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.

抽象的慢性抽动障碍 (CTD)，包括抽动秽语障碍和持续性抽动障碍，是一种重要的疾病。儿童和青少年残疾的根源，但药物治疗仍然非常不令人满意由于严重的不良事件，开发更安全的 CTD 治疗方法的理想方向是针对相同的生物过程，随着时间的推移，抽动会自发地增强和减弱；然而，其机制不同；这些波动背后的原因仍然知之甚少。解决这个问题的一个新机会可能来自最近的证据文件，即抽动的严重程度是了解肠道微生物群的组成是否发生变化。可能解释抽动加剧 - 以及通过分子机制 - 可能导致治疗 CTD 的突破；然而，这个问题仍有待探讨本 R21 中提出的研究目标。该应用的目的是探索肠道微生物群的变化是否以及如何导致抽动加剧。肠道微生物群可能通过多种机制影响抽动的严重程度，包括合成充足的相关证据表明肿瘤坏死因子-α (TNF) 是炎症细胞因子。炎症细胞因子与抽动加剧最相关，因此，要测试该细胞因子是否会增加抽动。我们评估了其在 CTD 小鼠模型中的影响，这些初步研究表明 TNF 水平较低。不引起疾病行为的剂量会显着增加这些小鼠的抽动样刻板印象。基于这些发现，我们勇敢地承认，在 CTD 患者中，肠道微生物群的改变会导致 TNF 或其他炎症细胞因子的产生，使抽动恶化。 R21 申请中提出的探索性研究将使用转化平台，结合临床 CTD 患者的分析和小鼠模型的机制实验具体如下： - 在目标 1 中，我们将评估与 CTD 相关的肠道微生物群的变化，并测试抽动是否发生通过测试，病情加重与肠道微生物群和炎症反应的改变有关来自 40 名 CTD 患者和 40 名未受影响对照者的粪便和血液样本。 - 在目标 2 中，我们将通过以下方式测试肠道微生物群改变与抽动加剧之间的因果关系：将受 CTD 影响的个体的粪便样本移植到我们的妥瑞氏症小鼠模型中；我们还将测试 TNF 或其他炎症细胞因子是否会导致抽动严重程度的潜在变化。 R21 申请中提出的转化研究将是对肠道作用的首次系统分析如果我们的假设得到验证，未来由 R01 资助的研究将测试粪便是否影响微生物群。来自未受影响个体的材料移植和/或益生菌治疗可以减轻抽动的严重程度。还研究了炎症增加抽动严重程度的下游机制。因此，我们的结果可能是这样的。导致开发新的、更安全的、基于机械的 CTD 治疗方法。