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: 10433531
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433531
• 关键词: Address; Aliquot; Animal Model; Animal Nutrition; Animals; Atrophic; Automobile Driving; Bacteroidetes; Bile Acid Biosynthesis Pathway; Bile Acids; Bilirubin; Catheters; Cholestasis; 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; Ligands; Lipids; Liver; Liver diseases; Measures; Messenger RNA; Metagenomics; Modeling; Monitor; Nutritional; Operative Surgical Procedures; Pathology; Pathway Analysis; 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; insight; liver injury; microbial; microbiota; microbiota transplantation; novel; nutrition; porcine model; prevent; receptor; restoration; serological marker; side effect; Address; Aliquot; Animal Model; Animal Nutrition; Animals; Atrophic; Automobile Driving; Bacteroidetes; Bile Acid Biosynthesis Pathway; Bile Acids; Bilirubin; Catheters; Cholestasis; 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; Ligands; Lipids; Liver; Liver diseases; Measures; Messenger RNA; Metagenomics; Modeling; Monitor; Nutritional; Operative Surgical Procedures; Pathology; Pathway Analysis; 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; 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 肠综合征短的患者（SBS）需要通过称为Total的过程进行静脉营养 肠胃外营养（TPN），因为它们无法通过定期的肠内营养（EN）来维持营养需求 肠道不足。全球，成千上万的患者需要TPN。不幸的是，SBS中的副作用 包括潜在的致命肝和可能多因素病因的肠道损伤。 尽管许多先前的研究都集中在TPN构成的可能有害影响上 相反，我们假设了新的假设，即在SBS中发生的腔内含量剥夺状态变化 肠道系统信号驱动损伤机制。使用新型的卧床进一步分析这些途径 我们开发的SBS小猪模型，该模型概括了人类SBS（SLU＃2346,43-R-011），我们已经显示了肠道 SBS中的微生物变化，细菌植物门的显着增加并减少了公司。 门以及明显的亚系统变化。相关，在SB中，我们也发表了 肠道保护成纤维细胞生长因子19（FGF19）的合成，肠道farnesoid x继发于不足 受体（FXR）激活和肠道生长马的降低，胰高血糖素像胡椒粉 - 2（GLP-2） 缺乏肠受体TGR5激活。实际上，在正常的肠球皮循环中，原发性胆汁酸（FXR） 配体），由肝脏合成的肠道转化为二胆酸（TGR5配体）由肠道 因此，微生物群，因此我们突出了一种新型机制，肠道微生物调节胆汁酸信号传导 性质，从而改变SBS的损伤进程。这就是我们注意到的，肠道菌群改变的 在SBS驱动损伤中的重要作用，并假设其在SBS动物中恢复了肠道菌群 从EN动物获得的移植（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中肝病和肠道损伤的缓解，证明其治疗作用。 如研究计划所述；使用AIM 1，我们将测试严格监控IMT对SB的影响 并评估肠道损伤。我们将使用独立于培养 靶向扩增子测序和shot弹枪宏基因组学，评估血清肠损伤标记，组织学和 执行肠道形态分析以获得机理见解。 AIM 2与评估IMT的影响有关 SBS肝损伤。因此，我们将评估肝损伤血清学标记，肝毒性细胞因子谱和 肝组织学评估IMT的影响。 AIM 3将专注于理解肠道系统的机制 SBS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，以获得对微生物调节剂的见解 及其造成SBS损伤的机制。 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 并发症并提供对SBS损伤损伤调制的微生物驱动调制的关键见解。