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 肠道微生物群和宿主免疫系统已经共同进化了数千年。但现代 社会条件扰乱了这种共同进化，与此同时，免疫介导的疾病急剧增加。 细菌移位穿过肠屏障并进入肠外器官，如内脏脂肪 组织可能具有严重的病理后果。我们最近发现衰老与 内脏中三级淋巴结构的形成，称为脂肪相关淋巴簇（Fat-associated lymphoid clusters，简称FALC）， 脂肪组织随着个体年龄的增长，抗炎肠道细菌的丰度随着平行的 机会性病原体的增加，最终导致肠道免疫和屏障功能的破坏。 在最近的两项研究中，发现肠道寄生菌种Enterococcus gallinarum 有效性，具有转移到肝脏并在遗传易感小鼠中诱导自身免疫的能力。在 我们的初步实验发现，两种不同的E.鸡表现出不同的能力， 易位率和单个E.在小鼠之间， 单菌落E.鸡大肠杆菌感染小鼠与E.存在复合肠道的情况下， 微生物群落我们假设肠道微生物移位到内脏脂肪组织导致 β-淀粉样蛋白C形成和年龄相关炎症导致代谢功能障碍。在本申请中，我们提出 1）确定E.鸡胚易位和持续性对衰老相关的CCLC形成的影响 和炎症的关系; 2）阐明E.鸡胚移位和诱导衰老- 相关的CD 40 C形成和炎症。这些研究将提供洞察的基本 肠道细菌穿过肠道屏障并诱导与年龄相关的 炎症因此，它们可能为延缓慢性衰老的新治疗策略阐明潜在的靶点 随年龄