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
基本信息
- 批准号:10580044
- 负责人:
- 金额:$ 21.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAliquotAnimal ModelAnimal NutritionAnimalsAtrophicAutomobile DrivingBacteroidetesBile Acid Biosynthesis PathwayBile AcidsBilirubinCathetersCholestasisClassificationDataDependenceDistalDuodenumDyslipidemiasEnteral FeedingEnteral NutritionEnterohepatic CirculationEtiologyExcisionFGF19 geneFailureFecesFibroblast Growth Factor ReceptorsFirmicutesG-Protein-Coupled ReceptorsGLP-2GPBAR1 geneGlucose IntoleranceGut MucosaHepaticHepatobiliaryHepatotoxicityHistologyHumanInflammationInflammatoryInjuryIntestinal permeabilityIntestinesIntravenousLifeLigandsLipidsLiverLiver diseasesMeasuresMessenger RNAMetagenomicsModelingMonitorNutritionalOperative Surgical ProceduresPathologyPathway interactionsPatientsPlayPopulation ControlProcessPropertyPublishingPumpReceptor ActivationResearchRodentRoleScheduleSecondary toSerologyShort Bowel SyndromeShotgunsSignal TransductionSignaling MoleculeSomatotropinSystemTestingTherapeuticTotal Parenteral NutritionVillouscytokinedeprivationglucagon-like peptidegut microbesgut microbiotahepatoprotectiveimprovedinsightliver injurymicrobialmicrobiotamicrobiota transplantationnovelnutritionporcine modelpreventreceptorrestorationserological markerside effect
项目摘要
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
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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,
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Ajay K. Jain其他文献
859 BILIARY ATRESIA THROUGH TARGETED ENDOTHELIAL DESTRUCTION (BATTED) PRESENTS A NOVEL LARGE ANIMAL MODEL, RECAPITULATING HUMAN DISEASE
- DOI:
10.1016/s0016-5085(24)04045-9 - 发表时间:
2024-05-18 - 期刊:
- 影响因子:
- 作者:
Kento Kurashima;Arun Verma;Si-Min Park;Marzena Swiderska-Syn;Sree L. Kolli;David J. Gosser;Jasmine Carter;Shaurya Mehta;Austin Sims;Jeffrey Teckman;Mustafa Nazzal;John Long;Chandrashekhara Manithody;Shin Miyata;Ajay K. Jain - 通讯作者:
Ajay K. Jain
Thrombus Entrapment by a Novel Mesh-Covered Stent in ST-Segment Elevation Myocardial Infarction
- DOI:
10.1016/j.jacc.2011.01.079 - 发表时间:
2011-11-22 - 期刊:
- 影响因子:
- 作者:
Ajay K. Jain;Martin T. Rothman - 通讯作者:
Martin T. Rothman
Bacterial skin infections in cirrhotics
- DOI:
10.1016/j.jceh.2013.02.221 - 发表时间:
2013-03-01 - 期刊:
- 影响因子:
- 作者:
Mayank Jain;Ajay K. Jain;Shohini Sircar;Chandrashekhar Waghmare;Sagar Adkar - 通讯作者:
Sagar Adkar
Increased morbidity in acute viral hepatitis with glucose-6-phosphate dehydrogenase deficiency
- DOI:
10.1007/s12664-012-0226-9 - 发表时间:
2012-08-07 - 期刊:
- 影响因子:2.100
- 作者:
Ajay K. Jain;Shohini Sircar;Mayank Jain;Sagar Adkar;Chandrashekhar Waghmare;Fatema Chahwala - 通讯作者:
Fatema Chahwala
Kinetics of n-propylaminolysis of some oxime ethers in 1:1 aqueous acetonitrile
- DOI:
10.1007/bf02069217 - 发表时间:
1987-03-01 - 期刊:
- 影响因子:1.700
- 作者:
Ajay K. Jain;V. K. Velu;K. N. Sarma - 通讯作者:
K. N. Sarma
Ajay K. Jain的其他文献
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{{ truncateString('Ajay K. Jain', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 21.4万 - 项目类别:
Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome
胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用
- 批准号:
10683281 - 财政年份:2021
- 资助金额:
$ 21.4万 - 项目类别:
Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome
胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用
- 批准号:
10343091 - 财政年份:2021
- 资助金额:
$ 21.4万 - 项目类别:
Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome
胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用
- 批准号:
10491865 - 财政年份:2021
- 资助金额:
$ 21.4万 - 项目类别:
Role of gut microbiota in total parenteral nutrition associated injury
肠道微生物群在全肠外营养相关损伤中的作用
- 批准号:
9910396 - 财政年份:2019
- 资助金额:
$ 21.4万 - 项目类别:
Role of the bile acid activated receptors FXR and TGR5 in Total Parenteral Nutrition associated hepatic and gut disease
胆汁酸激活受体 FXR 和 TGR5 在全肠外营养相关肝脏和肠道疾病中的作用
- 批准号:
10390680 - 财政年份:2016
- 资助金额:
$ 21.4万 - 项目类别:
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