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.

短肠综合征（SBS）是由于手术切除克罗恩病，缺血，创伤，坏死 在美国，小肠结肠炎或其他疾病是发病，死亡率和高医疗保健费用的主要原因 短肠患者经常取决于肠胃外营养，以满足其某些或全部营养 要求。肠切除后，其余的小肠上皮安装自适应 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 拟议的研究的最终目标是确定可以增强肠道适应的干预措施，从而 减少或消除对肠胃外营养的依赖。关于茎的特定介质知之甚少 细胞/增殖和对肠切除的功能自适应反应。因此，一个关键的未满足需求 是要了解调节肠道干细胞的信号传导途径（营养和微生物） 小肠切除后，与局部和腔内环境的相互作用。我们将使用 小儿和成人SBS患者均可检验总体假设，即成功成功的SBS患者 与改变血清和粪便ba相关的微生物群落中TPN的断奶明显变化 代谢组曲线和信号传导以及预测功能性的BA合成速率（C4测定） 肠道适应。 AIM 1将检验以下假设：独特的微生物组和BA代谢谱以及 补偿的BA合成与成功的肠道适应和允许断奶有关 从（PN）独立。 AIM 2将检验以下假设：BA信号通路的变化 在AIM 1中鉴定出的肠道微生物组改变了肠干和隐窝细胞增殖（CCP），以及 功能和代谢适应。因为成年人的适应时间长达2年 切除，我们将检查这些代谢和环境信号传导因素的时间演变 SBS患者。因此，我们的总体目标是识别键BA代谢组和宏基因组 预测成功适应并使用信息丰富的临床前模型来识别的变化 BA信号传导和茎/CCP的机制以及功能适应。这个目标将实现 通过两个目标。目标1。鉴定宏基因组和BA代谢组学（血液和粪便BA物种特征； 小儿切除后长达两年的小儿和成年SBS患者的BA合成率）， 定义其与身体成分，肠干/隐窝细胞增殖反应的功能关系， 和临床结果，包括脱离PN的独立性。目标2。确定变化的机制 BA信号代谢物的微生物组和相关的移位调节形态和功能 /使用体外茎/肠培养基和gnotobiotic小鼠的代谢适应。 Gnotobiotic LGR5EGFP小鼠 与从PN断奶（适配器）的患者相比 谁不能断奶（非适应器）并评估收获能量的能力。正常和SBS患者茎 细胞培养物将与个体和胆汁酸代谢物的组合以及高亲和力一起孵育 FXR配体，并评估了干细胞存活，肠内生长，萌芽和形态学分化。 拟议的研究加在一起很重要，因为它们将有助于识别可修改的腔内因子和胆汁。 酸代谢途径可能会增强适应性并导致SBS的创新疗法。