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，并包含必要的复杂性，以评估肠道代谢重新编程作为Roux-en-Y胃旁路手术(RYGBS)的关键作用机制之一的新概念。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”设计RYGBS；也就是解开RYGBS发挥代谢效应的分子机制，然后不需要手术就能产生这些效应。了解为什么接受了RYGBS的一些T2 DM患者没有得到缓解，最终将改善患者的管理。在动物模型和小型先导性人体研究中，强调转位肠(Roux肢体)作为RYGBS后代谢改善机制的关键解剖底物的作用。在啮齿动物和人类患者中，Roux肢体都会增加燃料利用率，以适应其日益增长的生物能量需求。在形态上，这种适应性反应表现为细胞增殖增加和细胞骨架/刷状边界重塑。在代谢方面，它表现为增加对葡萄糖、胆固醇和氨基酸的封存和利用，以支持生长和组织维持。该项目将解决目前阻碍进展的几个挑战和限制。这将增强我们对肠道适应性变化的性质和时间的理解，目前这些变化在很大程度上是未知的。通过在RYGBS时和RYGBS后1、6和12个月取自受试者的肠道活组织来评估肠道代谢，将极大地促进RYGBS后肠道生物学的研究。这一点目前受到RYGBS后肠道样本可获得性有限的阻碍。这些研究的另一个好处是初步建立了一个系统，该系统将允许使用被称为“迷你肠道”的人类肠道器官来全面检查RYGBS对肠道隐窝和肠道干细胞的影响。这一领域进展的另一个障碍是缺乏以肠道葡萄糖代谢为重点的体内研究。在拟议项目下的研究将量化肠道葡萄糖利用，使用PET-MRI扫描和[18F]FDG，在RYGBS前后，并将比较精细的定量和简化的肠道葡萄糖摄取的半定量算法。最后，对参与减肥手术纵向评估(LABS)研究的T2 DM患者的血清样本进行有针对性的代谢物分析，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缓解的预测因素。总体而言，拟议的项目将有助于我们了解RYGBS的机制，并将产生独特的资源、生物库和数据集，使迄今无法获得的肠道生物学的机械性研究成为可能。

 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.