Interactions of dietary protein intake and intestinal resident microbiota affecting susceptibility to persistent Giardia infection and Giardia mediated enteropathy

膳食蛋白质摄入量和肠道常驻微生物群的相互作用影响对持续性贾第虫感染和贾第虫介导的肠病的易感性

• 批准号: 10267765
• 负责人: Luther A Bartelt
• 金额: $ 59.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267765
• 关键词: Address; Affect; Animal Model; Animals; Antibiotics; Aromatic Amino Acids; Attenuated; B-Lymphocytes; Bacteria; Bacterial Infections; Bile Acids; Bile fluid; Body Weight decreased; Cellular Immunity; Child; Child Development; Child Health; Chronic; Clinical; Communities; Complex; Cresol; Data; Development; Diarrhea; Diet; Dietary Proteins; Disease; Disease Pathway; Environment; Enzymes; Epithelial; Family; Functional disorder; Germ-Free; Giardia; Giardia lamblia; Gnotobiotic; Growth; Health; Host Defense; Human; Immunity; Immunocompetent; Impairment; Individual; Infection; Inflammation; Injury; Intestinal permeability; Intestines; Lactobacillus; Lamina Propria; Lead; Life; Malnutrition; Mediating; Metabolic; Metabolism; Metagenomics; Microbe; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Nutrient; Oral; Outcome; Parasites; Parasitic infection; Pathogenesis; Pathogenicity; Pathway interactions; Permeability; Physiology; Predisposition; Protein Deficiency; Proteins; Proteolysis; Public Health; Reducing diet; Research; Risk; Role; Secondary to; Small Intestines; Symptoms; T-Lymphocyte; Testing; Therapeutic; Toxin; Transplantation; Tyrosine; Weaning; acute infection; adaptive immunity; bacterial community; base; bile acid metabolism; bile salts; chronic infection; clinically relevant; deprivation; dietary; enteric infection; enteric pathogen; gut health; gut microbiota; improved; innovation; intestinal barrier; metabolomics; microbial; microbial community; microbiota; mouse model; normal microbiota; novel; novel marker; nutrition; pathogen; prevent; protein intake

PROJECT SUMMARY Giardia lamblia belongs to a group of gut pathogens associated with impaired child development and gut function, especially in children with inadequate nutrition. Although most Giardia infections in these children are clinically silent, Giardia may lead to longterm detriments. For reasons that are unknown, many of these children cannot clear the parasite. Further, infected children may be at risk for gut dysfunction as a result of Giardia infection, even if they are asymptomatic. We hypothesize that susceptibility to Giardia and subsequent disease result from a change in the resident intestinal microbial community as a consequence of low dietary protein. Animal models provide an opportunity to dissect how an individual pathogen like Giardia impacts early life intestinal health, and a model to understand mechanisms whereby specific nutrients support host defenses and physiology. The objective of this proposal is to use our novel mouse models of Giardia infection in a state-of-the-art environment where we can define and control for all microbial exposures in the gut (gnotobiotics). We will combine our gnotobiotics expertise with expertise in microbial metagenomics and metabolomics for a rigorous examination of how dietary influences exert a functional change in the complex community or resident intestinal microbes. In Aim 1, we will determine how resident intestinal microbes normally protect against persistent Giardia infection by transferring intestinal microbes from a well-nourished animal into susceptible hosts, and vice versa transferring permissive microbes from hosts with chronic infection into nourished mice. We will specifically examine whether the ability of microbes to metabolize bile acids are key to protection against Giardia infection, and whether microbes are necessary for effective immunity. In Aim 2, we will determine how Giardia and protein deficiency synergize to cause intestinal barrier dysfunction. Our model has a clinically relevant outcome of growth restriction and loss of intestinal barrier function during the combined insult of limited protein intake and Giardia infection. We will use our gnotobiotic model to generate metagenomic and metabolomic data that will identify pathogenic shifts in microbial communities during Giardia infection. We will specifically elucidate the role of aromatic amino acid metabolites and bile acids on gut function in the protein deficient state, as well as whether Giardia promotes pathogenic bacterial functions to cause enteropathy. Our gnotobiotic approach is innovative and will allow us to characterize critical interactions between resident intestinal bacteria and infection with Giardia that have not previously been elucidated. The proposed research will address longstanding questions related to the role of Giardia on gut function, and specifically whether Giardia exerts pathogenesis by altering microbial metabolism. Beyond Giardia pathogenesis, these results are expected to lead to new considerations for how healthy bacteria provide protection against gut infection, and how chronic enteropathogen exposures cause gut dysfunction absent diarrhea. We hope to discover new pathways that might leverage emerging microbial or molecular-based therapeutics to improve health of children vulnerable to malnutrition and intestinal infections.

项目概要 贾第鞭毛虫属于一组与儿童发育和肠道功能受损相关的肠道病原体， 尤其是营养不足的儿童。尽管这些儿童中的大多数贾第鞭毛虫感染在临床上是 沉默的贾第鞭毛虫可能会导致长期损害。由于未知的原因，其中许多孩子无法 清除寄生虫。此外，受感染的儿童可能因贾第鞭毛虫感染而面临肠道功能障碍的风险， 即使他们没有症状。我们假设对贾第鞭毛虫和随后的疾病的易感性是由于 由于低膳食蛋白质导致肠道常驻微生物群落发生变化。动物模型 提供一个机会来剖析像贾第鞭毛虫这样的个体病原体如何影响生命早期的肠道健康，以及 一个了解特定营养素支持宿主防御和生理机制的模型。这 该提案的目标是在最先进的环境中使用我们的新型贾第鞭毛虫感染小鼠模型 我们可以定义和控制肠道中所有微生物的暴露（限菌素）。我们将结合我们的 具有微生物宏基因组学和代谢组学专业知识的无菌专业知识，可进行严格的检查 研究饮食影响如何对复杂的群落或常驻肠道微生物产生功能变化。在 目标 1，我们将确定肠道常驻微生物通常如何预防持续性贾第鞭毛虫感染 通过将肠道微生物从营养良好的动物转移到易感宿主中，反之亦然 将慢性感染宿主中允许的微生物转移到营养丰富的小鼠体内。我们将专门 检查微生物代谢胆汁酸的能力是否是预防贾第鞭毛虫感染的关键， 以及微生物是否是有效免疫所必需的。在目标 2 中，我们将确定贾第鞭毛虫和蛋白质如何 缺乏协同作用导致肠道屏障功能障碍。我们的模型具有临床相关的生长结果 限制蛋白质摄入和贾第鞭毛虫联合损伤期间肠道屏障功能的限制和丧失 感染。我们将使用我们的无菌模型来生成宏基因组和代谢组数据，以识别 贾第鞭毛虫感染期间微生物群落的致病性变化。我们将具体阐明其作用 芳香氨基酸代谢物和胆汁酸对蛋白质缺乏状态下肠道功能的影响，以及是否 贾第鞭毛虫促进致病菌功能，引起肠病。我们的无菌方法是创新的 并使我们能够表征肠道常驻细菌与贾第鞭毛虫感染之间的关键相互作用 以前没有被阐明过。拟议的研究将解决与以下相关的长期存在的问题 贾第虫对肠道功能的作用，特别是贾第虫是否通过改变微生物发挥发病机制 代谢。除了贾第鞭毛虫发病机制之外，这些结果预计还将引发人们对如何进行新的思考。 健康细菌可防止肠道感染，以及慢性肠道病原体暴露如何导致肠道感染 功能障碍无腹泻。我们希望发现可能利用新兴微生物或 基于分子的疗法，以改善易受营养不良和肠道感染影响的儿童的健康。