Role of intestinal microbiota in driving injury mechanisms in short bowel syndrome

肠道微生物群在驱动短肠综合征损伤机制中的作用

• 批准号: 10580044
• 负责人: Ajay K. Jain
• 金额: $ 21.4万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-25 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580044
• 关键词: Address; Aliquot; Animal Model; Animal Nutrition; Animals; Atrophic; Automobile Driving; Bacteroidetes; Bile Acid Biosynthesis Pathway; Bile Acids; Bilirubin; Catheters; Cholestasis; Classification; Data; Dependence; Distal; Duodenum; Dyslipidemias; Enteral Feeding; Enteral Nutrition; Enterohepatic Circulation; Etiology; Excision; FGF19 gene; Failure; Feces; Fibroblast Growth Factor Receptors; Firmicutes; G-Protein-Coupled Receptors; GLP-2; GPBAR1 gene; Glucose Intolerance; Gut Mucosa; Hepatic; Hepatobiliary; Hepatotoxicity; Histology; Human; Inflammation; Inflammatory; Injury; Intestinal permeability; Intestines; Intravenous; Life; Ligands; Lipids; Liver; Liver diseases; Measures; Messenger RNA; Metagenomics; Modeling; Monitor; Nutritional; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Play; Population Control; Process; Property; Publishing; Pump; Receptor Activation; Research; Rodent; Role; Schedule; Secondary to; Serology; Short Bowel Syndrome; Shotguns; Signal Transduction; Signaling Molecule; Somatotropin; System; Testing; Therapeutic; Total Parenteral Nutrition; Villous; cytokine; deprivation; glucagon-like peptide; gut microbes; gut microbiota; hepatoprotective; improved; insight; liver injury; microbial; microbiota; microbiota transplantation; novel; nutrition; porcine model; prevent; receptor; restoration; serological marker; side effect

PROJECT SUMMARY / ABSTRACT Patients with Short Bowel Syndrome (SBS) require intravenous nutrition via a process called Total Parenteral Nutrition (TPN) as they cannot sustain nutritional needs through regular enteral nutrition (EN) due to insufficient intestines. Worldwide, tens of thousands of patients require TPN. Unfortunately, side effects in SBS include potentially fatal liver and gut injury from a likely multifactorial etiology. While many prior studies have focused on the possible detrimental effects induced by TPN constituents, we instead postulate the novel hypothesis that the state of luminal content deprivation as occurring in SBS alters gut-systemic signals driving injury mechanisms. Further analyzing these pathways, using a novel ambulatory SBS piglet model developed by us, which recapitulates human SBS (SLU#2346,43-R-011), we have shown gut microbial shifts in SBS with a significant increase in the Bacteroidetes phylum and decrease in the Firmicutes phylum as well as significant sub phylum changes. Pertinently, in SBS we have also published decreased synthesis of hepato-protective Fibroblast Growth Factor 19 (FGF19) secondary to inadequate gut Farnesoid X Receptor (FXR) activation and a decrease in the gut growth hormone, glucagon like peptide – 2 (GLP-2) due to a lack of gut receptor TGR5 activation. Indeed, during normal enterohepatic circulation, primary bile acids (FXR ligands), synthesized by the liver undergo transformation to secondary bile acids (TGR5 ligands) by the gut microbiota and thus we highlight a novel mechanism by which gut microbes modulate bile acid signaling properties and thus alter the course of injury in SBS. Thus, we note that an altered gut microbiota, has a prominent role in driving injury in SBS and hypothesize that its restoration in SBS animals by intestinal microbiota transplant (IMT), obtained from EN animals, will mitigate injury. Using our model, as proof of concept, we have noted mitigation of hepatic and gut injury in SBS upon IMT, attesting to its therapeutic role. As detailed in the research plan; with Aim 1 we will test the impact of rigorously monitored IMT to SBS and evaluate gut injury. We shall objectively classify and quantify stool microbiota using culture-independent targeted amplicon sequencing and shotgun metagenomics, assess serological gut injury markers, histology and perform gut morphometric analysis to gain mechanistic insights. Aim 2 relates to assessing the impact of IMT in SBS on hepatic injury. We will thus assess liver injury serological markers, hepato-toxic cytokine profiles and liver histology to assess impact of IMT. Aim 3 will focus on understanding mechanisms along the gut-systemic signaling axis driving injury in SBS. We will evaluate key hepatobiliary receptors, transporters and signaling molecules along the FXR-FGF19 and TGR5-GLP-2 gut-systemic axis to gain insights into microbial modulators and their mechanisms driving SBS injury. This project, using a highly translatable SBS model will help advance strategies to mitigate serious complications and provide critical insights into microbiota driven modulation of injury in SBS.

项目摘要/摘要 短肠综合征(SBS)患者需要通过一种名为Total的过程进行静脉营养 肠外营养(TPN)，因为由于以下原因，他们无法通过常规肠内营养(EN)维持营养需求 肠子不足。在世界范围内，数以万计的患者需要TPN。不幸的是，SBS的副作用 包括可能由多因素引起的可能致命的肝脏和肠道损伤。 虽然之前的许多研究都集中在TPN成分可能产生的有害影响上， 相反，我们提出了新的假设，即SBS中发生的管腔内容物剥夺状态发生了变化 肠道系统信号驱动损伤机制。进一步分析这些路径，使用一种新的移动设备 我们开发的SBS仔猪模型，概括了人类SBS(SLU#2346，43-R-011)，我们已经展示了肠道 SBS中微生物的迁移：类杆菌门显著增加，菌丝减少 门以及显著的亚门的变化。与之相关的是，在SBS中，我们也发表了减少 继发于肠道法尼醇X不足的肝保护性成纤维细胞生长因子19的合成 受体(FXR)激活和肠道生长激素、胰高血糖素样肽-2(GLP-2)减少 缺乏肠道受体TGR5的激活。事实上，在正常的肠-肝循环期间，初级胆汁酸(FXR) 由肝脏合成的TGR5配体通过肠道转化为次级胆汁酸(TGR5配体 微生物区系，因此我们强调了肠道微生物调节胆汁酸信号的新机制 性质，从而改变SBS的损伤过程。因此，我们注意到，改变的肠道微生物区系具有 SBS中驱动损伤的重要作用及肠道微生物群对SBS动物恢复的假说 从EN动物身上获取的移植(IMT)将减轻损伤。使用我们的模型，作为概念的证明，我们有 注意到SBS对IMT的肝脏和肠道损伤的缓解，证明了它的治疗作用。 如研究计划中所述，我们将在目标1中测试严格监控IMT对SBS的影响 并评估肠道损伤情况。我们将使用非培养的方法对粪便微生物区系进行客观分类和量化。 靶向扩增子测序和鸟枪式元基因组学，评估血清肠道损伤标志物，组织学和 进行肠道形态测量分析以获得机械性的洞察。目标2涉及评估IMT的影响 SBS对肝损伤的影响。因此，我们将评估肝损伤血清标志物，肝毒性细胞因子谱和 肝组织学检查以评估IMT的影响。目标3将侧重于了解肠道系统的机制 SBS中的信号轴驱动损伤。我们将评估关键的肝胆受体、转运体和信号 FXR-FGF19和TGR5-GLP-2肠道系统轴上的分子以深入了解微生物调节剂 及其导致SBS损伤的机制。 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 并为SBS中微生物区系驱动的损伤调节提供了关键的见解。

项目成果

The Effect of a Merit Point Incentive System on the Willingness to Donate Organs.

功绩点激励制度对器官捐献意愿的影响。

• DOI: 10.1016/j.transproceed.2023.09.023
• 发表时间: 2023
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Nazzal,Mustafa;Engelhardt,Annabel;Hallcox,Taylor;VanGorp,Luke;Parrish,Paul;Okeke,Raymond;Kumanan,Krithika;Buchanan,Paula;Schnitzler,Mark;Rub,FadeeAbuAl;Caliskan,Yasar;Shacham,Enbal;Fleetwood,Vidyaratna;Lentine,KristaL;Jain,
• 通讯作者: Jain,