Gut permeability and variations in bio-available vitamin D as mechanisms of adverse cognitive development in HIV-affected & control children - Anested Pilot Study

肠道通透性和生物可利用维生素 D 的变化是 HIV 感染者认知发展不良的机制

• 批准号: 10742582
• 负责人: AMARA E EZEAMAMA
• 金额: $ 22.65万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10742582
• 关键词: Adaptive Immune System; Affect; Altitude; Area; Attention deficit hyperactivity disorder; Behavior assessment; Biological Availability; Biological Markers; Blood - brain barrier anatomy; Central Nervous System; Child; Clinical; Cognitive; Data; Development; Diagnosis; Disease; Future; General Population; HIV; High Prevalence; Homeostasis; Immune; Innate Immune System; Intestinal permeability; Investigation; Knowledge; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Perinatal; Persons; Pilot Projects; Prevalence; Probability; Regimen; Risk; System; United States National Institutes of Health; Variant; Vitamin D; Vitamin D Deficiency; autism spectrum disorder; cognitive development; design; developmental disease; disorder risk; dysbiosis; emotional adjustment; gut microbiome; indexing; metabolome; metabolomics; microbial; microbiota-gut-brain axis; neurocognitive disorder; neurodevelopment; nutrition; parent grant; social

Vitamin D deficiency (VDD) is common in the general population, especially among people living in higher altitudes or areas with limited sunshine as well as persons living with HIV (PLWH). VDD impacts the gut microbiome and disturbances along the gut-brain microbiota axis may influence the central nervous system (CNS) homeostasis, alter innate and adaptive immune systems, and increase intestinal permeability and microbial translocation making the gut and blood-brain barriers leaky. VDD is also associated with higher prevalence of developmental disorders like autism spectrum disorder (ASD), attention deficit and hyperactivity disorder (ADHD), and poor socio-emotional adjustment in children. Studies among cART treated persons suggest ART further dysregulates vitamin D metabolome in potentially regimen dependent fashion. For children HIV exposed but uninfected, whether peripartum-ART exposure during sensitive developmental windows results in long-lasting changes in the metabolome of vitamin D with consequence for gut microbial profile and neurodevelopmental trajectory remains unknown. Our ongoing RO1 study aims to develop a Cognitive Risk Index (CRI) by combining data on nutrition, immune parameters and HIV status and their interactions to validate CRI as a predictor of neurocognitive disorders at 12 months. In this pilot study we collect preliminary data for future definitive investigations and inform existing knowledge gap by investigating HIV status and early ART exposure related dysregulations in vitamin D metabolome and gut- microbial dysbiosis as modifiable mechanisms of adverse cognitive development and developmental disorder risk in vulnerable children. Specific aims include: To a) Assess vitamin D metabolites using a metabolomic approach to quantify relative abundance of bioactive forms of the respective Vitamin-D canonical forms (D2, D3). b) Assess biomarkers of intestinal permeability and its relationship with VDD, and HIV status. c) Clinically evaluate and diagnose 100 children selected per baseline disorder probability scores estimated per the Behavioral Assessment System for Children, Third Edition (BASC3) and the social Responsiveness Scale, Second Edition. Overall Impact: This data will provide preliminary data that serves as proof of concept to further establish the scientific rationale for a more definitive mechanistic study of variations in the metabolome of vitamin D and gut-microbial dysbiosis as modifiable determinants of adverse neurodevelopment among Ugandan HIV-affected and control children.

维生素D缺乏症（VDD）在普通人群中很常见，尤其是在 生活在高海拔地区或日照有限地区的人以及艾滋病毒感染者 （PLWH）。VDD影响肠道微生物组和沿着肠-脑微生物群轴的干扰 可能影响中枢神经系统（CNS）的稳态，改变先天和适应性 免疫系统，并增加肠道通透性和微生物易位，使 肠道和血脑屏障渗漏VDD也与较高的患病率有关， 发育障碍，如自闭症谱系障碍（ASD），注意力缺陷和多动症 注意力缺陷多动障碍（ADHD），以及儿童社会情绪适应不良。cART研究 接受ART治疗的患者表明，在潜在的治疗方案中，ART进一步失调维生素D代谢组 依赖的方式。对于暴露于艾滋病毒但未感染的儿童， 在敏感的发育窗口期暴露， 维生素D代谢组与肠道微生物谱和神经发育的关系 弹道仍然未知。 我们正在进行的RO 1研究旨在通过结合以下数据开发认知风险指数（CRI）： 营养、免疫参数和艾滋病毒状况及其相互作用，以验证CRI作为一种 12个月时神经认知障碍的预测因子。在这项试点研究中，我们收集了初步的 通过调查艾滋病毒，为未来的确定性调查提供数据，并告知现有的知识差距 维生素D代谢组学和肠道中与早期ART暴露相关失调的现状和 微生物生态失调作为不良认知发展的可改变机制， 易受伤害儿童的发育障碍风险。具体目标包括： a）使用代谢组学方法评估维生素D代谢物以量化相对丰度 各自维生素D典型形式的生物活性形式（D2，D3）。 B）评估肠通透性的生物标志物及其与VDD和HIV状态的关系。 c）根据基线障碍概率选择100名儿童进行临床评估和诊断 根据儿童行为评估系统（第三版）估计的分数 （BASC 3）和社会反应量表，第二版。 总体影响：该数据将提供初步数据，作为进一步 建立科学的理由，为更明确的机制研究的变化， 维生素D代谢组和肠道微生物生态失调作为不良反应的可改变决定因素 乌干达受艾滋病毒感染儿童和对照儿童的神经发育。