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

• 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
• 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

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.

外伤性脑损伤（TBI）相关神经变性（TReND）越来越被认为是一种主要的健康问题