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

项目概要/摘要 肠切除导致短肠综合征（SBS）的破坏性条件。SBS患者不能 由于肠道不足，通过定期肠内营养（EN）维持营养。这样的病人，在 没有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，成千上万的患者需要TPN。尽管有救命的TPN，SBS的副作用包括 可能致命的肝脏和肠道损伤虽然，许多研究人员都集中在有害影响的 TPN的成分，我们发表的研究结果强调了我们的新假设，即管腔的状态 SBS中的内容剥夺，破坏了正常的肠道来源的信号，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对肠法尼醇X受体（FXR）的激活导致成纤维细胞生长因子19（FGF 19）的释放。 FGF 19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SBS中，我们假设FXR-FGF 19信号传导轴受损。我们还公布了BA 通过增强胰高血糖素样肽（GLP）预防肠道萎缩。GLP通过BA激活的肠道调节 受体TGR 5。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TGR 5活化不足还导致肝脏和肠道损伤。 新模型：我们使用微型泵建立了一种新的非拴系行走SBS仔猪模型， 颈静脉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：我们已经发表了在没有肠切除的TPN动物中（并且没有 接受EN），用肠道FXR激动剂、鹅去氧胆酸（CDCA）或肠道TGR 5激动剂Oleurate治疗 酸（OA）以及静脉内FGF 19和GLP-1/GLP-2可以预防肝脏和肠道损伤。重要的是我们 显示SBS中肠道FXR和肠道TGR 5活化不足以及FGF 19、GLP-1/GLP-2降低 动物在初步研究中，我们注意到SBS中CDCA和OA治疗的肝脏和肠道保护作用。 因此，我们的中心前提是批判性地理解肠道FXR和肠道TGR 5驱动的信号传导的改变， SBS并测试其在SBS动物中的恢复是否减轻损伤。正如研究计划中详细说明的那样，我们将测试 我们的假设在以下目标。在Aim 1中，我们将严格测试静脉注射FGF 19的作用， 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， 运输者沿着FXR-FGF 19轴了解机械联系。通过Aim 2，我们将提供肠道 TGR 5激动剂、OA以及GLP-1/GLP-2在SBS动物中的作用，并探讨TGR 5-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，将有助于推进战略， 并发症，并提供了关键的见解，在SBS损伤的驱动程序。

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.