Intestinal Metabolic Reprogramming as a Key Mechanism of Gastric Bypass in Humans

 描述（由申请人提供）：拟议的项目是基础和临床研究团队之间的独特协同作用，包含必要的复杂性，以评估肠道代谢重编程的新概念，作为Roux-en-Y胃旁路手术（RYGBS）的关键作用机制之一。在过去的十年中，研究表明RYGBS是肥胖相关的2型糖尿病（T2 DM）的最佳治疗选择。最令人兴奋的进展将是“反向”工程RYGBS;也就是说，解开RYGBS发挥其代谢作用的分子机制，然后在不手术的情况下产生这些作用。了解为什么一些接受RYGBS的T2 DM患者没有进入缓解期，最终将改善患者管理。动物模型实验和小型试点人体研究强调了移位肠（Roux肢体）作为RYGBS后代谢改善机制的关键解剖基质的作用。在啮齿类动物和人类患者中，Roux肢体增加了其燃料利用率，以适应其增加的生物能量需求。在形态学上，这种适应性反应表现为细胞增殖增加和细胞骨架/刷状缘重塑。在代谢上，它表现为增加的葡萄糖、胆固醇和氨基酸的螯合和利用，以支持生长和组织维持。该项目将解决目前阻碍进展的若干挑战和限制。它将增强我们对肠道适应性变化的性质和时间的理解，这在很大程度上是未知的。使用在RYGBS时和RYGBS后1、6和12个月来自受试者的肠活检对肠代谢的系列评估将大大促进RYGBS后的肠生物学研究。目前，这受到RYGBS后肠道样本有限的阻碍。这些研究的另一个好处是首先建立了一个系统，该系统将允许使用被称为“迷你肠道”的人类肠道类器官来全面检查RYGBS对肠隐窝和肠干细胞的影响。该领域进展的另一个障碍是缺乏专注于肠道葡萄糖代谢的体内研究。根据拟议项目进行的研究将在RYGBS之前和之后使用[18 F]FDG进行PET-MRI扫描来量化肠道葡萄糖利用率，并将比较肠道葡萄糖摄取的详细定量和简化半定量算法。最后，参与减肥手术纵向评估（LABS）研究的T2 DM受试者血清样本的靶向代谢物分析将使我们能够检查肠道适应标志物是否可以作为RYGBS后T2 DM缓解的预测因子。总的来说，拟议的项目将促进我们对RYGBS机制的理解，并将产生独特的资源，生物库和数据集，这将使迄今为止无法获得的肠道生物学机制研究成为可能。

 DESCRIPTION (provided by applicant): The proposed project is a unique synergy between basic and clinical research teams and contains the requisite sophistication to evaluate the novel concept of intestinal metabolic reprogramming as one of the key mechanisms of action of Roux-en-Y Gastric Bypass Surgery (RYGBS). Over the last decade, research has shown that RYGBS is the best treatment option for obesity-related type 2 diabetes (T2DM). The most exciting advance would be to "reverse" engineer RYGBS; that is to unravel the molecular mechanisms by which RYGBS exerts its metabolic effects and then to produce those effects without surgery. Understanding why a number of patients with T2DM who underwent RYGBS do not go into remission would ultimately improve patient management. Experiments in animal models and small pilot human studies have emphasized the role of the transposed intestine (Roux limb) as the key anatomic substrate of the mechanisms of metabolic improvement after RYGBS. In both rodents and human patients, the Roux limb increases its fuel utilization in an attempt to accommodate its increased bioenergetic requirements. Morphologically, this adaptive response appears as increased cellular proliferation and cytoskeletal/brush border remodeling. Metabolically, it manifests as increased sequestration and utilization of glucose, cholesterol and amino acids to support growth and tissue maintenance. This project will tackle several challenges and limitations currently hindering progress. It will enhance our understanding about the nature and the timing of intestinal adaptive changes, which are currently largely unknown. The serial assessment of intestinal metabolism using intestinal biopsies derived from subjects at the time of and 1, 6 and 12 months after RYGBS, will substantially facilitate the study of intestinal biology after RYGBS. This is currently hindered by limited availability of post-RYGBS intestinal samples. A further benefit of these studies is the premier establishment of a system that will allow the comprehensive examination of the effects of RYGBS on intestinal crypts and intestinal stem cells, using human intestinal organoids known as "mini-guts". Another obstacle of progress in this field is the lack of in vivo studies focusing on intestinal glucose metabolism. Studies under the proposed project will quantify intestinal glucose utilization, with PET-MRI scanning with [18F]FDG, before and after RYGBS, and will compare elaborate quantitative and simplified semi-quantitative algorithms of intestinal glucose uptake. Finally, a targeted metabolite profiling of serum samples of subjects with T2DM, who participated in the Longitudinal Assessment of Bariatric Surgery (LABS) study, will allow us to examine whether markers of intestinal adaptation could serve as predictors of remission of T2DM after RYGBS. Overall, the proposed project will facilitate our understanding of the mechanisms of RYGBS and will generate unique resources, biobanks and datasets that will enable mechanistic studies of intestinal biology unobtainable to date.