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.

项目总结 数千年来，肠道微生物群和宿主免疫系统一直是共同进化的。然而，现代的 社会条件扰乱了这种共同进化，与免疫介导的疾病急剧上升不谋而合。 细菌跨过肠道屏障进入肠道外器官，如内脏脂肪 组织可能会产生严重的病理后果。我们最近发现，衰老与 内脏中第三级淋巴结构的形成，称为脂肪相关淋巴团(FALCs) 脂肪组织。随着年龄的增长，抗炎肠道细菌的丰度呈平行下降趋势。 机会性病原体增多，最终导致肠道免疫和屏障功能紊乱。 在最近的两项研究中，肠道共生菌鸡肠球菌被发现有很高的易位 药效，有能力转移到肝脏，并诱导遗传易感小鼠的自身免疫。在……里面 我们的初步实验发现，两种不同的鸡肠杆菌菌株表现出不同的能力 易位，单个鸡肠杆菌株易位速度在小鼠之间有很大差异 在复杂肠道中感染鸡冠埃希氏菌的小鼠与感染鸡冠埃希氏菌的小鼠的比较 微生物群落。我们假设肠道微生物移位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 目的：1)确定鸡肠杆菌易位和持续对衰老相关的Falc形成的影响 和炎症，以及2)阐明鸡冠埃希氏菌移位和诱导衰老的机制(S)。 相关的法尔克形成和炎症。这些研究将提供对基本的 共生细菌跨过肠道屏障并导致年龄相关的机制 发炎。因此，它们可能为延缓慢性衰老的新治疗策略提供潜在的靶点。 随着年龄的增长。