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.

肥胖在全球范围内继续上升。孕妇肥胖和高卡路里饮食的消费 继续成为公共卫生问题。宫内和早期产后环境 提供对后代正确发展和健康至关重要的支持。母亲高 怀孕期间的脂肪（HF）饮食消耗可能会对胎儿产生持续的有害影响 这种易感肥胖及其合并症。我们在大鼠模型中的初步数据表明 孕产妇饮食对食物摄入的后代控制造成负面影响 - 脑轴。我们的总体假设是，围产期暴露于 母体HF饮食改变肠道轴的发展和模糊介导的对照 进食后代，导致对肥胖症和其他代谢障碍的敏感性增加。 AIM 1将确定在大鼠后代中如何改变模糊介导的喂养控制 在怀孕和哺乳期间食用HF的大坝。我们假设HF后代将是 对外围肠道激素，进餐预载和/或营养素的敏感性不太敏感 促进饱腹感。 AIM 2将决定肠道与大脑之间的迷走神经交流 HF后代有所改变。我们假设饱食反应减少是因为 （a）从肠道到大脑的货车投影的结构发生了变化，（b）缺陷 在肠内分泌细胞号或功能中，/或（c）迷走神经对肠道的反应较低 反馈信号。 AIM 3将定义肠道菌群组成在HF后代中的作用 肥胖和其他代谢疾病的倾向。我们的初步数据表明HF 后代患有肠道营养不良和肠道通透性更大 在产后第21天。营养不良足以改变迷走神经结构和功能，因此我们 假设HF后代中的肠道营养不良会对肠道轴的发育产生负面影响 功能。我们将将不植物HF微生物群转移到无细菌的新生儿，以测试足够的功能 肠脑轴功能改变的营养不良，并确定是否使用益生元来归一化 HF喂养水坝的微生物群构成及其后代将改善后代 肠道轴的发展和功能。提出的实验将共同确定 肠道轴的成分会因早期寿命暴露于母性HF饮食和 可能是预防HF中不良长期代谢后果的干预目标 后代。