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.

项目概要/摘要 儿童营养不良是一项全球健康挑战，表现为体重生长受损（消瘦/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、中枢神经系统发育改变 加上其他异常情况。全球超过 3000 万儿童患有中度急性营养不良 (MAM) 随着 COVID-19 大流行，患病率预计将显着恶化。全球有 1.59 亿儿童 发育不良。目前的治疗效果有限。通过分析连续收集的粪便样本 在孟加拉国出生队列的健康成员和患有 MAM 的成员中，我们发现 MAM 与 微生物群发育受损（微生物群不成熟）。我们开发了一种针对微生物群的 配方补充食品可以修复微生物群，从而显着提高 与现有的营养干预相比，体重增长有所改善，并揭示了机制 通过这种方式，微生物群成员与健康生长的宿主介质联系起来。小肠的作用 (SI) 儿童营养不良中的微生物群仍然是个谜，部分原因是难以获得 样品。 SI 吸收功能改变、无症状肠道病原体感染和 发育迟缓，导致了亚临床肠道功能障碍导致生长迟缓的假设。 环境性肠功能障碍 (EED) 是一种病因不明的 SI 肠病，首次在成人 Peace 中描述 军团志愿者从粪口污染严重的地区返回，患有腹泻、肠道吸收不良、 绒毛高度/数量减少和肠道屏障功能破坏。 EED 研究依赖于未经验证的 粪便或血浆生物标志物对儿童营养不良的影响尚不明确。我们的孟加拉国 环境肠功能障碍 (BEED) 研究涉及对未通过试验的发育迟缓儿童进行内窥镜检查 营养干预，揭示了一组 SI 细菌类群，其绝对丰度呈负值 与线性增长相关；这些十二指肠类群的培养联合体在受者体内产生 SI 肠病 限生小鼠。我们现在建议检验 SI 微生物群导致 SI 肠病的假设 和育龄妇女的营养不良（低体重指数），并通过传染给她们的孩子，使 代际营养不良。我们的 4 个具体目标将比较 SI 微生物群和十二指肠粘膜 营养不良的孟加拉国育龄妇女（BMI<18.5kg/m2）的血浆蛋白质组和血浆蛋白质组 肠病的组织病理学证据与 BMI 正常 (20-24.9kg/m2) 且无组织病理学证据的患者相比 肠病的证据，确定他们的 SI 微生物群是否传播 SI 肠病和生长受损 对于限生小鼠，确定这些表型是否被 SI 微生物群落预防/拯救 来自体重指数正常且无肠病的孟加拉国女性的成员，并筛选生化多样性植物 在我们的小鼠模型中研究多糖对肠病/生长的影响，并取得进展 具有生殖能力的仔猪。