Intermittent Fasting-induced Gut Microbiome Modulation of CNS Autoimmunity

间歇性禁食诱导的肠道微生物组对中枢神经系统自身免疫的调节

• 批准号: 10000183
• 负责人: Yanjiao Zhou
• 金额: $ 34.62万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000183
• 关键词: Acetates; Address; Adipose tissue; Affect; Anaerobic Bacteria; Anti-Inflammatory Agents; Autoimmune Responses; Autoimmunity; Bacteria; CNS autoimmunity; Cells; Central Nervous System Diseases; Chronic; Clinic; Clostridium; Data; Development; Diet; Disease; Enrollment; Exhibits; Experimental Autoimmune Encephalomyelitis; FFAR3 gene; Fasting; Feces; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Goals; Immune; Immune response; Immune system; Immunity; In Vitro; Incidence; Inflammatory; Interleukin-17; Intermittent fasting; Knowledge; Lactobacillus; Lamina Propria; Leptin; Life; Measures; Mediating; Mediator of activation protein; Metabolic; Multiple Sclerosis; Mus; Neuraxis; Obesity; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient Education; Peripheral; Play; Probiotics; Production; Public Health; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Reporting; Resistance; Risk; Role; Serum; Severities; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Transplant Recipients; Transplantation; Volatile Fatty Acids; adipokines; adiponectin; base; chronic autoimmune disease; cytokine; dietary manipulation; experimental study; fecal transplantation; gut bacteria; gut microbiome; gut microbiota; immunoregulation; improved; microbial; microbiome; microbiome alteration; microbiota; mouse model; multiple sclerosis patient; novel; novel therapeutic intervention; novel therapeutics; nutrition; pilot trial; prebiotics; protective effect; response; socioeconomics

PROJECT SUMMARY/ABSTRACT The long-term objectives of the proposed project are to determine the role of the gut microbiome in multiple sclerosis (MS), as well as to develop dietary and gut microbiome-based therapeutic strategies for this disease. MS is a chronic autoimmune disease targeting the central nervous system. It affects 2.5 million people worldwide with significant personal and socioeconomic burdens. Current treatments are usually inadequate; thus there is a need for new therapeutic approaches. One potential therapeutic strategy is dietary manipulation. Preliminary studies show that intermittent fasting confers protection to experimental autoimmune encephalomyelitis (EAE), a murine model for MS, but the underlying mechanisms of protection are unknown. Microbial analysis revealed beneficial changes in the gut microbiome including increased bacteria diversity and increased levels of immuno-modulatory bacteria that could dampen the autoimmune response. In addition, changes in microbial metabolites could contribute to a reduction in autoimmunity. Our preliminary studies revealed that mice undergoing intermittent fasting produced less fecal acetate, a short-chain fatty acid that was reported to increase the production of a pro-inflammatory adipokine (leptin) in a G protein-coupled receptor 41- dependent manner. Importantly, the protective effects associated with the altered microbiome could be transferred from fasting mice to non-fasting mice through fecal microbial transplants. In a pilot trial we just concluded, intermittent fasting in MS patients induced changes in the gut flora and leptin levels recapitulating what we observed in mice with EAE. The proposed studies will delineate the potential pathways by which changes in the gut microbiome caused by intermittent fasting protect against EAE. Aim 1 will determine how the gut microbiome modulates local gut immunity and subsequently influences systemic immune responses, using whole stool transplants from fasting mice to non-fasting mice. The specific protective microbial species will be identified by isolating the over-represented taxa from intermittently fasting mice and testing their ability to modulate the local and systemic immune responses. Aim 2 will test the idea that the gut microbiome protects against EAE by altering leptin and adiponectin production through known pathways controlling their induction. The study will increase knowledge of the mechanisms in dietary-mediated regulation of EAE/MS pathogenesis, thereby laying the groundwork for development of novel therapeutic strategies for MS, including manipulation of the gut microbiome with probiotics and/or prebiotics.

项目摘要/摘要 拟议项目的长期目标是确定肠道微生物组在多个 硬化症（MS）以及为该疾病发展基于饮食和肠道微生物组的治疗策略。 MS是一种针对中枢神经系统的慢性自身免疫性疾病。它影响了250万人 全世界有巨大的个人和社会经济负担。目前的治疗通常不足； 因此，需要采用新的治疗方法。一种潜在的治疗策略是饮食 操纵。初步研究表明，间歇性禁食赋予对实验自身免疫的保护 脑脊髓炎（EAE），一种用于MS的鼠模型，但潜在的保护机制尚不清楚。 微生物分析显示肠道微生物组的有益变化，包括细菌的多样性增加和 免疫调节细菌水平增加，可能会抑制自身免疫反应。此外， 微生物代谢产物的变化可能导致自身免疫性降低。我们的初步研究 表明接受间歇性禁食的小鼠产生的乙酸粪便较少，这是一种短链脂肪酸 据报道会增加G蛋白偶联受体41-中促炎性脂肪因子（瘦素）的产生 依赖方式。重要的是，与改变的微生物组相关的保护作用可能是 通过粪便微生物移植从空腹小鼠转移到非燃烧的小鼠。在试点审判中，我们只是 总结，MS患者的间歇性禁食引起了肠道菌群和瘦素水平的变化 我们在EAE中观察到的东西。拟议的研究将描绘出的潜在途径 间歇性禁食保护剂抗EAE引起的肠道微生物组的变化。 AIM 1将决定如何 肠道微生物组调节局部肠道免疫，随后影响全身免疫反应， 使用从空腹小鼠到非燃烧小鼠的全粪便移植。特定的保护性微生物物种 将通过间歇性禁食小鼠隔离代表性分类单元并测试其能力来确定 调节局部和全身免疫反应。 AIM 2将测试肠道微生物组的想法 通过控制其的已知途径来改变瘦素和脂联素的产生，从而防止EAE 就职。该研究将增加对EAE/MS饮食介导的调节机制的了解 发病机理，从而为MS的新型治疗策略开发奠定了基础，包括 用益生菌和/或益生元来操纵肠道微生物组。