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

母亲高脂肪饮食对后代肠道菌群和 Th17 轴的影响

• 批准号: 8766100
• 负责人: Julie Mirpuri-Hathiramani
• 金额: $ 15.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766100
• 关键词: Adult; Affect; Age; American; Bacteria; Barker Hypothesis; Biological Response Modifiers; Birth; Blocking Antibodies; CD4 Positive T Lymphocytes; Cells; Colon; DNA Sequence; Data; Dendritic Cells; Detection; Development; Development Plans; Diet; Disease; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Enzymes; Epigenetic Process; Epithelial Cells; Fatty Acids; Fatty acid glycerol esters; Female of child bearing age; Flow Cytometry; Food; Fostering; Germ-Free; Goals; Helper-Inducer T-Lymphocyte; Human Milk; Immune; Immune response; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-17; Intestines; K-Series Research Career Programs; Lactobacillus casei rhamnosus; Lamina Propria; Link; Lipids; Lymphocyte; Lymphoid Cell; Mentors; Methylation; Microbiology; Microscopy; Modeling; Mothers; Mus; Necrotizing Enterocolitis; Neonatal; Obesity; Overweight; Physicians; Play; Population; Predisposition; Prevention; Probiotics; Production; Proteobacteria; Publishing; Regulation; Reporter; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Scientist; Site; Source; T-Lymphocyte; Techniques; Testing; Training; Training Programs; United States National Institutes of Health; Weaning; Woman; Work; base; career development; chemokine; cytokine; fetal; gut microbiota; innovation; insight; interest; novel; offspring; prenatal; programs; public health relevance; pup; rRNA Genes; response; saturated fat; transmission process; treatment strategy

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.

描述(由申请者提供)：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，该候选人是一名医生科学家，长期目标是成为一名独立的学术研究人员。候选人的目标是成为黏膜免疫学和微生物学方面的专家，研究重点是了解控制肠道微生物区系获取的因素以及随后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综合计划，其中包括新颖的科学想法、免疫学和微生物学方面的高级培训以及详细的职业发展计划。候选人建议建立在早期微生物区系的初步工作基础上，从机械上了解母亲高脂饮食(HFD)在改变后代肠道细菌组成、Th17反应和肠道损伤易感性方面的作用。候选人的初步工作表明，在常规饲养的小鼠中，微生物区系从出生到成年的转变存在主动的免疫调节。此外，60%高脂饮食的母亲生下的一周大的小鼠被发现有一个独特的微生物区系，与正常饮食的母亲所生的年龄匹配的对照组不同。研究还发现，HFD后代在结肠中增加了促炎细胞因子IL-17的表达，这种细胞因子主要由Th17细胞产生，并增加了对早期(10日龄)和晚期(成人)肠道损伤模型的易感性。这一提议的中心假设是，HFD后代的表观遗传学改变会导致独特的微生物区系，并与母乳中的因素结合，直接影响Th17轴的发育，从而容易发生肠道损伤。将考察3个具体目标：1)研究微生物区系如何改变HFD后代的肠道Th17反应；2)确定表观遗传学或母乳(BM)如何改变HFD后代的微生物区系和Th17反应；3)研究益生菌是否能调节HFD后代对肠道损伤的易感性。这项建议的一个创新是关注母体HFD引起的肠道炎症性疾病的胎儿起源。这项研究将提供深入的见解，了解母亲的饮食如何改变后代的微生物区系，以及随后的免疫肠道调节，以促进炎症性疾病的规划。它在坏死性小肠结肠炎和炎症性肠病中有特别的相关性，并可能有助于开发新的治疗策略。