Bile acid metabolomics and metagenomics in short bowel syndrome

短肠综合征的胆汁酸代谢组学和宏基因组学

• 批准号: 9354486
• 负责人: Nicholas O. Davidson
• 金额: $ 37.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354486
• 关键词: Acids; Address; Adult; Affinity; Area; Bacteria; Bile Acid Biosynthesis Pathway; Bile Acids; Blood; Body Composition; Cell Communication; Cell Culture Techniques; Cell Proliferation; Cell Survival; Chenodeoxycholic Acid; Childhood; Clinical; Colon; Crohn' s disease; Dependence; Disease; Electrolytes; Environment; Epithelial; Epithelium; Evolution; Excision; FGF19 gene; Feces; Fibroblast Growth Factor; GPBAR1 gene; Germ-Free; Gnotobiotic; Goals; Growth; Harvest; Health; Health Care Costs; Height; Hyperplasia; In Vitro; Incubated; Individual; Inflammatory disease of the intestine; Injury; Innovative Therapy; Intervention; Intestines; Ischemia; Lead; Length; Ligands; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Morbidity - disease rate; Morphology; Mus; Necrotizing Enterocolitis; Nutrient; Nutritional; Nutritional Requirements; Operative Surgical Procedures; Outcome; Parenteral Nutrition; Pathway interactions; Patients; Pre-Clinical Model; Process; Role; Serum; Short Bowel Syndrome; Signal Pathway; Signal Transduction; Small Intestines; Stem cells; Surface; Testing; Transplant Recipients; Trauma; Villus; Weaning; absorption; cohort; crypt cell; fexaramine; functional adaptation; functional loss; gut microbiome; human stem cells; innovation; metabolic profile; metabolomics; microbial; microbial community; microbiome; mortality; novel therapeutics; outcome forecast; pediatric patients; receptor; response; stem; teduglutide; virtual

Short bowel syndrome (SBS) due to surgical resection for Crohn's disease, ischemia, trauma, necrotizing enterocolitis or other disorders is a major cause of morbidity, mortality and high health care costs in the U.S. Short bowel patients are frequently dependent on parenteral nutrition to meet some or all of their nutritional requirements. Following intestinal resection, the remaining small bowel epithelium mounts an adaptive response that increases villus height, crypt depth and enhances nutrient and electrolyte absorption. The ultimate goal of the proposed studies is to identify interventions that can enhance intestinal adaptation and thus reduce or eliminate dependence on parenteral nutrition. Little is known about specific mediators of the stem cell/proliferative and the functional adaptive response to intestinal resection. Accordingly, a critical unmet need is to understand the signaling pathways (nutritional and microbial) that modulate intestinal stem cell interactions with the local and luminal environments following small bowel resection. We will use cohorts of both pediatric and adult SBS patients to test the overarching hypothesis that SBS patients who successfully wean from TPN manifest shifts in microbial communities associated with altered serum and fecal BA metabolomic profiles and signaling, as well as BA synthesis rates (C4 determination) that predict functional intestinal adaptation. Aim 1 will test the hypothesis that distinctive microbiome and BA metabolic profiles and compensated BA synthesis are associated with successful intestinal adaptation and permit weaning and independence from (PN). Aim 2 will test the hypothesis that changes in BA signaling pathways associated with altered gut microbiome, identified in Aim 1, promote gut stem and crypt cell proliferation (CCP), as well as functional and metabolic adaptation. Because adaptation in adults continues for up to 2 years following resection, we will examine the temporal evolution of these metabolic and environmental signaling factors in SBS patients. Accordingly, our overarching objective is to identify key BA metabolomic and metagenomic changes that predict successful adaptation and to use informative preclinical models to identify the mechanisms of BA signaling and stem/CCP and functional adaptation. This objective will be accomplished through two aims. Aim 1. Identify metagenomic and BA metabolomic (blood and stool BA species signatures; BA synthesis rates) in pediatric and adult SBS patients for up to two years after small bowel resection, and define their functional relationships with body composition, intestinal stem/crypt cell proliferative responses, and clinical outcomes including independence from PN. Aim 2. Identify the mechanisms by which changes in the microbiome and the associated shift in BA signaling metabolites modulate morphologic and functional /metabolic adaptation using in vitro stem/enteroid cultures and gnotobiotic mice. Gnotobiotic Lgr5eGFP mice will be gavaged with fecal microbial transplants from patients who wean (adapters) from PN compared to those who cannot wean (non-adapters) and assessed for the ability to harvest energy. Normal and SBS patient stem cell cultures will be incubated with individual and combinations of bile acid metabolites as well as high affinity FXR ligands and assessed for stem cell survival, enteroid growth, budding and morphologic differentiation. Together the proposed studies are significant as they will help to identify modifiable luminal factors and bile acid metabolic pathways that may enhance adaptation and lead to innovative therapies for SBS.

克罗恩病、缺血、创伤、坏死术后短肠综合征(SBS) 在美国，小肠结肠炎或其他疾病是发病率、死亡率和高昂的医疗费用的主要原因。 短肠病人经常依赖肠外营养来满足他们的部分或全部营养。 要求。肠切除后，剩余的小肠上皮细胞形成一种适应性 增加绒毛高度、隐窝深度并增强营养和电解质吸收的反应。这个 拟议研究的最终目标是确定能够增强肠道适应的干预措施，从而 减少或消除对肠外营养的依赖。鲜为人知的是茎的特定介体。 细胞/增殖和肠道切除后的功能适应性反应。因此，一个关键的未得到满足的需求 是了解调节肠道干细胞的信号通路(营养和微生物) 小肠切除后与局部和管腔环境的相互作用。我们将使用一批 对儿童和成人SBS患者进行测试，以检验SBS患者成功 与血清和粪便BA改变相关的微生物群落中TPN的明显变化 代谢组谱和信号，以及BA合成率(C4测定)，预测功能 肠道适应。目标1将检验这样一种假设，即独特的微生物组和BA代谢特征以及 BA的代偿合成与成功的肠道适应和允许断奶和 独立于(PN)。目标2将验证BA信号通路的变化与 目标1中确定的肠道微生物群改变，促进肠道干细胞和隐窝细胞增殖(CCP)，以及 功能和代谢适应。因为成年人的适应持续了长达两年的时间 切除后，我们将研究这些代谢和环境信号因子在 SBS患者。因此，我们的首要目标是确定关键的BA代谢组和元基因组 预测成功适应的变化，并使用信息丰富的临床前模型来识别 BA信号和茎/CCP的机制与功能适应这一目标将会实现 通过两个目标。目的1.鉴定后基因组和BA代谢体(血液和粪便中BA的种类特征； 儿童和成人SBS患者在小肠切除后长达两年的BA合成率)，以及 确定它们与身体成分、肠道干细胞/隐窝细胞增殖反应的功能关系， 以及临床结果，包括独立于PN。目标2.确定发生变化的机制 微生物组和BA信号代谢物的相关转变调节着形态和功能 /利用体外干细胞/肠样培养和诺生菌小鼠的代谢适应。诺生Lgr5eGFP小鼠 将与从PN脱机(适配器)的患者的粪便微生物移植一起灌胃 不能断奶的人(非适应性者)，并评估获得能源的能力。正常和SBS患者干细胞 细胞培养将与胆汁酸代谢物的单独和组合以及高亲和力培养。 FXR配体，并评估干细胞存活、肠样生长、出芽和形态分化。 总之，拟议的研究具有重要意义，因为它们将有助于确定可改变的管腔因子和胆汁 酸代谢途径，可能会增强适应并导致SBS的创新治疗。