PDF(Pubmed)
Abstract：
Evidence is accumulating that perturbed postnatal development of the gut microbiome contributes to childhood malnutrition1-4. Designing effective microbiome-directed therapeutic foods to repair these perturbations requires knowledge about how food components interact with the microbiome to alter its expressed functions. Here we use biospecimens from a randomized, controlled trial of a microbiome-directed complementary food prototype (MDCF-2) that produced superior rates of weight gain compared to a conventional ready-to-use supplementary food (RUSF) in 12-18-month-old Bangladeshi children with moderate acute malnutrition (MAM)4. We reconstructed 1000 bacterial genomes (metagenome-assembled genomes, MAGs) present in their fecal microbiomes, identified 75 whose abundances were positively associated with weight gain (change in weight-for-length Z score, WLZ), characterized gene expression changes in these MAGs as a function of treatment type and WLZ response, and used mass spectrometry to quantify carbohydrate structures in MDCF-2 and feces. The results reveal treatment-induced changes in expression of carbohydrate metabolic pathways in WLZ-associated MAGs. Comparing participants consuming MDCF-2 versus RUSF, and MDCF-2-treated children in the upper versus lower quartiles of WLZ responses revealed that two Prevotella copri MAGs positively associated with WLZ were principal contributors to MDCF-2-induced expression of metabolic pathways involved in utilization of its component glycans. Moreover, the predicted specificities of carbohydrate active enzymes expressed by polysaccharide utilization loci (PULs) in these two MAGs correlate with the (i) in vitro growth of Bangladeshi P. copri strains, possessing differing degrees of PUL and overall genomic content similarity to these MAGs, cultured in defined medium containing different purified glycans representative of those in MDCF-2, and (ii) levels of carbohydrate structures identified in feces from clinical trial participants. In the accompanying paper5, we use a gnotobiotic mouse model colonized with age- and WLZ-associated bacterial taxa cultured from this study population, and fed diets resembling those consumed by study participants, to directly test the relationship between P. copri, MDCF-2 glycan metabolism, host ponderal growth responses, and intestinal gene expression and metabolism. The ability to identify bioactive glycan structures in MDCFs that are metabolized by growth-associated bacterial taxa will help guide recommendations about use of this MDCF for children with acute malnutrition representing different geographic locales and ages, as well as enable development of bioequivalent, or more efficacious, formulations composed of culturally acceptable and affordable ingredients.
摘要：
越来越多的证据表明，肠道微生物组的出生后发育紊乱会导致儿童营养不良1-4。设计有效的微生物组指导的治疗食物来修复这些扰动需要了解食物成分如何与微生物组相互作用以改变其表达的功能。在这里，我们使用来自随机的生物样本，在12-18个月大的孟加拉国中度急性营养不良（MAM）儿童中，与常规即食补充食品（RUSF）相比，微生物组指导的补充食品原型（MDCF-2）产生更高的体重增加率的对照试验4。我们重建了1000个细菌基因组（宏基因组组装的基因组，MAGs)存在于它们的粪便微生物组中，确定了75个丰度与体重增加呈正相关(体重长度Z评分的变化，WLZ),这些MAG中的特征基因表达变化是治疗类型和WLZ反应的函数，并使用质谱法定量MDCF-2和粪便中的碳水化合物结构。结果揭示了治疗诱导的WLZ相关MAG中碳水化合物代谢途径表达的变化。比较服用MDCF-2和RUSF的参与者，在WLZ反应的上四分位数和下四分位数中，MDCF-2治疗的儿童表明，与WLZ呈正相关的两个PrevotellacopriMAG是MDCF-2诱导的代谢途径表达的主要贡献者，该代谢途径涉及其组分聚糖的利用。此外，这两个MAG中的多糖利用基因座（PULs）表达的碳水化合物活性酶的预测特异性与（i）孟加拉P.copri菌株的体外生长相关，与这些MAG具有不同程度的PUL和整体基因组含量相似性，在含有代表MDCF-2中的那些的不同纯化聚糖的限定培养基中培养,和(ii)在来自临床试验参与者的粪便中鉴定的碳水化合物结构的水平。在随附的论文5中，我们使用从该研究群体中培养的年龄和WLZ相关的细菌分类群定植的侏儒小鼠模型，喂食类似于研究参与者消耗的饮食，为了直接测试P.copri之间的关系，MDCF-2聚糖代谢，宿主隆重生长反应，以及肠道基因的表达和代谢。识别由生长相关细菌分类群代谢的MDCF中的生物活性聚糖结构的能力将有助于指导有关将MDCF用于代表不同地理区域和年龄的急性营养不良儿童的建议。以及促进生物等效物的发展，或者更有效，由文化上可接受和负担得起的成分组成的配方。
