Maternal diet and programming of offspring gut-brain axis

母亲饮食和后代肠脑轴的编程

• 批准号: 10656194
• 负责人: KELLIE L. K. TAMASHIRO
• 金额: $ 55.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-30 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656194
• 关键词: Adult; Afferent Neurons; Behavior; Birth; Brain; Calcium; Calories; Cell Count; Cell physiology; Child; Cholecystokinin; Communication; Consumption; Coronary Arteriosclerosis; Data; Development; Diet; Eating; Energy consumption; Enteroendocrine Cell; Environment; Epidemic; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Feedback; Fetus; Future; Germ-Free; Health; High Fat Diet; Homeostasis; Hormones; Hyperphagia; Hypertension; Image; Impairment; Individual; Inflammation; Inflammatory; Interdisciplinary Study; Intervention; Intestinal permeability; Intestines; Lactation; Leaky Gut; Life; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Methods; Modeling; Mothers; Neurobiology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Overweight; Pattern; Perinatal; Perinatal Exposure; Peripheral; Phenotype; Predisposition; Pregnancy; Prevalence; Public Health; Rattus; Regulation; Resistance; Risk; Role; Satiation; Sensory; Signal Transduction; Starch; Stimulus; Structure; Testing; Time; Tracer; Vagus nerve structure; Virus; Weaning; Weight Gain; combinatorial; comorbidity; critical period; diet-induced obesity; dysbiosis; early life exposure; experimental study; feeding; genome wide association study; genomic locus; gut dysbiosis; gut microbiota; gut-brain axis; improved; innovation; intestinal crypt; maternal obesity; microbiota; mother nutrition; negative affect; neonate; neural; neurotransmission; normal microbiota; nutrition; obesity in children; offspring; perinatal environment; physical inactivity; postnatal; postnatal period; prebiotics; prevent; response; skills; systemic inflammatory response; therapy development; translation to humans

Obesity continues to rise worldwide. Maternal obesity and consumption of high calorie diets continue to be public health concerns. The intrauterine and early postnatal environment provides support that is critical to the proper development and health of offspring. Maternal high fat (HF) diet consumption during pregnancy can have persistent detrimental effects on the fetus that predispose to obesity and its comorbidities. Our preliminary data in a rat model suggest that maternal HF diet has negative consequences on offspring controls of food intake via the gut- brain axis. Our overarching hypothesis is that gut dysbiosis resulting from perinatal exposure to maternal HF diet alters development of the gut-brain axis and vagally-mediated controls of feeding in offspring leading to increased susceptibility to obesity and other metabolic disorders. Aim 1 will determine how vagally-mediated controls of feeding are altered in rat offspring from dams consuming a HF during pregnancy and lactation. We hypothesize that HF offspring will be less sensitive to peripheral gut hormones, meal pre-loads, and/or nutrients that normally promote satiety. Aim 2 will determine how vagal communication between the gut and the brain is altered in HF offspring. We hypothesize that decreased satiation responses occur because (a) there is an alteration in the structure of VAN projections from the gut to the brain, (b) deficits in enteroendocrine cell number or function, and/or (c) the vagus nerve is less responsive to gut feedback signals. Aim 3 will define the role of gut microbiota composition in HF offspring propensity to obesity and other metabolic disorders. Our preliminary data indicate that HF offspring have gut dysbiosis and greater intestinal permeability by the time that they are weaned at postnatal day 21. Dysbiosis is sufficient to alter vagal structure and function, therefore we hypothesize that gut dysbiosis in HF offspring negatively affects gut-brain axis development and function. We will transfer dysbiotic HF microbiota to germ-free neonates to test sufficiency of dysbiosis in altered gut-brain axis function and determine whether use of prebiotics to normalize microbiota composition of HF fed dams, and consequently their offspring, will improve offspring gut-brain axis development and function. Together the proposed experiments will identify components of the gut-brain axis that are altered by early life exposure to maternal HF diet and could be targets for intervention to prevent adverse long-term metabolic consequences in HF offspring.

肥胖症在全球范围内持续上升。产妇肥胖和高热量饮食消费 仍然是公共卫生问题。宫内和出生后早期环境 提供对后代的正常发育和健康至关重要的支持。母体高 妊娠期食用高脂饮食可能对胎儿产生持续的有害影响 易患肥胖症及其合并症的疾病。我们在大鼠模型中的初步数据表明， 母体HF饮食对后代通过肠道控制食物摄入具有负面影响， 脑轴我们的总体假设是，围产期暴露于 母体HF饮食改变肠-脑轴的发育和迷走神经介导的 喂养后代，导致对肥胖和其他代谢紊乱的易感性增加。 目的1将确定迷走神经介导的摄食控制在大鼠后代中是如何改变的， 在妊娠和哺乳期间摄入HF的母鼠。我们假设HF后代将 对周围肠道激素、膳食前负荷和/或通常 促进饱腹感。目标2将确定肠道和大脑之间的迷走神经通信 在HF后代中发生改变。我们假设，减少饱足反应发生，因为 (a)从肠道到大脑的货车投射结构发生改变，（B）缺陷 在肠内分泌细胞数量或功能方面，和/或（c）迷走神经对肠内分泌细胞数量或功能的反应性较低， 反馈信号目的3将定义HF后代中肠道微生物群组成的作用 肥胖和其他代谢紊乱的倾向。我们的初步数据表明，HF 后代在断奶时会出现肠道生态失调和更大的肠道通透性 出生后第21天。生态失调足以改变迷走神经的结构和功能，因此我们 假设HF后代肠道生态失调对肠-脑轴发育有负面影响， 功能我们将把失调的HF微生物群转移到无菌新生儿身上，以测试 肠-脑轴功能改变的生态失调，并确定是否使用益生元来恢复正常 HF喂养母鼠的微生物群组成，以及因此它们的后代，将改善后代 肠脑轴的发育和功能。这些拟议的实验将共同确定 肠-脑轴的组成部分，这些组成部分因生命早期暴露于母体HF饮食而改变， 可能是干预的目标，以防止HF的不良长期代谢后果 后代