The small intestinal microbiota in undernourished women and undernourished children in Bangladesh: identifying causal mechanisms and therapeutic targets

孟加拉国营养不良妇女和营养不良儿童的小肠微生物群：确定因果机制和治疗目标

• 批准号: 10490421
• 负责人: JEFFREY I GORDON
• 金额: $ 100.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490421
• 关键词: Acute; Adult; Age; Animal Model; Area; Aspirate substance; Bacteria; Bangladesh; Bangladeshi; Biochemical; Biological Markers; Biological Specimen Banks; Biopsy; Birth; Body mass index; COVID-19 pandemic; Celiac Disease; Child; Child Malnutrition; Childhood; Collection; Consumption; Culture-independent methods; Development; Diarrhea; Diet; Dietary Intervention; Disease; Distal; Duodenum; Effectiveness; Endoscopy; Enteral; Esophagogastroduodenoscopy; Etiology; Female of child bearing age; Food; Formulation; Functional disorder; Germ-Free; Gnotobiotic; Growth; HIV; Height; Housing; Human; Immune System Diseases; Impairment; Incidence; Infant; Inflammation; Link; Malabsorption Syndromes; Malnutrition; Mediator of activation protein; Metabolic dysfunction; Micronutrients; Milk; Mothers; Mucous Membrane; Mus; Nutritional status; Oligosaccharides; Oral; Organism; Peace Corps; Phenotype; Plants; Plasma; Plasma Proteins; Play; Polysaccharides; Poverty; Prevalence; Prevention; Proteins; Proteome; Resource-limited setting; Role; Sampling; Slum; Small Intestines; Small intestine mucous membrane; Technology; Testing; Villus; Woman; aged; base; child bearing; cohort; colon microbiota; egg; enteric infection; enteric pathogen; experimental study; fecal microbiota; global health; gut microbiota; intergenerational; intestinal barrier; member; microbial community; microbiota; mouse model; mucosal microbiota; multiple omics; postnatal development; prevent; repaired; response; therapeutic candidate; therapeutic target; transmission process; volunteer; wasting

PROJECT SUMMARY/ABSTRACT Childhood undernutrition is a global health challenge manifested by impaired ponderal growth (wasting/acute malnutrition), impaired linear growth (stunting), immune and metabolic dysfunctions, altered CNS development plus other abnormalities. >30M children worldwide suffer from moderate acute malnutrition (MAM) with prevalence anticipated to worsen significantly with the COVID-19 pandemic. Globally, 159M children are stunted. Current treatments have limited effectiveness. By analyzing serially collected fecal samples from healthy members of Bangladeshi birth cohorts and those with MAM, we found that MAM is associated with impaired microbiota development (microbiota immaturity). We have developed a microbiota-directed formulation of complementary foods that repairs their microbiota, resulting in significantly greater improvements in ponderal growth compared to an existing nutritional intervention, and revealing mechanisms by which microbiota members are linked to host mediators of healthy growth. The role of the small intestinal (SI) microbiota in childhood undernutrition remains enigmatic in part because of the difficulty in obtaining samples. Associations between altered SI absorptive function, asymptomatic enteropathogen infection and stunting, have led to the hypothesis that subclinical enteric dysfunction contributes to growth faltering. Environmental enteric dysfunction (EED) is a SI enteropathy of unknown etiology first described in adult Peace Corps volunteers, returning from areas of high fecal-oral contamination, with diarrhea, intestinal malabsorption, reduced villus height/number and gut barrier function disruption. Studies of EED have relied on non-validated fecal or plasma biomarkers making its contribution to childhood undernutrition ill-defined. Our Bangladesh Environmental Enteric Dysfunction (BEED) study involved endoscopy of stunted children who failed a nutritional intervention, which revealed a group of SI bacterial taxa whose absolute abundances negatively correlate with linear growth; a cultured consortium of these duodenal taxa produced SI enteropathy in recipient gnotobiotic mice. We now propose to test the hypothesis that the SI microbiota contributes to SI enteropathy and malnutrition (low-BMI) in women of childbearing age and, via transmission to their children, to perpetuate intergenerational undernutrition. Our 4 specific aims will compare the SI microbiota plus the duodenal mucosal and plasma proteomes of malnourished Bangladeshi women (BMI<18.5kg/m2) of child-bearing age with histopathologic evidence of enteropathy versus those with normal BMIs (20-24.9kg/m2) and no histopathologic evidence of enteropathy, determine whether their SI microbiota transmits SI enteropathy and impaired growth to gnotobiotic mice, ascertain whether these phenotypes are prevented/rescued by SI microbial community members from normal-BMI Bangladeshi women without enteropathy, and screen biochemically-diverse plant polysaccharides in our mouse models for their effects on enteropathy/growth, with leads advanced to gnotobiotic piglets.

项目摘要/摘要 童年时期的营养不良是由洪水增长受损所表现出的全球健康挑战（浪费/急性 营养不良），线性生长受损（发育迟缓），免疫和代谢功能障碍，改变了中枢神经系统的发育 加上其他异常。全球> 30m儿童患有中度急性营养不良（MAM） 预计随着19号大流行而导致的患病率会显着恶化。在全球范围内，有159亿儿童是 发育不良。当前治疗的有效性有限。通过分析从 孟加拉国出生队列的健康成员和有妈妈的人，我们发现妈妈与 菌群发育受损（微生物群的不成熟）。我们已经开发了一个微生物群的 配制互补食品，以维修其微生物群，从而明显更大 与现有的营养干预相比，洪水增长的改善并揭示了机制 微生物群成员与健康生长的宿主介体相关。小肠的作用 （SI）童年营养不良的微生物群仍然存在着神秘的因素，部分原因是难以获得 样品。 SI吸收功能改变，无症状肠病的感染和 发育良好，导致了亚临床肠功能障碍有助于生长步履蹒跚的假设。 环境肠功能障碍（EED）是成人和平中首次描述的未知病因的SI肠病毒 军团志愿者，从高粪便污染区域返回，腹泻，肠道吸收不良， 绒毛的高度/数量和肠道障碍功能降低。 EED的研究依赖于未验证的 粪便或血浆生物标志物对童年的营养不良贡献不明显。我们的孟加拉国 环境肠功能障碍（BEED）研究涉及失败的儿童的内窥镜检查 营养干预措施，揭示了一组Si细菌分类群，其绝对丰富性负数 与线性生长相关；这些十二指肠分类单元的培养财团在接受者中产生了SI肠病 gnotobiotic小鼠。现在，我们建议检验SI微生物群有助于SI肠病的假设 和育龄妇女的营养不良（低-BMI），并通过传播给孩子 代际营养不良。我们的4个特定目标将比较Si Microbiota以及十二指肠粘膜 和营养不良的孟加拉国妇女的血浆蛋白质组织（BMI <18.5kg/m2） 肠病的组织病理学证据与患有正常BMI（20-24.9kg/m2）的组织病理学证据，没有组织病理学 肠病的证据，确定其Si Microbiota是否会传播SI肠病毒并增长受损 对于gnotobiotic小鼠，确定SI微生物群落是否阻止/营救了这些表型 来自普通BMI孟加拉国妇女的成员没有肠病毒，屏幕生化多样性植物 在我们的鼠标模型中，多糖对肠病/生长的影响，铅提高到 gnotobiotic小猪。