Impact of microbiota-derived metabolites on traumatic brain injury-related neurodegeneration

微生物群衍生代谢物对创伤性脑损伤相关神经变性的影响

基本信息

批准号：
10582762
负责人：
Robert S B Clark
金额：
$ 60.64万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582762
关键词：
16S ribosomal RNA sequencing Acceleration Acetates Acetylation Address Adult Age Antibiotics Attenuated Bacteria Behavioral Binding Brain Characteristics Chronic Circulation Clinical Clinical Trials Collaborations Critical Illness Data Diet Dietary Fiber Energy Metabolism Enteral FFAR2 gene Feces Female Fermentation Fiber Foundations Gene Expression Genes Genetic Health High Pressure Liquid Chromatography Histology Human Immunohistochemistry Impaired cognition Infiltration Inflammatory Injury Intake International Intervention Intestines Ipsilateral Lesion Linear Models Macrophage Magnetic Resonance Imaging Measures Medicine Memory Microglia Modeling Monitor Morbidity - disease rate Mus NADPH Oxidase Nerve Degeneration Nervous System Trauma Neurological outcome Observational Study Operative Surgical Procedures Outcome Assessment Patients Performance Peripheral Phenotype Population Production Randomized Reproducibility Research Resources Resuscitation Role Serum Severities Sorting Structure Supplementation Technology Testing Therapeutic Time Tissues Trauma Traumatic Brain Injury Traumatic Brain Injury recovery Universities Volatile Fatty Acids blood-brain barrier crossing brain health brain metabolism brain tissue commensal bacteria controlled cortical impact dietary differential expression drinking water dysbiosis fatty acid supplementation field study follow-up functional outcomes glial activation gut microbiome gut microbiota gut-brain axis immune function improved in vivo innovation male metabolomics metaproteomics microbial microbial community microbiome microbiome research microbiota microbiota metabolites monocyte morris water maze mouse model neuroinflammation neurological recovery neuron loss neuronal survival neuroprotection neurotoxic novel pharmacologic premature prevent prospective protein TDP-43 public health relevance restoration secondary outcome tau Proteins therapeutic target transcriptome sequencing translational study

项目摘要

Traumatic brain injury (TBI)-related neurodegeneration (TReND) is increasingly recognized as a major health concern and cause of cognitive decline. Neuroinflammation, a proposed mechanism of TReND, may persist for years after the primary injury. We propose that chronic intestinal dysbiosis after TBI, specifically the depletion of “healthy” commensal bacteria capable of fermenting dietary fiber to produce the short chain fatty acid (SCFA) acetate, leads to a maladaptive state of the microbiome-gut-brain axis. Microbially-derived acetate is the most abundant SCFA in the gut, enters the circulation, and is critical to brain and immune function. Depletion of acetate-producing bacteria is a consistent finding in critically ill humans and corresponding murine models. Restoration of depleted bacteria or their metabolites has the potential to reverse dysbiosis-associated phenotypes. Through a unique collaboration between internationally recognized centers for TBI and microbiome research, The Safar Center for Resuscitation Research, The Center for Medicine and the Microbiome, and the Neurotrauma Clinical Trials Center at the University of Pittsburgh, and The Biomedical Discovery Institute at Monash University, we have generated exciting data which demonstrates (1) depletion of acetate-producing bacterial populations in the gut after severe TBI in patients and controlled cortical impact (CCI) TBI in mice, (2) a marked reduction in fecal acetate after CCI, (3) progressive and sustained disruption of commensal bacteria and acetate production weeks after injury, (4) repletion in drinking water or a dietary strategy to target gut microbiota to deliver SCFAs is protective. Thus, we propose a translational study to discover if TReND and chronic neuroinflammation after TBI is fueled by depletion of commensal bacteria and deficient fermentation of dietary fiber. In Aim 1, we will address the hypothesis that deficiency of microbially-derived acetate contributes to TReND up to 6 months from injury. We will employ CCI in male and female mice and compare untreated controls (acetate deficient) to mice repleted using acetylated-fiber or gavage of acetate-producing bacteria. Assessments of lesion volume, memory, surviving neurons, and brain energy metabolism will be performed. Gut microbiome structure and function and acetate level in brain tissue, serum, and feces will be analyzed. In Aim 2, we will determine whether deficiency of acetate promotes chronic microglial activation and polarization to a tissue-destructive phenotype as assessed by immunohistochemistry and RNA-Seq. In Aim 3, we will address the hypothesis that TBI results in a reproducible, progressive, and sustained decrease in gut derived acetate. We will perform an observational study of adults with moderate and severe TBI. Clinical information including injury severity, antibiotics, diet, and neurologic outcome will be collected for secondary outcomes. Identifying a role of stable alterations to the gut microbiome and robust effects of a promising and translatable therapy, acetate, as a therapeutic target in humans by four highly complementary research centers will establish disruption of the microbiome-gut-brain axis as a TReND mechanism and provide a foundation for clinical trials.

创伤性脑损伤 (TBI) 相关的神经变性 (TReND) 越来越被认为是一种主要健康问题认知能力下降的担忧和原因，TReND 的一种拟议机制可能会持续存在。我们认为，TBI 后的慢性肠道菌群失调，特别是肠道菌群的消耗。能够发酵膳食纤维产生短链脂肪酸（SCFA）的“健康”共生细菌乙酸盐导致微生物组-肠-脑轴的适应不良状态，微生物来源的乙酸盐是最严重的。肠道中丰富的 SCFA 进入循环，对大脑和免疫功能的消耗至关重要。产生醋酸盐的细菌在危重病人和相应的小鼠模型中得到了一致的发现。恢复耗尽的细菌或其代谢物有可能逆转与菌群失调相关的问题通过国际公认的 TBI 和微生物组中心之间的独特合作。研究、萨法尔复苏研究中心、医学和微生物组中心以及匹兹堡大学神经创伤临床试验中心和匹兹堡大学生物医学发现研究所莫纳什大学，我们生成了令人兴奋的数据，表明 (1) 乙酸盐产生的消耗严重 TBI 患者和小鼠受控皮质冲击 (CCI) TBI 后肠道中的细菌群，(2) CCI 后粪便乙酸盐显着减少，(3) 共生细菌逐渐和持续破坏损伤后几周的醋酸盐产生，(4) 补充饮用水或针对肠道的饮食策略因此，我们提出一项转化研究来发现 TReND 和 SCFA 是否具有保护作用。 TBI 后的慢性神经炎症是由共生细菌的消耗和发酵不足引起的在目标 1 中，我们将讨论微生物来源的醋酸盐缺乏会导致的假设。受伤后 6 个月内进行 TReND 我们将在雄性和雌性小鼠中使用 CCI 并比较未治疗的情况。对照组（缺乏乙酸盐）为使用乙酰化纤维或灌胃产生乙酸盐的细菌的小鼠。将评估病变体积、记忆力、存活神经元和大脑能量代谢。将分析脑组织、血清和粪便中的微生物组结构和功能以及乙酸盐水平。 2、我们将确定醋酸盐缺乏是否会促进慢性小胶质细胞活化和极化通过免疫组织化学和 RNA 测序评估组织破坏性表型在目标 3 中，我们将解决这一问题。假设 TBI 导致肠道来源的乙酸盐可重复、渐进且持续地减少。我们将对患有中度和重度 TBI 的成人进行观察性研究，包括临床信息。将收集损伤严重程度、抗生素、饮食和神经系统结果以确定次要结果。肠道微生物组稳定改变的作用以及有前途且可转化的疗法的强大效果，四个高度互补的研究中心将建立醋酸盐作为人类治疗靶点微生物组-肠-脑轴的破坏作为一种 TReND 机制，并为临床试验提供基础。