Impact of maternal high fat diet on the gut microbiota and Th17 axis in offspring

描述（由申请人提供）：这份由NIH指导的职业发展奖提案描述了为候选人提供的为期三年的培训计划，该候选人是一名内科科学家，其长期目标是成为一名独立的学术研究者。该候选人的目标是成为粘膜免疫学和微生物学专家，研究重点是了解控制肠道微生物群获取的因素及其对肠道免疫反应编程的影响。为了实现这些目标，候选人和她的导师提出了一个完整的计划，包括新颖的科学思想，在免疫学和微生物学方面的高级培训和详细的职业发展规划。该候选人建议在早期微生物群的初步研究基础上，从机制上了解母体高脂肪饮食（HFD）对改变子代肠道细菌组成、Th17反应和肠道损伤易感性的作用。候选人的初步工作表明，在传统饲养的小鼠中，微生物群从出生到成年的过渡存在主动免疫调节。此外，喂食60%高热量食物的母亲所生的1周大的小鼠幼崽被发现具有独特的微生物群，与喂食常规食物的母亲所生的同龄对照小鼠不同。研究还发现，HFD后代结肠中促炎细胞因子IL-17的表达增加，IL-17主要由Th17细胞产生，并且对早期（10日龄）和晚期（成年）肠道损伤模型的易感性增加。该建议的核心假设是，HFD后代的表观遗传改变导致独特的微生物群，并与母乳中的因素结合，直接影响Th17轴的发育，易导致肠道损伤。研究的三个具体目的是：1)研究微生物群如何改变HFD后代肠道Th17反应；2)确定表观遗传学或母乳（BM）如何改变HFD后代肠道微生物群和Th17反应；3)研究益生菌是否可以调节HFD后代肠道损伤的易感性。该提案的一个创新之处在于关注母体HFD引起的肠道炎症性疾病的胎儿起源。这项研究将深入了解母体饮食如何改变后代的微生物群和随后的肠道免疫调节，从而促进炎症性疾病的编程。它与坏死性小肠结肠炎和炎症性肠病特别相关，可能有助于开发新的治疗策略。

DESCRIPTION (provided by applicant): This NIH mentored Career Development Award proposal describes a three-year training program for the candidate, a physician-scientist with the long-term goal of becoming an independent academic investigator. The candidate aims to become an expert in mucosal immunology and microbiology with a research focus on understanding the factors controlling the acquisition of the intestinal microbiota and subsequent effects on programming of the intestinal immune response. To accomplish these goals, the candidate and her mentors put forward an integrated plan encompassing novel scientific ideas, advanced training in immunology and microbiology and a detailed career development plan. The candidate proposes to build on preliminary work on the early microbiota to mechanistically understand the role of maternal high fat diet (HFD) on altering offspring gut bacterial composition, the Th17 response and susceptibility to intestinal injury. Preliminary work by the candidate has shown that there is active immune regulation of the transition of the microbiota from birth into adulthood in conventionally raised mice. Additionally, 1-week-old mouse pups born to mothers on a 60% HFD were found to have a unique microbiota, different from age-matched controls born to mothers on regular chow. HFD offspring were also found to have increased expression of the pro-inflammatory cytokine IL-17 in the colon, which is primarily produced by Th17 cells, and increased susceptibility to early (10-day-old) and late (adult) models of intestinal injury. The central hypothesis for this proposal is that epigenetic alteration in HFD offspring results in a unique microbiota, and combined with factors in breast milk, directly affects the development of the Th17 axis, predisposing to intestinal injury. 3 specific aims will be examined: 1) To examine how the microbiota alters the intestinal Th17 response in HFD offspring, 2) To determine how epigenetics or breast milk (BM) alter the microbiota and Th17 response in HFD offspring and 3) To examine whether probiotics can modulate the susceptibility to intestinal injury in HFD offspring. An innovation in this proposal is the focus o fetal origins of intestinal inflammatory diseases caused by maternal HFD. This study will provide insight into how maternal diet alters the offspring microbiota and consequent immune intestinal regulation to contribute to the programming of inflammatory disease. It has particular relevance in Necrotizing Enterocolitis and Inflammatory Bowel Disease and may contribute to the development of novel treatment strategies.