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.

项目概要/摘要 短肠综合症 (SBS) 患者需要通过称为 Total 的过程进行静脉营养 肠外营养（TPN），因为他们无法通过常规肠内营养（EN）来维持营养需求，因为 肠子不够。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 包括可能由多因素病因引起的潜在致命的肝脏和肠道损伤。 虽然许多先前的研究都集中在 TPN 成分可能引起的有害影响上， 相反，我们假设新的假设，即 SBS 中发生的管腔内容剥夺状态会改变 肠道系统信号驱动损伤机制。使用新型流动装置进一步分析这些途径 我们开发的 SBS 仔猪模型，再现了人类 SBS (SLU#2346,43-R-011)，我们展示了肠道 SBS 中的微生物变化，拟杆菌门显着增加，厚壁菌门减少 门以及显着的亚门变化。相应地，在SBS我们也发布了减少的 肠道 Farnesoid X 不足继发的保肝性成纤维细胞生长因子 19 (FGF19) 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 激活。事实上，在正常的肠肝循环过程中，初级胆汁酸（FXR 配体），由肝脏合成，经过肠道转化为次级胆汁酸（TGR5 配体） 微生物群，因此我们强调肠道微生物调节胆汁酸信号传导的新机制 特性，从而改变 SBS 的损伤过程。因此，我们注意到肠道微生物群的改变，具有 在 SBS 损伤中发挥重要作用，并假设肠道微生物群可在 SBS 动物中恢复损伤 从 EN 动物身上获得的移植物 (IMT) 将减轻损伤。使用我们的模型作为概念证明，我们有 注意到 IMT 后 SBS 减轻了肝脏和肠道损伤，证明了其治疗作用。 如研究计划中详细说明；通过目标 1，我们将测试严格监控的 IMT 对 SBS 的影响 并评估肠道损伤。我们将使用独立于培养物的方法客观地对粪便微生物群进行分类和量化 靶向扩增子测序和鸟枪法宏基因组学，评估血清学肠道损伤标记物、组织学和 进行肠道形态测量分析以获得机制见解。目标 2 涉及评估 IMT 对 SBS 关于肝损伤。因此，我们将评估肝损伤血清学标志物、肝毒性细胞因子谱和 肝脏组织学评估 IMT 的影响。目标 3 将侧重于了解肠道系统机制 SBS 中的信号轴驱动损伤。我们将评估关键的肝胆受体、转运蛋白和信号传导 沿 FXR-FGF19 和 TGR5-GLP-2 肠道系统轴的分子，以深入了解微生物调节剂 及其驱动 SBS 损伤的机制。 该项目使用高度可翻译的 SBS 模型，将有助于推进缓解严重问题的策略 并发症，并为微生物群驱动的 SBS 损伤调节提供重要见解。

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,