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.

项目概要 肠道常驻微生物群和宿主免疫系统已经共同进化了数千年。然而，现代 社会条件扰乱了这种共同进化，同时伴随着免疫介导疾病的急剧增加。 细菌易位穿过肠道屏障并进入肠外器官，例如内脏脂肪 组织可能产生重大病理后果。我们最近发现衰老与 在内脏中形成三级淋巴结构，称为脂肪相关淋巴簇（FALC） 脂肪组织。随着个体年龄的增长，抗炎肠道细菌的丰度也会相应减少 机会性病原体增加，最终导致肠道免疫和屏障功能破坏。 在最近的两项研究中，发现肠道共生鸡肠球菌具有高度易位 功效，能够转移到肝脏并在遗传易感性小鼠中诱导自身免疫。在 我们的初步实验中，我们发现两种不同的鸡大肠杆菌菌株表现出不同的能力 易位，并且单个鸡肠杆菌菌株的易位率在小鼠之间差异很大 单一定植有鸡肠球菌的小鼠与在存在复杂肠道的情况下定植有鸡肠球菌的小鼠 微生物群落。我们假设肠道微生物易位至内脏脂肪组织导致 FALC 形成和年龄相关炎症导致代谢功能障碍。在此应用中，我们建议 1) 确定鸡肠杆菌易位和持久性对衰老相关 FALC 形成的影响 和炎症，2) 阐明鸡肠杆菌易位并诱导衰老的机制 - 相关的 FALC 形成和炎症。这些研究将提供对基本原理的深入了解 共生细菌跨过肠道屏障并诱导年龄相关的机制 炎。因此，它们可能会阐明延缓慢性衰老的新型治疗策略的潜在目标 随着年龄的增长。