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（趋势）越来越被认为是主要健康关注和认知能力下降的原因。神经炎症是一种拟议的趋势机制，可能会持续存在初次受伤几年。我们建议在TBI之后的慢性肠道断症，特别是部署 “健康”的共生细菌，能够发酵饮食纤维以产生短链脂肪酸（SCFA）乙酸盐，导致微生物组 - 脑轴的适应不良状态。微生物衍生的醋酸盐最多肠道中最富有的SCFA进入循环，对大脑和免疫功能至关重要。耗尽产生醋酸盐细菌是重病人类和相应的鼠模型中的一致发现。恢复耗尽的细菌或其代谢产物有可能逆转营养不良相关的表型。通过国际公认的TBI和微生物组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，以及匹兹堡大学的Neurotrauma临床试验中心和生物医学发现研究所莫纳什大学（Monash University 患者严重TBI后肠道中的细菌种群和小鼠的受控皮质影响（CCI）TBI，（2） CCI之后（3）共生细菌的进行性和持续破坏明显降低受伤后数周和乙酸盐生产，（4）在饮用水中复制或饮食策略以靶向肠道微生物群可保护SCFA。这，我们提出了一项翻译研究，以发现趋势和是否趋势 TBI后的慢性神经炎症是由共生细菌耗竭和发酵不足的饮食纤维。在AIM 1中，我们将解决以下假设：微生物衍生的乙酸不足有助于受伤后长达6个月。我们将在男性和雌性小鼠中使用CCI，并比较未经治疗的对照（乙酸盐缺乏）用乙酸盐产生细菌替代小鼠的小鼠。将对病变体积，记忆，生存神经元和脑能量代谢的评估进行评估。肠将分析微生物组的结构和功能以及脑组织，血清和粪便中的乙酸水平。目标 2，我们将确定乙酸不足是否促进了慢性小胶质激活和极化通过免疫组织化学和RNA-Seq评估的组织毁灭性表型。在AIM 3中，我们将解决 TBI导致肠道衍生剂的可再现，进行性和持续降低的假设。我们将对具有中度和重度TBI的成年人进行检查。临床信息包括损伤严重程度，抗生素，饮食和神经系统结局将用于次要结局。识别稳定改变对肠道微生物组的作用以及可转换疗法的强大影响，乙酸盐，作为四个高度完整研究中心的人类治疗目标微生物组 - 脑轴的破坏是趋势机制，并为临床试验提供了基础。