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

项目摘要/摘要 肠切除会导致短肠综合征(SBS)的破坏性状况。SBS患者不能 由于肠道不足，通过常规肠内营养(EN)来维持营养。这样的病人，在 缺乏肠外营养，需要通过一种称为完全肠外营养(TPN)的过程进行静脉营养才能存活。 在世界范围内，数以万计的患者需要TPN。尽管TPN挽救了生命，但SBS的副作用包括 可能致命的肝脏和肠道损伤。尽管如此，许多研究人员已经把重点放在了 TPN的成分，我们发表的研究结果强调了我们的新假设，即流明状态 SBS中的内容剥夺，扰乱了正常的肠源性信号，并推动了SBS的损伤机制。 我们发表的数据表明，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、血脂和血糖的稳态。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 通过增加胰升糖素样肽(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调节肝脏脂肪变性、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。 新模型：我们利用微型泵建立了一种新的不拴系的可卧床SBS仔猪模型。 颈静脉和十二指肠导管和外科肠道切除术(SLU#2346，43-R-011) 人类SBS。概念验证：我们已经在没有肠切除的TPN动物身上发表了这一结果(并且没有 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可预防肝脏和肠道损伤。重要的是，我们 显示SBS患者肠道FXR和肠道TGR5激活不足，FGF19、GLP-1/GLP-2降低 动物。在初步研究中，我们注意到在SBS中，CDCA和OA治疗对肝脏和肠道具有保护作用。 因此，我们的中心前提是批判性地理解肠道FXR和肠道TGR5驱动的信号转导在 并测试在SBS动物身上恢复SBS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 我们的假设有以下几个目的。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肝损伤的治疗作用我们将分析血清、组织学、关键受体和 沿FXR-FGF19轴的运输器，以了解机械连接。在《目标2》中，我们将交付胆量 TGR5激动剂、OA以及GLP-1/GLP-2在SBS动物中的表达及TGR5-GLP轴驱动保护作用的探讨 SBS的机制，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，以缓解严重的 并提供了对SBS损伤的驱动因素的关键见解。

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.