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: 10438957
• 负责人: KELLIE L. K. TAMASHIRO
• 金额: $ 57.26万
• 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/10438957
• 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; 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; nutrition; obesity in children; offspring; perinatal environment; physical inactivity; postnatal; postnatal period; prebiotics; prevent; relating to nervous system; response; 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.

全球肥胖率持续上升。产妇肥胖和高热量饮食 仍然是公共卫生问题。宫内和产后早期环境 提供对后代的正常发育和健康至关重要的支持。产妇高 怀孕期间摄入脂肪（HF）饮食会对胎儿产生持续的有害影响 容易导致肥胖及其合并症。我们在大鼠模型中的初步数据表明 母亲的高频饮食会对后代通过肠道控制食物摄入产生负面影响 脑轴。我们的首要假设是，肠道菌群失调是由于围产期暴露于 母亲高频饮食改变肠脑轴的发育和迷走神经介导的控制 喂养后代会导致肥胖和其他代谢紊乱的易感性增加。 目标 1 将确定迷走神经介导的进食控制在大鼠后代中如何改变 在怀孕和哺乳期间服用 HF 的母鼠。我们假设 HF 后代将是 对外周肠道激素、膳食预负荷和/或通常情况下的营养素不太敏感 促进饱腹感。目标 2 将确定肠道和大脑之间的迷走神经通讯方式 HF 后代发生改变。我们假设饱足反应减少是因为 (a) 从肠道到大脑的 VAN 投射结构发生改变，(b) 缺陷 肠内分泌细胞数量或功能，和/或 (c) 迷走神经对肠道的反应较弱 反馈信号。目标 3 将定义肠道微生物群组成在 HF 后代中的作用 肥胖和其他代谢紊乱的倾向。我们的初步数据表明，HF 后代断奶时肠道菌群失调，肠道通透性更大 出生后第 21 天。生态失调足以改变迷走神经结构和功能，因此我们 假设 HF 后代的肠道菌群失调会对肠脑轴发育产生负面影响 功能。我们将把失调的 HF 微生物群转移到无菌新生儿身上，以测试其充足性 肠脑轴功能改变中的菌群失调，并确定是否使用益生元使肠脑轴功能正常化 HF喂养的母鼠及其后代的微生物群组成将改善后代 肠脑轴的发育和功能。拟议的实验将共同确定 肠脑轴的组成部分因生命早期接触母亲高频饮食而改变， 可能是预防心力衰竭的长期不良代谢后果的干预目标 后代。