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.

项目总结/摘要 拟议项目的长期目标是确定肠道微生物组在多种疾病中的作用。 硬化症（MS），以及开发针对这种疾病的基于饮食和肠道微生物组的治疗策略。 MS是一种慢性自身免疫性疾病，靶向中枢神经系统。影响了250万人 在全球范围内，他们都承受着巨大的个人和社会经济负担。目前的治疗通常是不够的; 因此需要新的治疗方法。一个潜在的治疗策略是饮食 操纵初步研究表明，间歇性禁食可以保护实验性自身免疫性疾病， 脑脊髓炎（EAE），MS的鼠模型，但保护的潜在机制是未知的。 微生物分析揭示了肠道微生物组的有益变化，包括细菌多样性增加， 增加免疫调节细菌的水平，这可能会抑制自身免疫反应。此外，本发明还提供了一种方法， 微生物代谢物的变化可能导致自身免疫的减少。我们的初步研究 研究表明，间歇性禁食的小鼠产生的粪便乙酸盐较少，这是一种短链脂肪酸， 据报道，在G蛋白偶联受体41中增加促炎脂肪因子（瘦素）的产生， 依赖的方式。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禁食小鼠转移到非禁食小鼠。在一个试点试验中， 结论是，MS患者的间歇性禁食引起肠道植物群和瘦素水平的变化， 我们在EAE小鼠中观察到的情况。拟议的研究将描绘潜在的途径， 由间歇性禁食引起的肠道微生物组的变化可以预防EAE。目标1将决定如何 肠道微生物组调节局部肠道免疫并随后影响全身免疫应答， 使用从禁食小鼠到非禁食小鼠的全粪便移植。特定的保护性微生物种类 将通过从间歇性禁食的小鼠中分离出过度代表的分类群并测试它们的能力来鉴定 以调节局部和全身免疫反应。目标2将测试肠道微生物组 通过已知的途径控制瘦素和脂联素的产生， 诱导该研究将增加对饮食介导的EAE/MS调节机制的认识 发病机制，从而为开发MS的新治疗策略奠定基础，包括 用益生菌和/或益生元操纵肠道微生物组。