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: 10468129
• 负责人: Luther A Bartelt
• 金额: $ 68.73万
• 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/10468129
• 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; Persons; 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.

项目摘要 贾第鞭毛虫lamblia属于与儿童发育和肠道功能受损相关的一组肠道病原体， 特别是在营养不足的儿童中。尽管这些孩子的大多数贾第鞭毛虫感染在临床上是 沉默，贾第鞭毛虫可能会导致长期损害。由于未知的原因，其中许多孩子不能 清除寄生虫。此外，受感染的儿童可能由于贾第鞭毛虫感染而面临肠道功能障碍的风险， 即使它们无症状。我们假设对贾第鞭毛虫的敏感性以及随后的疾病。 由于低饮食蛋白，居民肠道微生物群落的变化。动物模型 提供了一个机会，以剖析贾第鞭毛虫等个体病原体如何影响早期肠道健康，以及 一种模型，以了解特定营养素支持宿主防御和生理的机制。这 该建议的目的是在最先进的环境中使用我们新颖的贾第鞭毛虫感染的鼠标模型 我们可以在肠道中定义和控制所有微生物暴露（Gnotobiotics）。我们将结合我们的 gnotobiotics专业知识具有微生物宏基因组学和代谢组学专业知识，以进行严格检查 关于饮食的影响如何在复杂社区或常驻肠道微生物中产生功能变化。在 AIM 1，我们将确定居民肠道微生物通常如何防止持续的贾第鞭毛虫感染 通过将肠道微生物从良好的动物转移到易感宿主中，反之亦然 将慢性感染的宿主的允许微生物转移到滋养小鼠中。我们将具体 检查微生物代谢胆汁酸的能力是否是保护贾第鞭毛虫感染的关键， 以及微生物是否需要有效免疫。在AIM 2中，我们将确定贾第鞭毛虫和蛋白质如何 缺乏协同作用会引起肠道屏障功能障碍。我们的模型具有增长的临床相关结果 在有限的蛋白质摄入量和贾第鞭毛虫的联合损害期间，肠道屏障功能的限制和丧失 感染。我们将使用我们的gnotobiotic模型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转移。我们将特别阐明 芳香氨基酸代谢物和胆汁酸在蛋白质缺乏状态下的肠道功能，以及是否是否 贾第鞭毛虫促进致病性细菌功能引起肠病。我们的gnotobiotic方法是创新的 并将使我们能够表征居民肠细菌与贾第鞭毛虫感染之间的关键相互作用 以前尚未阐明。拟议的研究将解决与 贾第鞭毛虫在肠道功能上的作用，特别是贾第鞭毛虫是否通过改变微生物来发挥发病机理 代谢。除了贾第鞭毛虫的发病机理之外，这些结果有望导致新的考虑 健康细菌可保护抗肠道感染，以及慢性肠病的暴露如何引起肠道 功能障碍没有腹泻。我们希望发现可能利用新兴微生物或 基于分子的治疗剂，可改善容易受到营养不良和肠道感染的儿童的健康。