Prenatal alcohol effects on the gut microbiome contributing to failure to thrive and altered immune function

产前酒精对肠道微生物组的影响导致发育不良和免疫功能改变

• 批准号: 9391802
• 负责人: THOMAS G BLANCHARD
• 金额: $ 11.22万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391802
• 关键词: Actinobacteria class; Address; Adopted; Adoptive Transfer; Adult; Aftercare; Alcohol consumption; Alcohols; Animals; Back; Bacteria; Bacteroidetes; Biological Markers; Birth; Categories; Cells; Child health care; Colon; Consensus; Diet; Disadvantaged; Discipline of Nursing; Disease; Elements; Epithelial Cells; Failure to Thrive; Female; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Food; Funding; Future; Gestational Age; Growth; Health; Height; Homeostasis; Housing; Human; Human Microbiome; Immune; Immune response; Immune system; Immunity; Immunofluorescence Immunologic; Immunologics; Immunosuppression; In Vitro; Infant; Influentials; Intestines; Large Intestine; Life; Lymphocyte; Modeling; Mothers; Nature; Neonatal; Newborn Infant; Nurses; Oral; Parents; Play; Population; Population Dynamics; Prevalence; Probiotics; Production; Rattus; Regulatory T-Lymphocyte; Resistance; Risk; Rodent; Role; Sampling; Small Intestines; Social Interaction; Source; Spleen; Study Subject; Systems Development; T cell response; T-Lymphocyte; Taxonomy; Testing; Therapeutic; Time; Translating; United States National Institutes of Health; Weaning; alcohol exposure; base; chronic alcohol ingestion; clinical investigation; cytokine; design; fecal transplantation; gut microbiome; gut microbiota; high risk; human subject; immune function; immunoregulation; improved; in utero; microbiome; microbiota; neonate; nutrition; offspring; pregnant; pup; response; social; sound

Fetal Alcohol Spectrum Disorder (FASD) can include growth deficiency that is not attributable to parental height, gestational age, or poor nutrition. Recent studies on the gut microbiome indicate that perturbations in the population dynamics of the gut bacteria early in life can have deleterious consequences on the host including failure to thrive and other sequelae typically associated with poor nutrition throughout life. The impact of an altered microbiota can negate efforts to overcome these deficiencies with improved nutrition. Alcohol consumption has been demonstrated to alter the ratios of defined bacterial genera in adults. Since newborn babies adopt the flora of the birth mother, it is likely that neonates at high risk for a FASD have an altered gut microbiome that ultimately translates to poor nutrition given the importance of gut bacteria in processing certain food products and generating dietary needs. Gut bacteria also play a crucial role in promoting immunologic homeostasis. Alterations in bacterial populations may result in less down-regulatory IL-25 production by epithelial cells and increased proinflammatory T cells. The role of the gut microbiome in FASD associated immunological based diseases and failure to thrive has been understudied. We hypothesize newborn rats exposed to alcohol in utero will develop altered gut microbiota upon delivery compared to control rat pups and that this altered microbiota will contribute to delayed growth and immune dysregulation. To test this hypothesis we propose to 1) Compare the gut microbiota of female rats before and after chronic consumption of alcohol, and analyze the gut microbiota of their pups over time to determine if they adopt the flora of the mother. Additionally, we will determine if the flora is distinct from that of pups born to control dams not receiving alcohol. 2) Compare the intestinal immune features from pups exposed to alcohol in utero to control pups to determine if alcohol exposure results in reduced regulatory immune system elements and an increase in proinflammatory markers and T cells. 3) Identify bacterial profiles in the gut microbiota associated with failure to thrive and/or immune dysregulation and determine if these conditions can be treated by therapeutic application of probiotics designed to match the colonic flora of pups born to control dams. Future studies could readily be applied to human subjects if these studies in animals provide a sound premise for clinical investigation.

胎儿酒精谱系障碍（FASD）可包括不归因于父母的生长缺陷。 身高胎龄或营养不良最近对肠道微生物组的研究表明， 肠道细菌在生命早期的种群动态可对宿主产生有害后果 包括不能茁壮成长和通常与一生中营养不良有关的其他后遗症。的影响 改变的微生物群可能会抵消通过改善营养来克服这些缺陷的努力。醇 已证明食用可改变成年人中确定的细菌属的比例。从新生儿开始 如果婴儿接受了生母的植物群，那么FASD高危新生儿的肠道可能会发生改变 考虑到肠道细菌在处理某些食物中的重要性， 食品和产生饮食需求。肠道细菌在促进免疫系统中也起着至关重要的作用。 体内平衡细菌种群的改变可能导致IL-25产生的下调减少， 上皮细胞和增加的促炎性T细胞。肠道微生物组在FASD相关性中的作用 基于免疫的疾病和不能茁壮成长的问题尚未得到充分研究。我们假设新生的老鼠 与对照大鼠幼崽相比，在子宫内暴露于酒精将在分娩时产生改变的肠道微生物群， 这种改变的微生物群将导致生长延迟和免疫失调。为了验证这一假设 我们建议1）比较慢性饮酒前后雌性大鼠的肠道微生物群， 并分析幼鼠的肠道微生物群，以确定它们是否采用了母亲的植物群。 此外，我们将确定植物群是否与对照母鼠出生的幼崽不同， 酒精2)比较子宫内暴露于酒精的幼崽与对照幼崽的肠道免疫特征， 确定酒精暴露是否会导致调节性免疫系统元素减少， 促炎标志物和T细胞。3)确定与失败相关的肠道微生物群中的细菌谱 以茁壮成长和/或免疫失调，并确定这些条件是否可以通过治疗 应用益生菌，以匹配出生的幼崽的结肠植物群，以控制母鼠。未来的研究可以 如果这些动物研究为临床研究提供了合理的前提， 调查