Dietary and microbial predictors of childhood obesity risk

项目摘要/摘要：生命的前三年对于建立增长至关重要 轨迹和肠道微生物群组成，两者都受到饮食和其他环境因素的影响。 因素肥胖率在全球范围内不断上升，在出生后的前6个月内接受配方奶粉喂养的婴儿 婴儿在2岁时肥胖的可能性比母乳喂养的婴儿（BF）高2.5倍;然而， BF和FF（CF）的婴儿。肠道微生物组成是肥胖风险和微生物群的决定因素 BF喂养的婴儿与FF喂养的婴儿之间存在差异，但对CF婴儿的微生物群知之甚少。人类 乳低聚糖（HMO）和益生元发酵成短链脂肪酸（SCFA）， 宿主通过游离脂肪酸受体FFAR 2和FFAR 3影响免疫和代谢功能 和肥胖风险。我们已经证明FF和BF婴儿的微生物群和SCFA组成不同 并且系统生物学方法结合了联合收割机SCFA和FFAR相关基因在脱落细胞中的表达， 肠上皮细胞区分BF和FF婴儿。然而，目前尚不清楚这些因素是否直接 影响婴儿体重增加。该提案的目的是确定膳食益生元的差异 在440名儿童的纵向前瞻性出生队列中影响互惠宿主-微生物相互作用， 与婴儿生长轨迹、3岁时的体重和身体组成有关。我们的核心假设是 膳食HMO和益生元在HM、FF和CF中产生不同微生物组和SCFA组成 婴儿和SCFA将介导婴儿的生长轨迹和身体组成，通过相互作用， 肠道FFAR。拟议的实验将使用系统生物学方法来阐明转基因组交叉， 宿主脱落的肠上皮细胞和肠道微生物群之间的对话将为以下方面提供机制性见解： 与婴儿体重相关的肠道中宿主-微生物相互作用的分子途径 增益和身体组成。为了检验我们的中心假设，将采取两个具体目标：1）确定 早期营养对微生物群组成和短链脂肪酸组成影响及其相关因素 对生命最初3年的生长轨迹以及3岁时的BMI和身体成分的发现。和2） 注释宿主脱落上皮细胞转录组和细菌元转录组谱并阐明 宿主/宿主关系，侧重于FFAR相关途径，并将这些发现与生长相关 在生命的前3年的轨迹和BMI和身体组成在3岁。我们的团队是理想的定位， 进行这项研究。我们开创性的非侵入性方法，同时监测基因表达 在脱落的上皮细胞和肠道菌群的婴儿是非常创新的。这项工作意义重大 因为定义饮食摄入，微生物群组成， 将确定宿主基因表达和儿童健康结果。这些宿主微生物的分子指纹 将使患者驱动的精准医疗能够优化婴儿生长并降低儿童肥胖风险。

Project Summary/Abstract: The first three years-of-life are critically important for establishing growth trajectories and gut microbiota composition, both of which are influenced by diet and other environmental factors. Obesity rates are increasing worldwide and infants who are formula-fed (FF) for the first 6 months of life are ~2.5-times more likely to be obese at 2-years than breast-fed infants (BF); however, little data exists on infants who are both BF and FF (CF). Gut microbial composition is a determinant of obesity risk and microbiota differences exist between BF- vs. FF-fed infants, but less is known about the microbiota of CF infants. Human milk oligosaccharides (HMO) and prebiotics are fermented to short chain fatty acids (SCFA), which signal to the host through the free fatty acid receptors FFAR2 and FFAR3 to influence immune and metabolic function and obesity risk. We have shown that the microbiota and SCFA composition differ between FF and BF infants and that systems biology approaches that combine SCFA and FFAR-linked genes expression in exfoliated intestinal epithelial cells discriminate BF from FF infants. However, it is unknown whether these factors directly influence infant weight gain. The goal of this proposal is to determine how differences in dietary prebiotics influence mutualistic host-microbe interactions in a longitudinal, prospective birth cohort of 440 children and to relate those to infant growth trajectory and weight and body composition at age 3. Our central hypothesis is that dietary HMO and prebiotics produce different microbiome and SCFA composition in HM, FF and CF infants and that SCFA will mediate infant growth trajectories and body composition through interactions with gut FFAR. The proposed experiments will use systems biology approaches to illuminate transgenomic cross- talk between host exfoliated intestinal epithelial cells and the gut microbiota will provide mechanistic insight into the molecular pathways underlying host-microbe interactions in the gut that are associated with infant weight gain and body composition. Two specific aims will be undertaken to test our central hypothesis: 1) Determine the impact of early nutrition on microbiota composition and short chain fatty acid composition and relate those findings to growth trajectories in the first 3 years-of-life and BMI and body composition at age 3.; and 2) Annotate host exfoliated epithelial cell transcriptome and bacterial metatranscriptome profiles and elucidate host/commensal relationships focusing on FFAR-linked pathways and relate those findings to growth trajectories in the first 3 years-of-life and BMI and body composition at age 3. Our team is ideally positioned to undertake this research. Our pioneering noninvasive approach that simultaneously monitors gene expression in exfoliated epithelial cells and gut microbiota of infants is highly innovative. This body of work is significant because molecular biomarkers that define the relationship between dietary intake, microbiota composition, host gene expression and child health outcomes will be identified. These host-microbial molecular finger prints will enable patient-powered precision medicine to optimize infant growth and reduce childhood obesity risk.