Detrimental Effects of Age Related Dysbiosis

项目摘要 近年来，已经很明显的是，存在"微生物-肠道-大脑"轴，其中双向 在肠道、其微生物群内容物和大脑之间发生通信。在本提案中，我们将开发 这一"微生物群-肠-脑"轴在中风后起作用的假设。也就是说，中风产生肠道 微生态失调是肠道微生物群的病理变化，随着年龄的增长， 中风后的结果。我们的总体假设是，年龄相关的生态失调有助于高 老年动物中风后出现的死亡率和功能恢复差。扭转老年人的生态失调 通过操纵常驻细菌种群（"微生物群"）将导致增强的恢复 实验性中风后我们用强有力的初步数据支持我们的假设。a）发生肠道生态失调 与衰老的关系(b)随着年龄的增长，先天免疫和适应性免疫的变化被逆转， 将年轻的微生物群转移到老年小鼠中。(c)将来自年轻小鼠（3个月）的肠道微生物群清除到 实验性中风后的老年小鼠（18 - 20个月）改善了恢复。(d)缺乏短链脂肪酸 老年小鼠肠道中的SCFAs（主要是乙酸盐、丙酸盐和丁酸盐）与不良结局相关 中风后(e)中风后管饲短链脂肪酸产生细菌（益生菌）增强 老年小鼠的恢复。我们将发展这样一种观点，即肠道和胃肠道中与年龄相关的T细胞亚群的变化 大脑介导了这些有害的影响，SCFAs的缺乏是造成这些影响的原因。 有害的T细胞变化。本提案的主要目标是了解 "微生物群-肠-脑"轴随着年龄和中风而变化，重点是脑炎症（小胶质细胞和脑 常驻T细胞; Aim 1）、肠道炎症（调节性和γ δ T细胞; Aim 2）和细菌产物 (the短链脂肪酸，丁酸盐，乙酸盐和丙酸盐），以促进衰老小鼠中风的恢复 (Aim 3）。我们将利用细菌代谢产物（简短）来操纵整个生物群落（异时粪便转移） 链脂肪酸），并与有针对性的下一代益生菌。此外，我们将确定每个人的角色， 短链脂肪酸对中风恢复的直接注入盲肠和结肠通过慢性 留置套管。中风现在是美国长期残疾的最常见原因， 随着人口的老龄化，中风后的"微生物群-肠-脑轴"是一个关键的和新颖的 研究领域，以充分了解中风的病理生理学，并提供了一个有前途的方法， 治疗干预，以改善中风的恢复，特别是在老年人中。

PROJECT SUMMARY In recent years, it has become apparent that a “microbiota-gut-brain” axis exists where bidirectional communications occur between the gut, its microbiota contents, and the brain. In this proposal, we will develop the hypothesis that this “microbiota-gut-brain” axis is operational after stroke. That is, stroke produces gut dysbiosis, a pathological change in the gut microbiota, and gut dysbiosis, as occurs with aging, negatively affects outcomes following stroke. Our overall hypothesis is that age-related dysbiosis contributes to the high mortality and poor functional recovery seen after stroke in aged animals. Reversing dysbiosis in aged mice by manipulating the resident bacterial population (“the microbiota”) will lead to enhanced recovery after experimental stroke. We support our hypothesis with strong preliminary data. a) Gut dysbiosis occurred with aging in mice. (b) Changes in the innate and adaptive immunity, occurring with age, were reversed with transfer of young microbiota into aged mice. (c) Gavaging the gut microbiota from young mice (3 months) into aged mice (18-20 months) after experimental stroke improved recovery. (d) A deficit of short chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, in the gut of aged mice is associated with poor outcome after stroke. (e) Post-stroke gavage of short chain fatty acid producing bacteria (probiotics) enhanced recovery in aged mice. We will develop the idea that age-related changes in T-cell subsets in both the gut and the brain mediate these detrimental effects and that deficiency of SCFAs is responsible for these detrimental T-cell changes. The main goal of this proposal is to understand how the components of the “microbiota-gut-brain” axis change with age and stroke with a focus on brain inflammation (microglia and brain resident T-cells; Aim 1), gut inflammation (regulatory and gamma delta T-cells; Aim 2) and bacterial products (the short chain fatty acids, butyrate, acetate, and propionate) to enhance the recovery from stroke in aging mice (Aim 3). We will manipulate the biome in entirety (heterochronic fecal transfers), with bacterial metabolites (short chain fatty acids), and with targeted next-generation probiotics. Furthermore, we will determine the role of each short chain fatty acid on stroke recovery by directly infusing into the cecum and colon through a chronically indwelling cannula. Stroke is now the most common cause of long-term disability in the US and the incidence continues to rise with our aging population. The “microbiota-gut-brain axis” after stroke is a critical and novel area of investigation to fully understand the pathophysiology of stroke and offers a promising approach to therapeutic interventions to improve recovery from stroke, especially in the elderly.