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

• 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
• 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

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.

项目概要/摘要 目前的营养策略无法满足极低出生体重婴儿的需求，其中一半以上正在发育 营养不良、生长障碍和其他不良结果。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。胎盘移植 LCPUFAs 的含量在妊娠晚期最高，但这种转移在早产时突然停止。当前的 营养策略不能纠正产后 LCPUFA 缺乏。肝-肠-微生物轴调节肠道 脂肪和脂肪酸的消化、同化和吸收。肠道细菌代谢肠道脂质并分泌 通过胆汁盐水解酶和其他微生物改变脂质摄取并形成胆汁酸稳态的分子 酶。反过来，包括 LCPUFA 在内的膳食脂肪酸会直接影响生理机能并通过塑造肠道 微生物群落的组成和功能。目前尚不清楚 VLBW 中未成熟的肠道微生物群和胆汁酸如何 婴儿会导致脂肪酸和 LCPUFA 吸收受损。我们已经证明，VLBW 婴儿喂养的捐赠者 与母乳喂养相比，母乳喂养会损害生长，肠道微生物群的α多样性也较低。我们 假设生长受损和α多样性减少是由于缺乏完整的脂肪酶造成的 捐赠母乳的巴氏灭菌和脂肪酸吸收受损。我们已经证明粪便来自于胆汁淤积 生长受损的 VLBW 婴儿含有较少的微生物胆汁盐水解酶活性，较少 与未结合的极低出生体重婴儿相比，粪便胆汁酸未结合，次级胆汁酸合成受损 胆汁淤积。总之，这些结果表明脂肪酸吸收受损与不成熟的脂肪酸吸收之间存在关联。 肝脏-肠道-微生物轴，以及改变的胆汁酸代谢。我们假设未成熟的肝肠- 微生物组 Axis 缺乏关键的微生物胆汁酸修饰基因，导致胆汁酸成分改变 脂肪酸和 LCPUFA 吸收受损。目标 1：建立脂肪酸的纵向系数 前瞻性 VLBW 婴儿队列中关键脂肪酸的吸收。脂肪吸收系数 (CFA) 为 使用 GC-MS 计算，测量 72 小时饮食摄入量和粪便损失中的不同个体脂肪酸。 我们将使用线性模型来确定 CFA 随着时间的推移的临床决定因素。目标 2：量化相对值 微生物胆汁酸修饰基因和活性的丰度并确定它们对胆汁酸的影响 早产儿的成分和脂肪酸吸收系数。总胆汁酸浓度和个体胆汁酸浓度 使用 MS 在 VLBW 婴儿的血清和粪便中进行检测。将在粪便中鉴定微生物胆汁酸修饰基因 使用全宏基因组鸟枪法测序，并通过 qPCR 确认基因拷贝数。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 专家团队将增进我们对肠道微生物改变、胆汁酸稳态和脂肪酸的理解 极低出生体重婴儿的吸收，以确定增强营养的新机制和未来治疗目标 摄取并改善极低出生体重婴儿的脂肪吸收、生长和健康结果。