Maternal diet and programming of offspring gut-brain axis

肥胖症在全球范围内继续上升。母亲肥胖与高热量饮食的摄入 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。母性兴奋 怀孕期间摄入脂肪(HF)可能会对胎儿产生持续的有害影响 易患肥胖症及其并发症。我们在老鼠模型中的初步数据表明 母体的HF饮食对后代通过肠道控制食物摄入量有负面影响。 脑轴。我们最重要的假设是，围产期接触铅引起的肠道微生物失调 母体HF饮食改变肠-脑轴的发育和迷走神经介导的控制 哺育后代会增加肥胖和其他代谢紊乱的易感性。 目标1将确定如何改变迷走神经介导的摄食控制在大鼠的后代中 在怀孕和哺乳期间消耗HF的水坝。我们假设HF后代将会是 对外周胃肠激素、餐前负荷和/或正常情况下的营养物质不太敏感 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 在HF后代中发生改变。我们假设减少饱腹感的反应是因为 (A)从肠道到大脑的VAN投射结构发生变化；(B)缺陷 肠内分泌细胞的数量或功能，和/或(C)迷走神经对肠道的反应较差 反馈信号。目标3将确定肠道微生物区系组成在心力衰竭后代中的作用 肥胖和其他代谢紊乱的倾向。我们的初步数据显示，高频 到断奶时，后代的肠道生态失调，肠道通透性更强 出生后第21天。生物失调足以改变迷走神经的结构和功能，因此我们 假设HF子代的肠道生物失调对肠道-脑轴的发育和 功能。我们将把非生物的HF微生物区系转移到无菌新生儿身上，以测试是否足够 肠道-脑轴功能改变中的微生物失调，并确定是否使用益生菌使其正常化 饲喂HF的母鸡的微生物区系组成，以及它们的后代，将改善后代 肠脑轴的发育和功能。总之，拟议中的实验将确定 肠道-脑轴的组成部分，因早期接触母体HF饮食而改变 可作为干预措施预防心力衰竭长期不良代谢后果的靶点 后代。

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.