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.

项目摘要 /摘要 肠切除导致短肠综合征（SBS）的毁灭性状况。 SBS患者不能 由于肠道不足，通过常规肠内营养（EN）维持营养。这样的患者在 缺乏EN，需要通过称为总肠胃外营养（TPN）的过程进行静脉营养才能生存。 全球，成千上万的患者需要TPN。尽管救生TPN，但SBS中的副作用包括 潜在的致命肝脏和肠道损伤。虽然，许多研究人员专注于 TPN的成分是我们发表的研究的结果，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。 我们已发表的数据表明，在EN期间，作为正常肠肝循环的一部分，胆汁酸（BA）， 通过BA激活肠道Farnesoid X受体（FXR）会导致成纤维细胞生长因子19（FGF19）的释放。 FGF19调节肝BA，胆汁淤积，脂质和葡萄糖稳态。由于缺乏肠道FXR激活 在SB中，我们假设FXR-FGF19信号轴受损。我们还发表了BA 通过增强胰高血糖素（如肽（GLP））来预防肠道萎缩。通过BA激活的肠道调节GLP 受体TGR5。而GLP-2是肠道营养因子； GLP-1调节肝脂肪变性，胰岛素和葡萄糖。 我们假设SBS中的肠道TGR5激活不足另外驱动肝脏和肠道损伤。 新型模型：我们使用微型泵建立了一种新型的不受限制的非卧床SBS小猪模型， 颈和十二指肠导管，以及手术肠切除（SLU＃2346,43-R-011），以密切概括 人类SB。概念证明：我们已经发表了在没有肠切除的情况下在TPN的动物中发表的（而不是 接受EN），用肠道FXR激动剂，氯氧化节胆酸（CDCA）或肠道TGR5激动剂蛋白粉的治疗 酸（OA）以及静脉内FGF19和GLP-1/GLP-2可以防止肝脏和肠道损伤。重要的是，我们 已经显示出不足的肠道FXR和肠道TGR5激活，并减少了FGF19，SBS中的GLP-1/GLP-2 动物。在试点研究中，我们注意到SBS中使用CDCA和OA处理的肝和肠道保护。 因此，我们的中心前提是批判性地了解肠道FXR和肠道TGR5驱动的信号的改变 SBS并测试其在SBS动物中的恢复是否会减轻伤害。正如研究计划中详细介绍的，我们将测试 我们的假设在以下目的下。使用AIM 1，我们将批判性地测试静脉内FGF19和 肠道FXR激动剂，CDCA关于SBS的肝损伤。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理链接。使用AIM 2，我们将交付肠道 SBS动物中的TGR5激动剂，OA以及GLP-1/GLP-2并探索TGR5-GLP轴驱动保护性保护性 SBS中的机制，评估血清学，组织学，肠道营养因子，形态图和基因表达。 该项目使用高度可翻译的SBS模型将有助于提高策略以减轻严重 并发症并为SBS损伤驱动因素提供关键见解。