Dietary and microbial predictors of childhood obesity risk

项目摘要/摘要：出生后的头三年对于实现成长至关重要 轨迹和肠道微生物区系组成，两者都受到饮食和其他环境的影响 各种因素。肥胖率在全球范围内不断上升，#年前6个月使用配方奶粉喂养的婴儿 两岁时肥胖的可能性是母乳喂养婴儿(BF)的大约2.5倍；然而，关于这方面的数据很少 既是BF又是Ff(CF)的婴儿。肠道微生物组成是肥胖风险和微生物区系的决定因素 BF和FF喂养的婴儿之间存在差异，但对CF婴儿的微生物区系知之甚少。人类 牛奶低聚糖(HMO)和益生元发酵成短链脂肪酸(SCFA)，这是信号 宿主通过游离脂肪酸受体FFAR2和FFAR3影响免疫代谢功能 和肥胖风险。我们已经证明了胎儿和胎儿之间的微生物区系和单链脂肪酸组成不同。 系统生物学方法结合了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。这项提案的目标是确定饮食中益生元的差异 在440名儿童的纵向预期出生队列中影响互惠宿主-微生物相互作用 将它们与婴儿3岁时的生长轨迹、体重和身体组成联系起来。 饲粮中HMO和益生素对HM、FF和CF3种微生物组分和SCFA组成的影响 SCFA将通过与婴儿的互动来调节婴儿的生长轨迹和身体组成 Gut FFAR。拟议的实验将使用系统生物学方法来阐明转基因交叉基因组。 宿主脱落的肠道上皮细胞和肠道微生物区系之间的对话将提供对 肠道中宿主-微生物相互作用与婴儿体重相关的分子途径 增重和身体成分。将采取两个具体目标来检验我们的中心假设：1)确定 早期营养对微生物区系组成和短链脂肪酸组成的影响及其相关关系 出生前3年的生长轨迹和3岁时的BMI和身体成分的研究结果； 注释宿主脱落上皮细胞转录组和细菌转录组并阐明 关注FFAR相关途径的寄主/共生关系，并将这些发现与生长相关 出生前3年的轨迹和3岁时的BMI和身体成分。我们的团队处于理想的位置 进行这项研究。我们开创性的同时监测基因表达的非侵入性方法 在婴儿的脱落上皮细胞和肠道微生物区系方面具有很高的创新性。这项工作意义重大 因为分子生物标志物定义了饮食摄入量、微生物区系组成、 将确定宿主基因表达和儿童健康结果。这些宿主微生物分子指纹 将使患者驱动的精准医学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.