Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome

胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用

• 批准号: 10343091
• 负责人: Ajay K. Jain
• 金额: $ 37.88万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343091
• 关键词: Address; Agonist; Animal Model; Animals; Atrophic; Automobile Driving; Bile Acid Biosynthesis Pathway; Bile Acids; Blood Circulation; CYP7A1 gene; Catheters; Chenodeoxycholic Acid; Cholestasis; Cholesterol 7-alpha-Monooxygenase; Complication; Data; Dependence; Dose; Duodenum; Dyslipidemias; Enteral; Enteral Feeding; Enteral Nutrition; Enterocytes; Enterohepatic Circulation; Etiology; Excision; FGF19 gene; Failure; Fatty Liver; Fibroblast Growth Factor Receptors; GLP-2; GPBAR1 gene; Gene Expression; Glucose; Glucose Intolerance; Hepatic; Histology; Hour; Human; Impairment; Inflammation; Injury; Insulin; Intestinal permeability; Intestines; Intravenous; Knowledge; Link; Lipids; Liver; Liver diseases; Modeling; Nuclear Receptors; Nutritional; Oleanolic Acid; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peptide Signal Sequences; Pilot Projects; Prevention; Process; Proteins; Publishing; Pump; Receptor Activation; Repression; Research; Research Personnel; Rodent; Role; Schedule; Serology; Serum; Short Bowel Syndrome; Signal Pathway; Signal Transduction; Testing; Total Parenteral Nutrition; Treatment outcome; base; blood glucose regulation; clinically relevant; deprivation; glucagon-like peptide; glucagon-like peptide 1; insight; intrahepatic; liver injury; novel; nutrition; porcine model; prevent; receptor; restoration; side effect

PROJECT SUMMARY / ABSTRACT Bowel resection leads to the devastating condition of Short Bowel Syndrome (SBS). SBS patients cannot maintain nutrition through regular enteral nutrition (EN) due to insufficient intestines. Such patients, in the absence of EN, require intravenous nutrition via a process called Total Parenteral nutrition (TPN) for survival. Worldwide, tens of thousands of patients require TPN. Despite the lifesaving TPN, side effects in SBS include potentially fatal liver and gut injury. Although, many researchers have focused on the detrimental effects of the constituents of TPN, results from our published studies highlight our novel hypothesis that the state of luminal content deprivation in SBS, disrupts the normal gut derived signals and drives injury mechanisms in SBS. Our published data shows that during EN, as part of normal enterohepatic circulation of bile acids (BA), activation of gut Farnesoid X Receptor (FXR) by BA results in release of Fibroblast Growth Factor 19 (FGF19). FGF19 regulates hepatic BA, cholestasis, lipid, and glucose homeostasis. Due to a lack of gut FXR activation in SBS we hypothesize that the FXR-FGF19 signaling axis is impaired. We have also published that BA prevent gut atrophy by enhancing Glucagon Like Peptides (GLPs). GLPs are regulated via BA activated gut receptor TGR5. While GLP-2 is a gut trophic factor; GLP-1 modulates hepatic steatosis, insulin, and glucose. We hypothesize that inadequate gut TGR5 activation in SBS additionally drives liver and gut injury. Novel Model: We have established a novel untethered ambulatory SBS piglet model using miniature pumps, jugular and duodenal catheters, and surgical bowel resection (SLU#2346,43-R-011) to closely recapitulate human SBS. Proof of Concept: We have published that in animals on TPN without bowel resection (and not receiving EN), treatment with gut FXR agonist, Chenodeoxycholic acid (CDCA) or gut TGR5 agonist Oleanolic Acid (OA), as well as intravenous FGF19 and GLP-1/GLP-2 can prevent liver and gut injury. Importantly, we have shown inadequate gut FXR and gut TGR5 activation and decreased FGF19, GLP-1/GLP-2 in SBS animals. In pilot studies we have noted hepatic and gut protection with CDCA and OA treatment in SBS. Thus, our central premise is to critically understand alteration in gut FXR and gut TGR5 driven signaling in SBS and to test if its restoration in SBS animals mitigates injury. As detailed in the research plan, we will test our hypothesis under the following aims. With Aim 1 we will critically test the roles of intravenous FGF19 and the gut FXR agonist, CDCA on liver injury in SBS. We will analyze serum, histology, key receptors, and transporters along the FXR-FGF19 axis to understand mechanistic links. With Aim 2 we will deliver the gut TGR5 agonist, OA as well as GLP-1/GLP-2 in SBS animals and explore TGR5-GLP axis driven protective mechanisms in SBS, assessing serology, histology, gut trophic factors, morphometrics and gene expression. This project, using a highly translatable SBS model will help advance strategies to mitigate serious complications and provide key insights into drivers of injury in SBS.

项目概要/摘要 肠切除会导致短肠综合症（SBS）的破坏性病症。 SBS 患者不能 由于肠道不足，需要通过定期肠内营养（EN）来维持营养。此类患者，在 缺乏 EN，需要通过称为全肠外营养 (TPN) 的过程进行静脉营养才能生存。 在世界范围内，数以万计的患者需要 TPN。尽管 TPN 可挽救生命，但 SBS​​ 的副作用包括 潜在致命的肝脏和肠道损伤。尽管许多研究人员都将注意力集中在了 TPN 的组成部分，我们发表的研究结果强调了我们的新假设，即管腔状态 SBS 中的内容剥夺会破坏正常的肠道衍生信号并驱动 SBS 中的损伤机制。 我们发表的数据显示，在 EN 期间，作为胆汁酸 (BA) 正常肠肝循环的一部分， BA 激活肠道法尼醇 X 受体 (FXR)，导致成纤维细胞生长因子 19 (FGF19) 的释放。 FGF19 调节肝脏 BA、胆汁淤积、脂质和葡萄糖稳态。由于缺乏肠道 FXR 激活 在 SBS 中，我们假设 FXR-FGF19 信号轴受损。我们还发布了 BA 通过增强胰高血糖素样肽 (GLP) 来预防肠道萎缩。 GLP 通过 BA 激活的肠道进行调节 受体TGR5。而GLP-2是一种肠道营养因子； GLP-1 调节肝脂肪变性、胰岛素和葡萄糖。 我们假设 SBS 中肠道 TGR5 激活不足还会导致肝脏和肠道损伤。 新颖模型：我们使用微型泵建立了一种新颖的不受束缚的可移动 SBS 仔猪模型， 颈静脉导管和十二指肠导管，以及外科肠切除术 (SLU#2346,43-R-011)，以密切概括 人类SBS。概念验证：我们已经在未进行肠切除（且未进行肠切除）的 TPN 动物中发表了这一结论 接受 EN），用肠道 FXR 激动剂、鹅去氧胆酸 (CDCA) 或肠道 TGR5 激动剂齐墩果酸治疗 酸 (OA) 以及静脉注射 FGF19 和 GLP-1/GLP-2 可以预防肝脏和肠道损伤。重要的是，我们 已显示 SBS 中肠道 FXR 和肠道 TGR5 激活不足，FGF19、GLP-1/GLP-2 减少 动物。在试点研究中，我们注意到 SBS 中 CDCA 和 OA 治疗对肝脏和肠道的保护作用。 因此，我们的中心前提是批判性地理解肠道 FXR 和肠道 TGR5 驱动信号的改变 SBS 并测试其在 SBS 动物中的恢复是否可以减轻伤害。正如研究计划中详细说明的那样，我们将测试 我们的假设基于以下目标。在目标 1 中，我们将严格测试静脉注射 FGF19 和 肠道FXR激动剂CDCA对SBS肝损伤的影响。我们将分析血清、组织学、关键受体和 沿 FXR-FGF19 轴的转运蛋白以了解机械联系。通过目标 2，我们将提供肠道 TGR5 激动剂、OA 以及 GLP-1/GLP-2 在 SBS 动物中的作用，并探索 TGR5-GLP 轴驱动的保护作用 SBS 机制，评估血清学、组织学、肠道营养因子、形态计量学和基因表达。 该项目使用高度可翻译的 SBS 模型，将有助于推进缓解严重问题的策略 并发症并提供对 SBS 损伤驱动因素的重要见解。