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

肠道代谢重编程是人类胃绕道手术的关键机制

• 批准号: 9148259
• 负责人: Nicholas Stylopoulos
• 金额: $ 45.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148259
• 关键词: Accounting; Address; Advocate; Affect; Algorithms; Amino Acids; Anatomy; Animal Model; Basic Science; Bioenergetics; Biology; Biopsy; Body Weight decreased; Brush Border; Cell Proliferation; Cholesterol; Citrulline; Clinical; Clinical Research; Comorbidity; Cytoskeletal Modeling; Data; Data Set; Development; Diabetes Mellitus; Disease; Disease remission; Engineering; Epidemic; Exhibits; Gastric Bypass; Gene Proteins; Glucose; Growth; Health; Hospitals; Human; Intestines; Journals; Lead; Limb structure; MRI Scans; Magnetic Resonance Imaging; Maintenance; Matched Group; Measures; Metabolic; Metabolic Diseases; Metabolism; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patient Care; Patients; Pilot Projects; Positron-Emission Tomography; Postoperative Period; Process; Public Health; Publishing; Research; Research Personnel; Resources; Rodent; Rodent Model; Role; Sampling; Science; Serum; Stem cells; System; Testing; Time; Tissues; United States; United States National Institutes of Health; Work; amino acid metabolism; bariatric surgery; base; biobank; blood glucose regulation; cell growth; cohort; glucose metabolism; glucose uptake; glycemic control; health economics; human subject; improved; improved outcome; in vivo; intestinal crypt; intestinal epithelium; jejunum; metabolic profile; novel; obesity treatment; protein metabolite; research study; response; specific biomarkers; theories

 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.

 描述（由适用提供）：拟议的项目是基本研究团队和临床研究团队之间的独特协同作用，并包含必要的精致，以评估新颖的肠道代谢重编程的概念，这是Roux-en-Y-Y-Y-Y-Y-Y胃旁路旁路手术（Rygbs）的关键机制之一。在过去的十年中，研究表明，RYGBS是肥胖相关2型糖尿病（T2DM）的最佳治疗选择。最激动人心的进步是“逆转”工程师Rygbs；那是为了揭示RYGBS执行其代谢作用，然后在没有手术的情况下产生这些作用的分子机制。理解为什么许多接受RYGB的T2DM患者不会康复，最终会改善患者的管理。动物模型和小型试验人类研究的实验强调了转置肠道（Roux Limb）作为RYGBS后代谢改善机制的关键解剖基质。在啮齿动物和人类患者中，roux肢体都会增加其燃料利用，以适应其增加的生物能量需求。从形态上讲，这种适应性反应似乎是增加的细胞增殖和细胞骨架/刷子边界重塑。在代谢上，它表现为增加葡萄糖，胆固醇和氨基酸的隔离和利用增加，以支持生长和组织维持。该项目将应对目前阻碍进度的几个挑战和局限性。它将增强我们对肠道自适应变化的性质和时机的理解，这些变化目前在很大程度上未知。使用从受试者和RYGBS后1、6和12个月的受试者衍生的肠活检对肠道代谢的串行评估将基本上支持Rygbs后肠生物学的研究。目前，这受到了晶体后肠样品的可用性有限的阻碍。这些研究的进一步好处是，使用人类肠道类器官（称为“迷你甲状腺”），将允许对RYGBS对肠道隐窝和肠道干细胞的影响进行全面检查。该领域进步的另一个障碍是缺乏关注肠道葡萄糖代谢的体内研究。拟议项目下的研究将量化肠道葡萄糖的利用，并在RYGBS之前和之后使用[18F] FDG进行PET-MRI扫描，并将比较肠道葡萄糖摄取的详细定量和简化的半定量算法。最后，参与减肥手术纵向评估（LABS）研究的T2DM受试者血清样本的有针对性的代谢物分析将使我们能够检查肠道适应的标志物是否可以作为Rygbs后T2DM缓解的预测指标。总体而言，拟议的项目将有助于我们对RYGBS机制的理解，并将产生独特的资源，生物库和数据集，从而使迄今为止无法获得的肠生物学的机械研究。