Liver-Gut-Microbiome Axis and Fatty acid absorption in Preterm Infants

早产儿的肝脏-肠道-微生物轴和脂肪酸吸收

基本信息

批准号：
10635182
负责人：
Amy Boriskie Hair
金额：
$ 70.9万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-16 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10635182
关键词：
Address Age Animals Bile Acid Biosynthesis Pathway Bile Acids Biological Availability Birth Blood Brain Characteristics Cholestasis Chronic lung disease Clinical Clinical Nutrition Coupled Development Diet Dietary Fatty Acid Dietary intake Digestion Early Intervention Enteral Enzymes Failure Fatty Acids Fatty acid glycerol esters Feces Future Gene Dosage Genes Growth Health Health Benefit Homeostasis Hour Human Milk Hydrolase Immunologic Factors Impairment In Vitro Individual Infant Inflammatory Infrastructure Intestinal Absorption Intestines Knowledge Life Linear Models Link Lipase Lipids Liver Malabsorption Syndromes Malnutrition Mass Fragmentography Measures Metabolic Pathway Microbe Modeling Morbidity - disease rate Necrotizing Enterocolitis Neonatal Nutrient Nutritional Outcome Pathogenesis Physiology Placenta Polyunsaturated Fatty Acids Population Premature Birth Premature Infant Regulation Retina Retinopathy of Prematurity Risk Sepsis Serum Shapes Shotgun Sequencing Technology Third Pregnancy Trimester Time Very Low Birth Weight Infant Weight Gain absorption analytical tool bile acid metabolism bile salts cohort donor milk effective intervention enzyme activity experience gut bacteria gut microbiome gut microbiota high risk immune function improved infancy infant outcome long chain fatty acid metagenome microbial mortality neonatal care neonatal morbidity novel novel therapeutics nutrition pasteurization placental transfer postnatal premature prospective recruit therapeutic target uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Current nutritional strategies fail to meet the needs of very low birth weight infants, with more than half developing malnutrition, growth failure, and other poor outcomes. Long Chain Polyunsaturated Fatty Acids (LCPUFAs) are vital for brain and retinal development, immune function, inflammatory regulation, and health. Placental transfer of LCPUFAs is highest in the third trimester, but this transfer abruptly stops upon premature birth. Current nutritional strategies do not correct postnatal LCPUFA deficits. The Liver-Gut-Microbiome Axis regulates enteral fat and fatty acid digestion, assimilation, and absorption. Gut bacteria metabolize intestinal lipids and secrete molecules that alter lipid uptake and shape bile acid homeostasis via bile salt hydrolases and other microbial enzymes. In turn, dietary fatty acids including LCPUFAs impact physiology both directly and by shaping gut microbial community composition and function. It is unclear how immature gut microbiota and bile acids in VLBW infants contribute to impaired fatty acid and LCPUFA absorption. We have shown that VLBW infants fed donor milk have impaired growth and less alpha-diversity of gut microbiota than those fed maternal milk. We hypothesize that impaired growth and decreased alpha-diversity is caused by the lack of intact lipase due to pasteurization of donor milk and by impaired fatty acid absorption. We have shown that stool from cholestatic VLBW infants with impaired growth contains less microbial bile salt hydrolase enzymatic activity, fewer unconjugated fecal bile acids, and impaired secondary bile acid synthesis compared to VLBW infants without cholestasis. Together, these results suggest an association between impaired fatty acid absorption, an immature Liver-Gut-Microbiome Axis, and altered bile acid metabolism. We hypothesize that an immature Liver-Gut- Microbiome Axis lacks key microbial bile acid modifying genes, resulting in altered bile acid composition and impaired fatty acid and LCPUFAs absorption. Aim 1: Establish the longitudinal coefficient of fatty acid absorption of key fatty acids in a prospective VLBW infant cohort. Coefficients of fat absorption (CFA) will be calculated using GC-MS to measure different individual fatty acids from 72-hour dietary intakes and fecal losses. We will use linear modeling to identify clinical determinants of CFA over time. Aim 2: Quantify relative abundances of microbial bile acid modifying genes and activity and determine their impact on bile acid composition and fatty acid absorption coefficients in preterm infants. Total and individual bile acid concentrations in serum and stool from VLBW infants using MS. Microbial bile acid modifying genes will be identified in stool using whole metagenome shotgun sequencing and gene copy numbers will be confirmed by qPCR. Bile salt hydrolase enzyme activity will be quantified in vitro. Using state-of-the-art technologies and analytic tools, our expert team will advance our understanding of gut microbial alterations, bile acid homeostasis, and fatty acid absorption in VLBW infants to define novel mechanisms and future therapeutic targets to enhance nutrient uptake and to improve fat absorption, growth, and health outcomes in VLBW infants.

项目摘要/摘要当前的营养策略无法满足非常低的出生体重婴儿的需求，其中一半以上发展营养不良，生长失败和其他差的结果。长链多不饱和脂肪酸（LCPUFA）是对于大脑和视网膜发育，免疫功能，炎症调节和健康至关重要。胎盘转移 LCPUFA在三个月中最高，但是这种转移在早产后突然停止。当前的营养策略不能纠正产后LCPUFA缺陷。肝甲状腺微生物组轴调节肠脂肪和脂肪酸消化，同化和吸收。肠道细菌代谢肠脂质并分泌通过胆汁盐水解酶和其他微生物改变脂质摄取并塑造胆汁酸稳态的分子酶。反过微生物社区组成和功能。目前尚不清楚VLBW中未成熟的肠道菌群和胆汁酸如何婴儿有助于脂肪酸和LCPUFA吸收受损。我们已经证明VLBW婴儿喂养供体牛奶的生长受损，肠道菌群的α多样性较少，而牛奶比喂孕产妇的牛奶。我们假设生长受损和α多样性降低是由于缺乏完整脂肪酶引起的供体牛奶的巴氏杀菌和脂肪酸吸收受损。我们已经证明了胆汁淤积的凳子生长受损的VLBW婴儿含有较少的微生物胆汁盐水解酶酶活性，较少与没有VLBW的婴儿相比胆汁淤积。总之，这些结果表明脂肪酸吸收受损（未成熟）之间存在关联肝甲状腺微生物组轴，并改变了胆汁酸代谢。我们假设未成熟的肝脏 - 微生物组轴缺乏关键的微生物胆汁酸修饰基因，从而改变了胆汁酸成分以及脂肪酸和LCPUFAS吸收受损。目标1：建立脂肪酸的纵向系数在前瞻性VLBW婴儿队列中吸收钥匙脂肪酸。脂肪吸收系数（CFA）将是使用GC-MS计算出72小时饮食摄入量和粪便损失的不同个体脂肪酸。我们将使用线性建模来确定CFA的临床决定因素。目标2：量化相对微生物胆汁酸修饰基因和活性，并确定其对胆汁酸的影响早产儿的组成和脂肪酸吸收系数。总胆汁酸浓度使用MS的VLBW婴儿的血清和粪便。将在粪便中鉴定出微生物胆汁酸修饰基因使用整个元基因组shot弹枪测序和基因拷贝数将由qPCR确认。胆汁盐水解酶活性将在体外进行定量。使用最先进的技术和分析工具，我们专家团队将促进我们对肠道微生物改变，胆汁酸稳态和脂肪酸的了解 VLBW婴儿的吸收以定义新的机制和未来的治疗靶标，以增强养分 VLBW婴儿的吸收并改善脂肪的吸收，生长和健康结果。