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Metabolic And Spatial Competition For Dietary Fiber Between Commensal And Pathogenic Gut Microbes

共生肠道微生物和致病肠道微生物之间膳食纤维的代谢和空间竞争

基本信息

批准号：
10132316
负责人：
Michael L Patnode
金额：
$ 16.22万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132316
关键词：
Adhesions Adhesives Bacteria Bacterial Adhesion Bacteroides Bar Codes Binding Biological Assay Carbohydrates Carbon Cecum Cell Adhesion Cells Collection Communities Consumption Databases Diarrhea Diet Dietary Carbohydrates Dietary Component Dietary Fiber Dietary Intervention Disease Enteral Epithelial Escherichia coli Fiber Food Genes Gnotobiotic Goals Growth Harvest Health Homeostasis Human Immune In Situ Incubated Individual Infection Intervention Intestines Knock-out Knowledge Lactobacillus Libraries Measures Mediating Metabolic Metabolism Microbe Microbial Genetics Modeling Mus Nitrogen Nutrient Organism Outcome Pathogenicity Plants Polysaccharides Preparation Probiotics Proteobacteria Proteomics Psyllium Research Resources Sampling Surface Testing Urinary tract infection Uropathogenic E. coli Work base beneficial microorganism commensal microbes design dietary enteric infection experimental study fitness genetic analysis gut colonization gut microbes gut microbiota in vivo insight interest magnetic beads member microbial community microbiota mutant particle pathogen pathogenic Escherichia coli pathogenic microbe prebiotics response therapy design tool

项目摘要

PROJECT SUMMARY The microbial community that resides in the human intestine profoundly influences host metabolism, immune homeostasis, and the outcome of enteric infections. Dietary fiber is a promising tool for manipulating the gut microbiota to promote organisms that provide beneficial functions to the host. Though, it is currently difficult to predict which gut bacterial species will respond to fiber-based dietary interventions, interspecies competition makes it possible to precisely target beneficial species of interest using a particular fiber type. Bacterial species with pathogenic potential, such as uropathogenic E. coli (UPEC), are present in the gut microbiota of asymptomatic individuals and these species have the capacity to expand in response to fiber. Exploiting competition between pathogens and their non-pathogenic relatives to reduce pathogen load in the gut will require detailed knowledge of the genes underlying these species’ overlapping nutrient harvesting strategies, including genes mediating adhesion to nutrient-rich diet-derived particles. The following aims will test the hypotheses that (i) expansion of commensal E. coli in the gut in response to dietary fiber can reduce the fitness of pathogenic E. coli, and that (ii) commensal and pathogenic bacterial species compete for adhesion to the same diet-derived surfaces in the intestinal lumen. In Aim1, I will identify dietary fibers that selectively increase the abundance of commensal E. coli in vivo. Preliminary studies have identified a widely consumed fiber that increases the abundance of commensal E. coli in a model microbial community. I will define the mechanism of action by colonizing these mice with an E. coli transposon mutant library and performing community-wide quantitative proteomics and forward genetic analyses. To model a gut reservoir of pathogenic E. coli, I will substitute UPEC for commensal E. coli in this community, and then administer commensal E. coli with or without fiber to identify interventions that reduce UPEC abundance. In Aim2, I will determine whether commensal and pathogenic microbes adhere to the same surfaces in the gut. A multiplex adhesion assay, using glycan-coated magnetic beads, identified dietary fibers that support adhesion of both UPEC and commensal E. coli. I will validate adhesive interactions in vivo by administering these particles to mice and measuring bacterial localization around beads in situ. Application of the bead-based adhesion assay to cecal microbiota of mice colonized with uncultured human fecal samples will identify additional E. coli strains, as well as uncharacterized gut microbes, that adhere to dietary glycans in vivo. This research will (i) provide insights into the ecological relationships that determine the outcome of dietary interventions designed to promote beneficial species at the expense of known pathogens and ii) provide candidate dietary components, bacterial strains, and microbial genetic targets for manipulating these relationships to enhance human health.

项目总结