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

项目总结/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、CNS发育改变 还有其他异常全球超过3000万儿童患有中度急性营养不良（MAM）， 疫情预计将随着COVID-19大流行而显著恶化。全球有1.59亿儿童 发育不良目前的治疗方法效果有限。通过分析连续收集的粪便样本， 孟加拉国出生队列的健康成员和MAM患者，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的 制定补充食品，修复他们的微生物群，导致显着更大的 与现有的营养干预相比，体重增长的改善，以及揭示机制 微生物群成员通过其与健康生长的宿主介质相关联。小肠的作用 (SI)儿童营养不良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，从高粪口污染地区返回，腹泻，肠道吸收不良， 绒毛高度/数量减少和肠屏障功能破坏。EED的研究依赖于未经验证的 粪便或血浆生物标志物使其对儿童营养不良的贡献不明确。孟加拉国 环境性肠功能障碍（BEED）研究涉及对发育不良儿童进行内窥镜检查， 营养干预，揭示了一组SI细菌类群，其绝对丰度为负 与线性生长相关;这些十二指肠分类群的培养联合体在接受者中产生SI肠病 无菌小鼠我们现在提出检验SI微生物群导致SI肠病的假设 和营养不良（低体重指数），并通过传播给他们的孩子， 代际营养不良我们的4个具体目标将比较SI微生物群加上十二指肠粘膜 营养不良的孟加拉国育龄妇女（BMI <18.5kg/m2）的血浆蛋白质组， 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gnotobiotic小鼠，确定这些表型是否被SI微生物群落预防/拯救 来自没有肠病的正常BMI孟加拉国妇女的成员，并筛选生物化学多样性植物 多糖在我们的小鼠模型中对肠病/生长的影响， 无菌仔猪

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.