Detrimental Effects of Age Related Dysbiosis

年龄相关的生态失调的有害影响

• 批准号: 10132409
• 负责人: ROBERT M BRYAN
• 金额: $ 59.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132409
• 关键词: Acetates; Affect; Age; Aging; Animals; Area; Bacteria; Bacterial Antigens; Behavioral; Biological Assay; Blood - brain barrier anatomy; Brain; Butyrates; CD8-Positive T-Lymphocytes; Cannulas; Cecum; Cells; Chronic; Colon; Communication; Communities; Data; Elderly; Encephalitis; Enteral; Female; Functional disorder; Goals; Gut Mucosa; Immune; Immune system; Immunity; Incidence; Infarction; Inflammation; Inflammatory; Interleukin-17; Investigation; Laboratory Animals; Lead; Mediating; Microglia; Middle Cerebral Artery Occlusion; Mus; Natural Immunity; Neuraxis; Neutrophil Infiltration; Outcome; Pathologic; Pathway interactions; Phagocytosis; Play; Population; Probiotics; Production; Propionates; Public Health; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Role; Sampling; Signaling Molecule; Stroke; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Volatile Fatty Acids; Whole-Genome Shotgun Sequencing; Work; adaptive immunity; age effect; age related; aged; aging brain; aging population; brain health; brain repair; central nervous system injury; cognitive recovery; cytokine; disability; dysbiosis; fecal transplantation; gastrointestinal epithelium; gut bacteria; gut dysbiosis; gut microbiota; improved; improved outcome; inflammatory disease of the intestine; juvenile animal; male; microbiome; microbiota; microbiota-gut-brain axis; microorganism; mortality; motor recovery; negative affect; next generation; novel; peripheral blood; post stroke; prevent; reconstitution; response; sham surgery; stroke recovery; γδ T cells

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.

项目概要 近年来，“微生物群-肠-脑”轴的存在已经变得越来越明显，其中双向 肠道、其微生物群内容物和大脑之间发生通讯。在本提案中，我们将开发 假设“微生物群-肠-脑”轴在中风后仍能发挥作用。也就是说，中风产生肠道 肠道菌群失调是肠道菌群的一种病理变化，随着年龄的增长，肠道菌群失调会对健康产生负面影响 中风后的结果。我们的总体假设是，与年龄相关的生态失调导致高 老年动物中风后出现死亡率和功能恢复不良。逆转老年人的生态失调 通过操纵常驻细菌群（“微生物群”），小鼠将加速康复 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) 发生肠道菌群失调 随着小鼠的衰老。 (b) 随着年龄的增长，先天性和适应性免疫发生的变化被逆转 将年轻的微生物群转移到老年小鼠体内。 (c) 将幼鼠（3 个月）的肠道微生物群灌入小鼠体内 实验性中风后老年小鼠（18-20 个月）的恢复得到改善。 (d) 短链脂肪酸缺乏 (SCFA)，主要是乙酸盐、丙酸盐和丁酸盐，在老年小鼠的肠道中与不良结果相关 中风后。 (e) 中风后增强产生短链脂肪酸的细菌（益生菌）的管饲 老年小鼠的恢复。我们将提出这样的观点：肠道和肠道中的 T 细胞亚群均会发生与年龄相关的变化。 大脑会介导这些有害影响，而 SCFA 的缺乏是造成这些有害影响的原因 有害的 T 细胞变化。该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，重点是大脑炎症（小胶质细胞和大脑） 常驻T细胞；目标 1)、肠道炎症（调节性 T 细胞和 γ δ T 细胞；目标 2）和细菌产物 （短链脂肪酸、丁酸盐、乙酸盐和丙酸盐）可促进衰老小鼠中风的恢复 （目标 3）。我们将利用细菌代谢物（短时间）来操纵整个生物群落（异时粪便转移） 链脂肪酸），以及有针对性的下一代益生菌。此外，我们将确定每个人的角色 短链脂肪酸通过长期直接注入盲肠和结肠来促进中风恢复 留置插管。中风现在是美国长期残疾的最常见原因，并且发病率 随着人口老龄化，这一数字持续上升。中风后的“微生物群-肠-脑轴”是一个重要且新颖的 研究领域，以充分了解中风的病理生理学，并提供一种有前途的方法 改善中风康复的治疗干预措施，尤其是老年人。