Effects of gastric bypass on the gut microbiota and energy balance

描述（由申请人提供）：拟议研究项目的目的是检验以下假设：Roux-en-Y胃旁路（RYGB）手术后的体重减轻、葡萄糖稳态改善和能量消耗增加部分是由肠道微生物群落的变化介导的。 RYGB是目前糖尿病和肥胖症最有效的长期手术治疗选择，在显著和持续的体重减轻之前，并独立于显著和持续的体重减轻，导致胰岛素敏感性的巨大改善。对肠道的物理操作导致营养物质和胃肠道分泌物的流动改变，这可能影响调节能量平衡和葡萄糖代谢的肠道源性信号传导途径。存在于胃肠道中的微生物（肠道微生物群）受到饮食的严重影响，最近被认为是肥胖相关脂肪沉积、能量消耗减少和胰岛素抵抗的强大调节剂。人类和大鼠的研究表明，肠道微生物生态学在RYGB后发生了显着变化，并且与在瘦或肥胖个体中观察到的微生物群落不同。考虑到手术后这种生态学中观察到的这些变化，以及微生物群在调节能量平衡和葡萄糖代谢中的新兴作用，肠道微生物群可能是RYGB效应的介体。然而，肠道微生物生态学的变化在多大程度上有助于RYGB后的代谢结果仍不清楚。 拟议的研究旨在表征小鼠RYGB后肠道微生物群落的变化程度，以及这些变化在多大程度上介导RYGB结果。通过对术后随时间纵向采集的粪便样本以及沿沿着胃肠轴采集的管腔和粘膜粘附群落进行16 S rRNA基因测序，评估肠道微生物变化。为了确定这些微生物变化介导代谢结果的程度，将用来自经历RYGB或SHAM处理的供体动物的肠道内容物接种无菌小鼠。然后评估这些受体动物的体重、肥胖、摄食量、能量消耗和葡萄糖参数的变化。随后，我们将根据观察到的生理表型，确定哪些代谢信号传导途径最有可能受到来自RYGB供体的微生物群在无菌动物中的定殖的影响。 成功完成拟议项目将增加我们对胃肠道在调节代谢功能中的生理作用的理解，包括微生物群对肠道传入信号的贡献，以及能够识别新的治疗靶点来治疗肥胖和糖尿病，这些靶点将模拟RYGB的生理学，而无需手术本身。 公共卫生相关性：该项目旨在了解生活在肠道中的数万亿微生物如何受到Roux-en-Y胃旁路术的影响，这是一种对能量平衡，葡萄糖稳态和其他代谢功能具有深远有益影响的手术干预，以及肠道细菌种群的变化在多大程度上影响这些代谢改善。拟议的研究将包括评估肠道微生物在生理和分子水平上对代谢调节多个方面的贡献，包括食物摄入、脂肪沉积和身体组成、能量消耗、脂质代谢和葡萄糖代谢。

DESCRIPTION (provided by applicant): The objective of the proposed research project is to test the hypothesis that weight loss, improved glucose homeostasis, and increased energy expenditure following Roux-en-Y gastric bypass (RYGB) surgery are, in part, mediated by a change in the gut microbial community. RYGB is currently the most effective long-term surgical treatment option for both diabetes and obesity, resulting in vast improvements in insulin sensitivity prior to, and independent of, marked and sustained weight loss. Physical manipulation of the gut results in an altered flow of nutrients and gastrointestinal secretions, which likely affects gut-derived signaling pathways regulating energy balance and glucose metabolism. The microorganisms that reside in the gastrointestinal tract (the gut microbiota) are heavily influenced by diet and have recently been implicated as powerful regulators of obesity-associated fat deposition, decreased energy expenditure, and insulin resistance. Human and rat studies have demonstrated that the gut microbial ecology changes markedly following RYGB and is different from the microbial communities observed in either lean or obese individuals. Given these observed shifts in this ecology after surgery, and given the emerging role of the microbiota in regulating energy balance and glucose metabolism, the gut microbiota is a likely mediator of the effects of RYGB. However, the extent to which changes in gut microbial ecology contribute to post-RYGB metabolic outcomes remains unclear. The proposed studies aim to characterize the degree to which the gut microbial community is changed after RYGB in the mouse and to what degree these changes mediate RYGB outcomes. Gut microbial changes will be assessed by 16S rRNA gene sequencing of fecal samples, collected longitudinally over time after surgery, and of luminal and mucosal adherent communities collected along the gastrointestinal axis. To determine the extent to which these microbial changes mediate metabolic outcomes, germ free mice will be inoculated with gut contents from donor animals that had undergone either RYGB or SHAM treatment. These recipient animals will then be assessed for changes in body weight, adiposity, food intake, energy expenditure, and glucose parameters. Subsequently, we will determine which metabolic signaling pathways are most likely impacted by colonization of microbiota from RYGB donors in the gnotobiotic animals, based on the physiologic phenotypes that are observed. Successful completion of the proposed project will increase our understanding of the physiological role of the gastrointestinal tract in regulating metabolic function, including the contribution of the microbiota on afferent signaling i the gut, as well as enable identification of new therapeutic targets to treat obesity and diabetes that will mimic the physiology of RYGB without the need for surgery itself. PUBLIC HEALTH RELEVANCE: This project aims to understand how the trillions of micro-organisms that live in the gut are affected by Roux- en-Y gastric bypass, a surgical intervention that has profound beneficial effects on energy balance, glucose homeostasis, and other metabolic functions, and to what extent changes in gut bacterial populations affect these metabolic improvements. The proposed studies will include assessments of gut microbial contributions to multiple aspects of metabolic regulation on both a physiological and molecular level, including food intake, fat deposition and body composition, energy expenditure, lipid metabolism and glucose metabolism.