Exploring the role of microbiota and inflammation in tic fluctuations

探索微生物群和炎症在抽动波动中的作用

基本信息

批准号：
10431544
负责人：
Marco Bortolato
金额：
$ 24.36万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431544
关键词：
Acute Adolescent Affect Animal Model Animals Anti-Inflammatory Agents Archaea Area Bacteria Behavior Biological Process Blood Blood specimen Brain Child Chronic Clinical Clinical Research Communities Corpus striatum structure Development Dietary Factors Dose Feces Functional disorder Funding Future Germ-Free Gilles de la Tourette syndrome Goals Individual Inflammation Inflammatory Inflammatory Response Intestines Lead Leukocyte L1 Antigen Complex Lifestyle-related condition Link Measures Modification Molecular Mus Participant Pathogenesis Patients Peripheral Pharmaceutical Preparations Pharmacology Probiotics Problem Solving Production Role Running Safety Sampling Serious Adverse Event Severities Shapes Source Specimen TNF gene Testing Thalamic structure Therapeutic Tic disorder Time Transplantation Variant Waxes antagonist associated symptom base behavioral response beta-Defensins cytokine dietary disability experimental study factor A fecal transplantation fungus gastrointestinal system gut microbiota microbiota mouse model novel psychiatric comorbidity psychiatric symptom rRNA Genes relating to nervous system stereotypy translational impact translational study transplant model

项目摘要

ABSTRACT Chronic tic disorders (CTD), including Tourette’s disorder and persistent tic disorders, are a significant source of disability for children and adolescents, yet pharmacological therapies remain highly unsatisfactory due to serious adverse events. An ideal direction to develop safer treatments for CTD would be to target the same biological processes whereby tics spontaneously wax and wane over time; however, the mechanisms underlying these fluctuations remain poorly understood. A novel opportunity to solve this problem may come from recent evidence documenting that tic severity is influenced by the gut microbiota. Understanding whether changes in the composition of the gut microbiota may account for tic exacerbations - and through which molecular mechanisms - may lead to therapeutic breakthroughs in CTD; this issue, however, remains unexplored. The goal of the studies proposed in this R21 application is to explore whether and how variations in the gut microbiota contribute to tic exacerbations. The gut microbiota may influence tic severity through multiple mechanisms, including the synthesis of inflammatory cytokines. Ample correlational evidence points to tumor necrosis factor-α (TNF) as the inflammatory cytokine best associated with tic exacerbations. Thus, to test whether this cytokine increases tic severity, we evaluated its effects in a mouse model of CTD. These preliminary studies showed that low TNF doses that do not elicit sickness behavior significantly increase tic-like stereotypies in these mice. Based on these findings, we hypothesize that, in CTD patients, gut microbiota alterations lead to increased production of TNF or other inflammatory cytokines, which exacerbate tics. To test this hypothesis, the exploratory studies proposed in this R21 application will use a translational platform, combining clinical analyses in CTD patients and mechanistic experiments in mouse models. Specifically: - In Aim 1, we will assess the alterations of gut microbiota associated with CTD and test whether tic exacerbations are associated with alterations of the gut microbiota and inflammatory responses by testing fecal and blood samples from forty CTD patients and forty non-affected controls. - In Aim 2, we will test the causal link between gut microbiota alterations and tic exacerbations by transplanting fecal specimens from CTD-affected individuals into our mouse models of Tourette’s disorder; we will also test whether TNF or other inflammatory cytokines contribute to potential changes in tic severity. The translational studies proposed in this R21 application will be the first systematic analyses of the role of gut microbiota in tic fluctuations. If our hypothesis is verified, future R01-funded studies will test whether fecal material transplant from non-affected individuals and/or probiotic treatments can reduce tic severity. We will also study the downstream mechanisms whereby inflammation increases tic severity. Thus, our results may lead to the development of new, safer, mechanistically based treatments for CTD.

抽象的慢性抽动疾病（CTD），包括图雷特的疾病和持续性抽动疾病，是一个重要的儿童和青少年的残疾来源，但药理学疗法仍然高度令人满意由于严重的不良事件。为CTD开发安全治疗的理想方向是针对同样的生物学过程，随着时间的流逝，TICS会发出蜡和衰落。但是，机制这些波动的基础知识仍然很少。解决此问题的新型机会可能来自最近的证据，证明TIC严重性是受肠道菌群的影响。了解肠道菌群组成的变化是否变化可能会说明细胞的恶化以及通过哪种分子机制 - 可能导致治疗 CTD的突破；但是，这个问题仍然出乎意料。在此R21中提出的研究的目标应用是探索肠道微生物群的变化以及如何促进恶化的变化。肠道菌群可能通过多种机制影响抽动严重程度，包括合成炎症细胞因子。充分的相关证据指出肿瘤坏死因子-α（TNF）作为炎症性细胞因子与TIC加重有关。为了测试这种细胞因子是否增加了抽动严重程度，我们在CTD的小鼠模型中评估了其效果。这些初步研究表明TNF低不引起疾病行为的剂量会显着增加这些小鼠的tic样刻板印象。根据这些发现，我们假设在CTD患者中，肠道菌群改变导致增加 TNF或其他炎症细胞因子的产生，这加剧了TICS。为了检验这一假设，在此R21应用中提出的探索性研究将使用翻译平台，结合临床 CTD患者的分析和小鼠模型中的机理实验。具体来说： - 在AIM 1中，我们将评估与CTD相关的肠道微生物群的变化，并测试是否抽动恶化与肠道微生物群的改变和炎症反应有关来自40例CTD患者和40例未受影响的对照的粪便和血液样本。 - 在AIM 2中，我们将测试肠道微生物群改变和通过TIC加剧之间的因果关系从受CTD影响的个体将粪便标本移植到我们的Tourette疾病的鼠标模型中；我们还将测试TNF或其他炎症性细胞因子是否有助于潜在的TIC严重性变化。 R21应用中提出的翻译研究将是肠道作用的第一个系统分析微生物群在抽动波动中。如果我们的假设得到验证，未来的R01资助研究将测试粪便是否来自非影响个体和/或益生菌治疗的物质移植可以降低抽动严重程度。我们将还研究下游机制，炎症会增加抽动严重程度。那我们的结果可能导致开发针对CTD的新，更安全，基于机械的治疗方法。