming increasingly clear that gut microbiota are key players in homeostasis and also mediate true first-pass metabolism of dietary compounds. Furthermore, the high protein and fiber content of fenugreek seeds is particularly suited to modify intestinal bacteria and offset the dysbiotic effects of high fat/low fiber Western-style diets. Indeed, data from our lab shows that fenugreek significantly alters intestinal microbial populations, and reverses key Western diet- induced changes to gut microbiota. Based on these observations, we propose the following hypothesis: Fenugreek induces physiologic resiliency via changes to intestinal microbiota Our hypothesis is based on the ability of fenugreek to offset diet-induced gut dysbiosis, and on data showing that fenugreek-shaped microbiota can replicate selected effects of fenugreek. While these data support a role for gut bacteria in beneficial responses to fenugreek, key data are needed to confirm and identify mechanisms by which fenugreek-microbiota interactions drive physiologic benefits. First, the impact of gut microbiota on the beneficial profile of fenugreek needs to be established. Further, whether fenugreek-microbiota interactions alter the gut metabolome directly via unmasking/generation of otherwise-inaccessible botanical phytochemicals; or indirectly via altered metabolism of Western diets should be resolved. Finally, identification of intestinal and blood-based metabolites that mediate fenugreek-based physiologic resiliency is needed to accelerate the translation of these findings. To meet these needs, we have devised a unique experimental approach combining conventional and germ-free mice, an adaptive microbiome transplantation paradigm, and a series of cutting-edge in silico analyses to identify microbiome-derived, fenugreek-based metabolites that drive physiologic resiliency. Specific aim 1 conventionally-housed and germ-free mice to determine how intestinal microbiota shape the beneficial effects of fenugreek. Aim 2 will use microbiome transplants to determine if specific microbiota are both necessary and sufficient for the beneficial effects of fenugreek, and will determine if fenugreek-microbiota interactions alter the gut metabolome directly via unmasking/generation of otherwise- inaccessible botanical phytochemicals; or indirectly via altered metabolism of Western diets. Aim 3 will identify the exact metabolites in blood and intestinal fractions that predict neurobehavioral and metabolic impairment using validation cohorts and state-of-the art bioinformatic tools. Identification of these metabolites, and the commensal bacteria responsible for their production, could spearhead the formulation of safe and effective strategies to preserve health in the today's modern environment. Furthermore, improved understanding how gut microbiota balance the interactions of adverse and beneficial dietary elements could be harnessed to promote physiologic resilience in all patients regardless of diet.