Detrimental Effects of Age Related Dysbiosis

项目总结 近年来，“微生物-肠道-大脑”轴的双向存在已变得明显。 通信发生在肠道、其微生物区系内容物和大脑之间。在这项提案中，我们将发展 这个“微生物-肠道-大脑”轴在中风后可以运作的假说。也就是说，中风会产生内脏 肠道微生物区系的一种病理变化--生物失调，以及随着年龄增长而发生的肠道生物失调，都会对人体产生负面影响。 卒中后的转归。我们的总体假设是，与年龄相关的生物失调导致了高 老年动物中风后的死亡率和功能恢复不良。逆转老年人的生物失调 通过操控小鼠体内的细菌群(“微生物区系”)将促进恢复。 实验性中风后。我们用强劲的初步数据支持我们的假设。A)出现肠道生物失调 随着小鼠的衰老。(B)先天免疫和获得性免疫随年龄增长而发生的变化随着年龄的增加而逆转 将幼年微生物区系移植到老龄小鼠体内。(C)将幼鼠(3个月)的肠道微生物区系灌胃到 老龄小鼠(18-20个月)实验性卒中后恢复良好。(D)短链脂肪酸不足 衰老小鼠肠道中的单链脂肪酸(SCFAs)，主要是醋酸盐、丙酸和丁酸盐，与不良结局有关 中风后。(E)中风后短链脂肪酸产生菌(益生菌)的灌胃增加 衰老小鼠的康复。我们将发展这样一种想法，即两个肠道中T细胞亚群的年龄相关变化 大脑调节这些有害的影响，而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 “微生物区系-肠道-脑”轴随年龄和中风而改变，重点是脑部炎症(小胶质细胞和脑 常驻T细胞；目标1)、肠道炎症(调节性和伽马三角洲T细胞；目标2)和细菌产物 (短链脂肪酸、丁酸、醋酸盐和丙酸)促进老龄小鼠卒中后的恢复 (目标3)。我们将用细菌代谢物(简称细菌代谢物)完整地操纵生物群(异慢性粪便转移) 链脂肪酸)，以及靶向下一代益生菌。此外，我们将确定每个角色的作用 短链脂肪酸通过慢性途径直接注入盲肠和结肠对中风康复的影响 留置插管。在美国，中风现在是导致长期残疾的最常见原因，其发病率 随着人口老龄化，这一数字继续上升。卒中后的“微生物区系-肠道-脑轴”是一个关键而新颖的 研究领域，以全面了解中风的病理生理学，并提供了一种有希望的方法 促进中风，特别是老年人中风后康复的治疗干预。

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.