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.

项目摘要 近年来，显然存在一个“微生物群”轴，而双向都存在 肠道，其菌群含量和大脑之间发生通信。在此提案中，我们将发展 中风后这种“微生物群”轴轴是运行的假设。也就是说，中风会产生肠道 营养不良，肠道微生物群的病理变化和肠道营养不良，如衰老而发生的，负面影响 中风后的结果。我们的总体假设是与年龄相关的营养不良有助于高 老年动物中风后死亡率和功能恢复不良。逆转衰老的营养不良 通过操纵居民种群（“微生物群”）来操纵小鼠，将导致恢复增强 实验性中风后。我们通过强大的初步数据来支持我们的假设。 a）肠道营养不良发生 小鼠衰老。 （b）随着年龄的增长而发生的先天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）将年轻小鼠的肠道菌群（3个月）散入 实验中风后老年小鼠（18-20个月）改善了恢复。 （d）短链脂肪酸的防御 （SCFAS），乙酸原发性，丙酸和丁酸酯，在老年小鼠的肠道中与不良结果有关 中风后。 （e）短链脂肪酸产生细菌（益生菌）增强的势势块 老年小鼠的恢复。我们将提出这样的想法，即肠道中与年龄相关的T细胞子集的变化 大脑介导了这些有害的影响，而SCFA的不足是为此造成的 有害的T细胞变化。该提议的主要目标是了解 “微生物群 - 脑”轴随着年龄和中风而变化，重点是脑感染（小胶质细胞和脑 居民T细胞； AIM 1），肠道注射（调节和伽马三角洲T细胞； AIM 2）和细菌产物 （短链脂肪酸，丁酸酯，乙酸盐和丙酸），以增强衰老小鼠中风的恢复 （目标3）。我们将用细菌代谢物（短的粪便转移）操纵全面的生物群体（异缘粪便转移） 链脂肪酸），并具有针对性的下一代益生菌。此外，我们将确定每个的作用 短链脂肪酸在中风恢复时通过长期直接注入盲肠和结肠。 留置套管。中风现在是美国长期残疾的最常见原因和事件 随着我们老龄化的人口，继续上升。中风后的“微生物群 - 脑轴”是一种关键而新颖的 投资领域充分了解中风的病理生理学，并提供了一种有希望的方法 治疗性干预措施以改善中风的恢复，尤其是在较早的情况下。