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