Impact of dysbiosis on the development of age-related inflammation

生态失调对年龄相关炎症发展的影响

• 批准号: 10331167
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 7.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331167
• 关键词: Adipose tissue; Age; Aging; Anti-Inflammatory Agents; Autoimmunity; Bacterial Translocation; Chronic; Chronic Disease; Complex; Development; Disease; Enterococcus gallinarum; Evolution; Exhibits; Fatty acid glycerol esters; Genetic Predisposition to Disease; Immune; Immune system; Immunity; Impairment; Individual; Inflammaging; Inflammation; Intestines; Liver; Lymphoid; Mediating; Metabolic dysfunction; Modernization; Mus; Organ; Pathologic; Process; Social Conditions; Visceral; commensal bacteria; dysbiosis; experimental study; gut bacteria; gut microbes; gut microbiota; insight; intestinal barrier; new therapeutic target; novel therapeutic intervention; opportunistic pathogen; regenerative; tertiary lymphoid organ

Project summary The resident gut microbiota and the host immune system have co-evolved for millennia. However, modern societal conditions have disturbed this co-evolution, coinciding with a steep rise in immune-mediated diseases. Bacterial translocation across the intestinal barrier and into extraintestinal organs such as the visceral adipose tissues can have major pathological consequences. We recently discovered that aging is associated with formation of tertiary lymphoid structures, known as Fat-associated lymphoid clusters (FALCs), in the visceral adipose tissue. As an individual ages, the abundance of anti-inflammatory gut bacteria decreases with a parallel increase in opportunistic pathogens, ultimately leading to disruption of intestinal immunity and barrier function. In two recent studies, the gut commensal species Enterococcus gallinarum was found to have high translocation efficacy, with the ability to translocate to the liver and induce autoimmunity in genetically predisposed mice. In our preliminary experiments, we found that two different strains of E. gallinarum exhibit distinct capacities for translocation, and that rates of translocation for a single E. gallinarum strain vary dramatically between mice mono-colonized with E. gallinarum versus mice colonized with E. gallinarum in the presence of a complex gut microbial community. We hypothesize that translocation of gut microbes to visceral adipose tissue results in FALC formation and age-related inflammation leading to metabolic dysfunction. In this application, we propose to: 1) determine the effect of E. gallinarum translocation and persistence on aging-associated FALC formation and inflammation, and 2) elucidate the mechanism(s) that enable E. gallinarum to translocate and induce aging- associated FALC formation and inflammation. These studies will provide insight into the fundamental mechanisms by which commensal bacteria translocate across the intestinal barrier and induce age-related inflammation. Thus, they may illuminate potential targets for novel therapeutic strategies delay chronic aging with age.

项目摘要 常驻肠道微生物群和宿主免疫系统已经共同发展了数千年。但是，现代 社会条件打扰了这一共同进化，与免疫介导的疾病急剧上升。 跨肠屏障的细菌易位，进入肠外器官，例如内脏脂肪 组织可能会带来重大的病理后果。我们最近发现衰老与 内脏中的三级淋巴结构的形成，称为脂肪相关的淋巴样簇（FALC） 脂肪组织。作为一个年龄，抗炎肠道细菌的丰度与平行 机会性病原体的增加，最终导致肠道免疫和障碍功能的破坏。 在最近的两项研究中，发现肠道肠球菌肠球菌具有很高的易位 功效，能够转移到肝脏并诱导遗传性易感小鼠的自身免疫性。在 我们的初步实验，我们发现两种不同的gallinarum菌株具有不同的能力 易位，以及小鼠之间单一的gallinarum菌株的易位速率变化很大 用大肠杆菌与在复杂肠道存在下殖民地gallinarum的小肠殖民地殖民 微生物社区。我们假设将肠道微生物转移到内脏脂肪组织会导致 FALC的形成和与年龄相关的炎症导致代谢功能障碍。在此应用程序中，我们建议 至：1）确定gallinarum大肠杆菌易位和持久性对衰老相关的FALC形成的影响 和炎症，以及2）阐明了能够易位并诱导衰老的机制 相关的FALC形成和炎症。这些研究将提供有关基本的洞察力 共生细菌在肠屏障中转运并诱导与年龄有关的机制 炎。因此，它们可能会阐明新型治疗策略的潜在目标延迟慢性老龄化 随着年龄的增长。