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) 可能包括非父母原因造成的生长缺陷 身高、胎龄或营养不良。最近对肠道微生物组的研究表明，扰动 生命早期肠道细菌的种群动态可能对宿主产生有害后果 包括发育迟缓和其他通常与一生营养不良相关的后遗症。影响 微生物群的改变可能会抵消通过改善营养来克服这些缺陷的努力。酒精 已证明食用会改变成人中特定细菌属的比例。从新生儿开始 婴儿继承了生母的菌群，因此 FASD 高风险新生儿的肠道很可能发生了改变 鉴于肠道细菌在处理某些特定物质方面的重要性，微生物组最终会导致营养不良 食品并产生饮食需求。肠道细菌在促进免疫功能方面也发挥着至关重要的作用 体内平衡。细菌种群的改变可能导致 IL-25 产生的下调减少 上皮细胞和促炎性 T 细胞增加。肠道微生物组在 FASD 相关中的作用 基于免疫的疾病和生长障碍尚未得到充分研究。我们假设新生老鼠 与对照大鼠幼仔相比，在子宫内接触酒精会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。为了检验这个假设 我们建议 1) 比较长期饮酒前后雌性大鼠的肠道微生物群， 随着时间的推移，分析幼崽的肠道微生物群，以确定它们是否采用了母亲的菌群。 此外，我们将确定该菌群是否与为控制不接收的水坝而出生的幼崽的菌群不同。 酒精。 2) 比较子宫内接触酒精的幼仔的肠道免疫特征，以控制幼仔 确定酒精暴露是否会导致调节性免疫系统元素减少和免疫系统元素增加 促炎标记物和 T 细胞。 3) 识别与失败相关的肠道微生物群中的细菌谱 茁壮成长和/或免疫失调，并确定这些病症是否可以通过治疗来治疗 应用益生菌来匹配出生幼崽的结肠菌群，以控制母鼠。未来的研究可以 如果这些动物研究为临床提供了合理的前提，那么很容易应用于人类受试者 调查。