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

项目摘要/摘要 儿童营养不良是一个全球性的健康挑战，表现为体重增长受损(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 再加上其他异常情况。全球有3000万儿童患有中度急性营养不良(MAM)， 随着新冠肺炎大流行，流行率预计将显著恶化。在全球范围内，1.59亿儿童 发育迟缓。目前的治疗方法效果有限。通过分析连续收集的粪便样本 在孟加拉出生队列的健康成员和患有MAM的人中，我们发现MAM与 微生物区系发育受损(微生物区系不成熟)。我们已经开发出一种微生物群 补充食品的配方，修复他们的微生物区系，导致显著更大的 与现有的营养干预相比，体重增长的改善，并揭示了机制 微生物区系成员通过它与健康生长的宿主介体联系在一起。小肠的作用 (Si)儿童营养不良的微生物区系仍然是个谜，部分原因是难以获得 样本。SI吸收功能改变、无症状肠道病原体感染与 发育迟缓，导致了亚临床肠道功能障碍导致生长迟缓的假说。 环境肠道功能障碍(EED)是一种病因不明的SI肠病，首次在《成人和平》中描述 兵团志愿者，从粪口污染严重的地区回来，腹泻，肠道吸收不良， 减少绒毛高度/数量和肠道屏障功能障碍。EED的研究依赖于未经验证的 粪便或血浆生物标记物对儿童营养不良的影响不明确。我们的孟加拉国 环境肠道功能障碍(BEED)研究涉及发育迟缓儿童的内窥镜检查 营养干预，揭示了一组绝对丰度为负的SI细菌分类群 与线性生长相关；这些十二指肠分类群的培养联合体在受体中产生SI肠病 灵知生菌小鼠。我们现在建议检验SI微生物区系对SI肠病的影响这一假设 和营养不良(低体重指数)的育龄妇女，并通过传播给她们的孩子，永久 代际营养不良。我们的4个特定目标将比较SI微生物群和十二指肠粘膜 和营养不良的孟加拉国育龄妇女(BMI&lt；18.5 kg/m2)的血浆蛋白质组 肠病的组织病理学证据与体重指数正常(20-24.9公斤/平方米)且无组织病理学的对照 肠病的证据，确定他们的SI微生物区系是否传播SI肠病和生长受损 对于诺生菌小鼠，确定这些表型是否被SI微生物群落预防/拯救 来自正常体重指数的孟加拉妇女，没有肠道疾病，并筛选生化多样性的植物 在我们的小鼠模型中，多糖对肠病/生长的影响，领导进展到 灵知生猪。

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.