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
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
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
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
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
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
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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