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: 9334211
• 负责人: Nicholas Stylopoulos
• 金额: $ 44.9万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334211
• 关键词: 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; Morphology; 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; experimental study; 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; public health relevance; response; specific biomarkers; synergism; 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（由申请人提供）：拟议项目是基础研究团队和临床研究团队之间的独特协同作用，并且包含必要的复杂性来评估肠道代谢重编程的新概念作为 Roux-en-Y 胃绕道手术 (RYGBS) 的关键作用机制之一。过去十年的研究表明，RYGBS 是肥胖相关 2 型糖尿病 (T2DM) 的最佳治疗选择。最令人兴奋的进步是对 RYGBS 进行“逆向”工程；也就是说，要解开 RYGBS 发挥其代谢作用的分子机制，然后在不进行手术的情况下产生这些作用。了解为什么许多接受 RYGBS 的 T2DM 患者没有进入缓解状态将最终改善患者管理。动物模型实验和小型人体试验强调了转位肠道（Roux 肢）作为 RYGBS 后代谢改善机制的关键解剖学基础的作用。在啮齿类动物和人类患者中，Roux 肢体都会增加其燃料利用率，以适应其增加的生物能需求。在形态学上，这种适应性反应表现为细胞增殖和细胞骨架/刷状缘重塑的增加。在代谢上，它表现为葡萄糖、胆固醇和氨基酸的隔离和利用增加，以支持生长和组织维护。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，而目前这些变化尚不清楚。使用 RYGBS 时以及 RYGBS 后 1、6 和 12 个月时的受试者肠道活检对肠道代谢进行系列评估，将极大地促进 RYGBS 后肠道生物学的研究。目前，由于 RYGBS 后肠道样本的可用性有限，这一目标受到阻碍。这些研究的另一个好处是首次建立了一个系统，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针对肠道葡萄糖代谢的体内研究。拟议项目下的研究将在 RYGBS 之前和之后通过 [18F]FDG 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复杂定量和简化半定量算法。最后，对参与减肥手术纵向评估 (LABS) 研究的 T2DM 受试者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 T2DM 缓解的预测因子。总体而言，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，从而实现迄今为止无法获得的肠道生物学机制研究。