A systems-level approach to probe the effect of a high- fat/high-protein diet in Clostridioides difficile infection

探讨高脂肪/高蛋白饮食对艰难梭菌感染影响的系统级方法

基本信息

  • 批准号:
    10515273
  • 负责人:
  • 金额:
    $ 44.73万
  • 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:
    2022-07-13 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Clostridioides (formerly Clostridium) difficile infection (CDI) is the leading cause of healthcare-associated and antibiotic-associated infections in all age groups in North America. In the U.S., there are ~500,000 cases of CDI annually, and over 25,000 deaths per year are attributed to CDI. CDI prevention and treatment costs the healthcare system an estimated $6.3 billion/year. The predominant risk factor for CDI is the use of broad-spectrum antibiotics and can be directly attributed to disruption of the intestinal microbiome. Diet also exerts strong controls on the structure and function of the gut microbiome; however, the role of diet in CDI risk and severity is not well understood. Existing reports are contradictory regarding the effects of diet on CDI. We have conducted initial experiments on the effect of diet on CDI using a mouse model of antibiotic-associated CDI. Strikingly, our studies showed that mice fed a high-fat/high-protein, Atkins-like diet suffered 100% mortality, whereas mice fed a high-carbohydrate diet developed few or no signs of disease. In this proposal, we will test the hypothesis that a combination of host and pathogen responses to a high-fat/high-protein diet, within the context of a depleted microbiome, together promote an environment conducive to C. difficile pathogenesis. In Specific Aim 1, we will determine whether the high-fat/high-protein diet, alone or in combination with antibiotics, induces inflammation and increased intestinal permeability prior to exposure to C. difficile. We will also document changes in lumen metabolites and assess CDI severity and mortality compared to an improved matched- ingredient, high-carbohydrate diet. In Specific Aim 2, we will probe the structure and function of the microbiome using both metagenomics and metatranscriptomics at each stage of the experiment (diet only, diet plus antibiotics, diet plus antibiotics and CDI) to explore the hypothesis that antibiotic treatment leads to the absence of a few specific competitors for amino acids that leads to an open niche for C. difficile overgrowth. We will also specifically examine relationships between the C. difficile transcriptome and changes in metabolite pools to delineate two different metabolic states that define CDI outcome, leading to either fulminant CDI and mortality and an asymptomatic carrier state. As a result of this project, we will have a better understanding of the influence of diet, particularly high-fat/high-protein diets, on the host and microbiome and how these diets mediate fulminant CDI. A positive impact would eventually be better management of diet in high-risk individuals, especially during antibiotic treatments, and possible pre- or probiotics for CDI. 1
项目摘要 艰难梭菌(Clostridioides)(以前称为Clostridium difficile)感染(CDI)是医疗保健相关和 在北美所有年龄组中的疟疾相关感染。在美国,大约有50万例CDI 每年有超过25,000人死于CDI。CDI预防和治疗费用 医疗保健系统估计每年63亿美元。 CDI的主要危险因素是使用广谱抗生素,可直接归因于 破坏肠道微生物组。饮食也对肠道的结构和功能施加强有力的控制 然而,饮食在CDI风险和严重程度中的作用尚不清楚。现有的报告是 关于饮食对CDI的影响,存在矛盾。 我们已经使用小鼠模型进行了关于饮食对CDI的影响的初步实验, CDI.引人注目的是,我们的研究表明,喂食高脂肪/高蛋白,阿特金斯式饮食的小鼠死亡率为100%, 而喂食高碳水化合物饮食的小鼠很少或没有疾病迹象。在本提案中,我们将测试 假设宿主和病原体对高脂肪/高蛋白饮食的反应, 在微生物组耗竭的背景下,共同促进有利于C.难治性发病机制在 具体目标1,我们将确定高脂肪/高蛋白饮食,单独或与抗生素联合, 在暴露于C.很难我们还将记录 管腔代谢物的变化,并评估CDI的严重程度和死亡率, 高碳水化合物饮食。在具体目标2中,我们将探索微生物组的结构和功能 在实验的每个阶段使用宏基因组学和元转录组学(仅饮食,饮食加 抗生素,饮食加抗生素和CDI),以探讨抗生素治疗导致缺乏 一些特定的氨基酸竞争者,导致C.艰难的过度生长我们还将 具体考察了C.艰难梭菌转录组和代谢物池的变化, 描述两种不同的代谢状态,定义CDI结果,导致暴发性CDI和死亡率 和无症状携带者状态。由于这个项目,我们将有一个更好的了解的影响, 饮食,特别是高脂肪/高蛋白饮食对宿主和微生物组的影响,以及这些饮食如何介导暴发性疾病 CDI.一个积极的影响最终将是更好地管理高风险个体的饮食,特别是在 抗生素治疗和可能的前体或益生菌用于CDI。 1

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Brian P Hedlund其他文献

Brian P Hedlund的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Brian P Hedlund', 18)}}的其他基金

Novel Repair Replicase
新颖的修复复制酶
  • 批准号:
    10323823
  • 财政年份:
    2021
  • 资助金额:
    $ 44.73万
  • 项目类别:

相似海外基金

Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
  • 批准号:
    2300890
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Continuing Grant
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
  • 批准号:
    2888395
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
    Studentship
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
  • 批准号:
    10761044
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
  • 批准号:
    10728925
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
  • 批准号:
    10757309
  • 财政年份:
    2023
  • 资助金额:
    $ 44.73万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了