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

创伤性脑损伤(TBI)相关的神经变性(趋势)越来越被认为是一种主要的健康问题 认知功能衰退的原因及关注。神经炎症，一种被提出的趋势机制，可能会持续 原发伤情发生数年后。我们认为创伤性脑损伤后的慢性肠道生态失调，尤其是细胞外基质的耗竭。 能够发酵膳食纤维产生短链脂肪酸(SCFA)的“健康”共生菌 醋酸盐会导致微生物-肠道-脑轴的不适应状态。微生物衍生的醋酸盐是最多的 肠道中含有丰富的单链脂肪酸，进入血液循环，对大脑和免疫功能至关重要。耗尽 在病情危重的人类和相应的小鼠模型中，产醋酸酯细菌的发现是一致的。 枯竭的细菌或其代谢物的恢复有可能逆转与生物失调相关的 表型。通过国际公认的TBI中心和微生物组之间的独特合作 研究中心、萨法尔复苏研究中心、医学和微生物中心，以及 匹兹堡大学神经创伤临床试验中心和生物医学发现研究所 莫纳什大学，我们已经产生了令人兴奋的数据，证明(1)醋酸盐生产的枯竭 重型颅脑损伤患者和受控皮质撞击(CCI)小鼠的肠道细菌种群，(2) CCI后粪便醋酸盐的显著减少，(3)共生菌的进行性和持续性破坏 和受伤后几周的醋酸盐产生，(4)饮用水中的补充或针对肠道的饮食策略 运送单链脂肪酸的微生物群具有保护性。因此，我们建议进行一项翻译研究，以发现趋势和 颅脑损伤后慢性神经炎症是由共生菌的枯竭和发酵不足所致 膳食纤维。在目标1中，我们将解决这样的假设，即缺乏微生物衍生的醋酸盐有助于 从受伤到趋势长达6个月。我们将在雄性和雌性小鼠身上应用CCI，并将未治疗的小鼠 对照(醋酸盐缺乏)小鼠，使用乙酰化纤维或灌胃产醋酸菌。 将进行病变体积、记忆力、存活神经元和脑能量代谢的评估。肠 将分析微生物群的结构和功能以及脑组织、血清和粪便中的醋酸盐水平。在AIM 2，我们将确定缺乏醋酸盐是否会促进慢性小胶质细胞的激活和极化 用免疫组织化学和RNA-Seq法检测组织破坏性表型。在目标3中，我们将解决 一种假说，认为TBI会导致肠道中醋酸盐的可重复、渐进和持续的下降。 我们将对患有中、重度脑外伤的成人进行观察性研究。临床信息包括 损伤严重程度、抗生素、饮食和神经学结果将被收集为次要结果。确定 肠道微生物群稳定变化的作用和一种有前景的可翻译疗法的强大效果， 作为人体治疗靶点的醋酸盐，由四个高度互补的研究中心将建立 破坏微生物-肠道-脑轴作为一种趋势机制，并为临床试验提供基础。

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.