Towards a mechanistic understanding of the role of gut microbiota in postnatal growth impairment

从机制上理解肠道微生物群在产后生长障碍中的作用

基本信息

批准号：
10765586
负责人：
JESSICA A. GREMBI
金额：
$ 0.25万
依托单位：
STANFORD UNIVERSITY
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：
2022-09-26 至 2025-09-25
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10765586
关键词：
3 year old Address Age Antibiotics Antimicrobial Resistance Bangladesh Bifidobacterium Bioinformatics Biological Blood Blood specimen Carbohydrates Characteristics Child Child Health Childhood Clinical Clinical Trials Competence Diet Disease Endotoxins Engineering Environmental Risk Factor Etiology Feces Fellowship Food Foundations Future Gastroenterology Genes Genome Genomics Goals Growth Health Human Human Biology Human Microbiome Immune response Impairment Inflammation Inflammatory Inflammatory Response Intervention Intestinal permeability Intestines Life Lipids Malnutrition Measurement Mediating Mentorship Metabolic Metagenomics Microbe Modeling Mucosal Immune System Multiomic Data Mus Outcome Pathway interactions Periodicals Permeability Physiological Production Research Research Personnel Risk Role Rural Sampling Sanitation Site Specimen Statistical Models Taxonomy Training Transplantation Variant Work career cohort commensal microbes dietary supplements enteric pathogen experience gut inflammation gut microbes gut microbiome gut microbiota improved in vivo insight metabolomics metagenomic sequencing microbial microbiota mouse model novel nutrient absorption nutritional supplementation postnatal programs rRNA Genes rational design reconstitution resistance gene skills small molecule statistics stem systemic inflammatory response

项目摘要

PROJECT SUMMARY Precision engineering of the gut microbiota requires a mechanistic understanding of how microbes interact with host physiological pathways in order to produce desired health outcomes. In stunted children, commensal gut microbes have been correlated with aberrant host inflammation and growth impairment, but mechanisms underlying these associations are poorly understood. Mouse models have suggested causality, but they fail to recapitulate the dynamics of the mucosal immune system in humans and the complexity of the human gut microbiota. This project will interrogate these questions in vivo in a cohort of >1500 children from rural Bangladesh at risk for stunting, for which biological specimens were collected longitudinally from 0-3 years of age. Preliminary analysis of 16S rRNA gene sequences from >3700 fecal samples collected from these children has identified a Bifidobacterium sequence variant that is highly correlated with intestinal inflammation and subsequent growth faltering. In Aim 1, I will identify strain-specific microbial genes that might mediate these observed associations. In Aim 2, I will interrogate the mechanistic underpinnings by evaluating microbial small- molecule metabolites in feces and blood associated with high levels of Bifidobacterium and concurrent gut and/or systemic inflammation in children 14 months old. In Aim 3, I will use advanced latent variable statistical modeling to determine the importance of associated groups of microbial (taxonomic, metagenomic, and metabolic) and host (gut and systemic inflammation) features on future growth faltering. I will also estimate the maximum achievable improvement in child growth from a theoretical, 100% efficacious microbiota-manipulation intervention, providing an expected effect size for comparison with other intervention alternatives. This work will increase our mechanistic understanding of the associations between early life gut microbiota and aberrant intestinal/systemic inflammation as well as future growth faltering, producing new options for predictably manipulating the gut microbiota to mitigate adverse health outcomes. The proposed project will provide a rigorous training experience in the fields of gut microbiota, microbial metabolites, multivariate statistics, and pediatric gastroenterology under the mentorship of a group of scientific experts, and will equip me with the skills necessary to become an independent researcher.

项目概要肠道微生物群的精密工程需要对微生物如何与宿主生理途径以产生期望的健康结果。在发育不良的儿童中，共生肠道微生物与异常宿主炎症和生长障碍相关，但机制人们对这些关联的背后知之甚少。小鼠模型已经暗示了因果关系，但他们未能概括人类粘膜免疫系统的动态和人类肠道的复杂性微生物群。该项目将在超过 1500 名来自农村的儿童身上探究这些问题孟加拉国有发育迟缓的风险，生物标本是从 0-3 岁的纵向收集的年龄。对从这些儿童收集的超过 3700 份粪便样本中的 16S rRNA 基因序列进行初步分析已鉴定出与肠道炎症高度相关的双歧杆菌序列变异体随后的增长步履蹒跚。在目标 1 中，我将识别可能介导这些作用的菌株特异性微生物基因。观察到的关联。在目标 2 中，我将通过评估微生物小分子来探究其机制基础。粪便和血液中的分子代谢物与高水平的双歧杆菌和并发的肠道和/或 14个月大儿童全身炎症。在目标 3 中，我将使用高级潜变量统计建模确定相关微生物组（分类学、宏基因组和代谢）的重要性宿主（肠道和全身炎症）的特征是未来生长缓慢。我也会估计最大通过理论上 100% 有效的微生物群调控可实现儿童生长的改善干预，提供预期效果大小，以便与其他干预替代方案进行比较。这项工作将增加我们对早期肠道微生物群与异常之间关联的机制理解肠道/全身炎症以及未来生长缓慢，为可预见的情况提供了新的选择操纵肠道微生物群以减轻不良健康后果。拟议的项目将提供在肠道菌群、微生物代谢物、多变量统计等领域拥有严格的培训经验在一组科学专家的指导下学习儿科胃肠病学，并使我掌握技能成为一名独立研究员所必需的。