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

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

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

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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