Mechanism of action of a microbiota-directed complementary food that promotes ponderal growth in Bangladeshi children with moderate acute malnutrition

项目摘要 1.44亿儿童患有营养不良，这是一种长期并存的疾病。对…的延误 生长，包括身高发育迟缓和体重减少，是最突出的疾病之一 营养不良。虽然目前针对营养不良的治疗方法已经降低了死亡率，但他们对 修复相关疾病的疗效有限。最近的研究表明，营养不良也是 与肠道微生物区系发育失败有关，导致营养不良的儿童肠道不成熟 微生物区系。对老鼠的研究表明，将未成熟的肠道微生物群落移植到 传播营养不良儿童的发育迟缓表型。微生物区系未成熟的修复可能 为治疗营养不良造成的儿童发育迟缓提供了一种新的治疗策略。 为了研究更成熟的肠道微生物区系是否可以挽救这种延迟的生长，戈登实验室 设计了一系列能够修复微生物区系的微生物区系导向补充食品(MDCF) 不成熟。最近，我们在营养不良的情况下进行了一项概念验证控制喂养试验 孟加拉的儿童要么食用我们最有希望的MDCF(MDCF-2)，要么消费一种即用即用的标准 补充食品(RUSF)不是为修复微生物群未成熟而设计的。MDCF-2产生了显著的 即使MDCF-2的卡路里密度比RUSF低，体重增加的速度也比RUSF快。本研究 还发现了23个细菌菌株，它们在肠道中的丰度与宿主体重的变化有关。 最近，研究还表明，与RUSF相比，MDCF-2含有一组不同的碳水化合物。这些非常 令人鼓舞的结果为这项旨在更好地理解基因组的提议提供了动力 这些重量相关分类群的特征，并揭示了它们对MDCF-2作出反应的机制。 鉴于肠道微生物区系在处理膳食多糖过程中起着关键作用， 已知碳水化合物相关酶(CAZymes)基因谱系的差异会影响细菌 健身，我假设MDCF-2通过特定生物活性的存在促进宿主体重增加 在发育中的微生物区系中，由CAZymes代谢的促进生长的碳水化合物。 这项提议的目标是首先在计算机中识别这些假定的促进体重的CAZyme，然后验证 这些CAZymes在体外和体内。在目标1中，我试图通过计算识别与体重相关的CAZyme 获得，表征他们的‘宿主’细菌菌株的基因组，并表征它们在肠道中的表达。在……里面 目的2，我将直接测试含有这些CAZyme的细菌菌株是否促进了灵芝中的体重增加 饲喂添加MDCF-2的饲料的小鼠。这项努力是为了识别含有促生长作用的特定微生物 CAZymes将使我们能够在不同人群的营养不良儿童中开发有效的治疗食品 并扩大我们对微生物群影响出生后发育的机制的理解。

PROJECT ABSTRACT 144 million children suffer from undernutrition, a condition with numerous long co-morbidities. A delay in growth, including stunting of height and wasting of weight, is one of the most prominent morbidities of undernutrition. While current therapeutics against undernutrition have reduced mortality, they have had very limited efficacy in repairing the associated morbidities. Recent studies have indicated that undernutrition is also associated with failed gut microbiota development, resulting in undernourished children having an immature gut microbiota. Research efforts in mice have shown that transplanting immature gut microbial communities transmits the growth faltering phenotypes seen in undernourished children. Repair of microbiota immaturity could represent a new therapeutic strategy for treating childhood growth delays caused by undernutrition. To investigate whether more mature gut microbiota could rescue this delayed growth, the Gordon Lab designed a series of microbiota-directed complementary foods (MDCF) that were able to repair microbiota immaturity. Recently, we performed a proof-of-concept controlled feeding trial where undernourished Bangladeshi children consumed either our most promising MDCF (MDCF-2) or a ‘standard’ ready-to-use supplementary food (RUSF) not designed to repair microbiota immaturity. MDCF-2 produced a significantly greater rate of weight gain than RUSF even though MDCF-2 has a lower caloric density than RUSF. This study also revealed 23 bacterial strains whose abundance in the gut was associated with host weight changes. Recently, it was also shown that MDCF-2 has a different set of carbohydrates compared to RUSF. These very encouraging results provide the motivation for this proposal which seeks to better understand the genomic features of these weight-associated taxa and uncover the mechanisms by which they respond to MDCF-2. Given that the gut microbiota plays a key role in processing of dietary polysaccharides and that differences in carbohydrate-associated enzymes (CAZymes) gene repertoires are known to affect bacterial fitness, I hypothesize MDCF-2 promotes host weight gain through the presence of specific bioactive carbohydrates that are metabolized by CAZymes in growth-promoting members of the developing microbiota. The goal of this proposal is to identify these putative weight-promoting CAZymes first in silico and then validating those CAZymes in vitro and in vivo. In Aim 1, I seek to computationally identify CAZymes associated with weight gain, characterize the genomes of their ‘host’ bacterial strains, and characterize their expression in the gut. In Aim 2, I will directly test whether bacterial strains containing these CAZymes promote weight gain in gnotobiotic mice fed a diet supplemented with MDCF-2. This effort to identify specific microbes containing growth-promoting CAZymes will allow us to develop effective therapeutic foods in different populations of undernourished children and expand our understanding of the mechanisms by which the microbiome influences postnatal development.