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

项目摘要 1.44亿儿童营养不良，这是一种有许多长期并发症的疾病。延迟 生长，包括身高发育迟缓和体重消瘦，是最突出的发病率之一， 营养不良虽然目前针对营养不良的治疗方法降低了死亡率，但它们的效果非常差。 修复相关疾病的疗效有限。最近的研究表明，营养不良也是 与肠道微生物群发育失败有关，导致营养不良的儿童肠道发育不成熟 微生物群对小鼠的研究表明，移植不成熟的肠道微生物群落 传播营养不良儿童的生长迟缓表型。微生物群不成熟的修复可以 这是治疗营养不良引起的儿童发育迟缓的一种新的治疗策略。 为了研究更成熟的肠道微生物群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群的微生物导向补充食品（MDCF） 不成熟最近，我们进行了一项概念验证控制喂养试验， 孟加拉国儿童食用了我们最有前途的MDCF（MDCF-2）或“标准”即用型 补充食品（RUSF）并非旨在修复微生物群不成熟。MDCF-2产生了显著的 尽管MDCF-2的热量密度低于RUSF，但体重增加率高于RUSF。本研究 还揭示了23种细菌菌株，其在肠道中的丰度与宿主体重变化相关。 最近，还表明MDCF-2与RUSF相比具有不同的碳水化合物组。这些非常 令人鼓舞的结果为这项旨在更好地了解基因组的提议提供了动力。 这些重量相关类群的功能，并揭示其响应MDCF-2的机制。 鉴于肠道微生物群在膳食多糖的加工中起关键作用， 已知碳水化合物相关酶（CAZymes）基因组的差异会影响细菌 健身，我假设MDCF-2促进宿主体重增加，通过存在特定的生物活性 碳水化合物是由发育中的微生物群的生长促进成员中的CAZymes代谢的。 本提案的目标是首先通过计算机模拟鉴定这些推定的增重CAZymes，然后验证 这些CAZymes在体外和体内。在目标1中，我试图通过计算来识别与体重相关的CAZymes 获得，表征其“宿主”细菌菌株的基因组，并表征其在肠道中的表达。在 目的2，我将直接测试含有这些CAZymes的细菌菌株是否促进gnotobiotic中的体重增加， 喂食补充有MDCF-2的饮食的小鼠。这种努力，以确定特定的微生物含有生长促进 CAZymes将使我们能够在不同的营养不良儿童群体中开发有效的治疗食品 并扩大我们对微生物组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.