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: 10259710
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 41.88万
• 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/10259710
• 关键词: 16S ribosomal RNA sequencing; Adipocytes; Adipose tissue; Age; Aging; Antibiotic Therapy; Antibiotics; Antigens; B-Lymphocytes; Bacterial Translocation; Bacteroides thetaiotaomicron; Caloric Restriction; Cells; Chronic; Chronic Disease; Coupled; Data; Development; Enterococcus; Fatty acid glycerol esters; Fucose; Funding; G-Protein-Coupled Receptors; Gene Expression Profile; Germ-Free; Health; Homeostasis; Human; Impairment; Infection; Inflammaging; Inflammation; Intestines; Life; Liver; Longevity; Lymphoid; Lymphoid Tissue; Mediating; Mesentery; Metabolic; Metabolic dysfunction; Microbe; Modeling; Monosaccharides; Mus; Omentum; Plant Roots; Play; Process; Randomized Clinical Trials; Role; T-Lymphocyte; Testing; Visceral; Visceral fat; aged; base; commensal bacteria; conventional therapy; dysbiosis; experience; experimental study; fly; gut bacteria; gut microbes; gut microbiome; gut microbiota; healthspan; intestinal barrier; lymph nodes; macrophage; member; microbial; microbiome; microbiota; pathogen; prevent; regenerative; response; restoration; tertiary lymphoid organ; tissue injury

PROJECT SUMMARY The “pillars of aging” hypothesis entails that chronic unresolved inflammation, coupled with metabolic dysfunction and macromolecular damage are among the key mechanisms that impairs cellular renewal and regenerative processes that contribute to aging and chronic diseases. Inflammation is a protective mechanism that has evolved to protect against pathogens and tissue injury that enables a host to survive life-threatening challenges by restoration of homeostasis. How then does a protective response like inflammation become chronic, drive aging and serve as a trigger of chronic disease? In absence of overt infections in aging, alterations in the gut microbiota (dysbiosis) or potential translocation of microbiota derived PAMPs to liver, mesenteric and omental adipose tissue could contribute to the mechanism of age-related inflammation. In line with this possibility, recent studies have demonstrated profound changes in the microbiome associated with aging and suggest that the microbiome may play a causal role in certain aspects of inflammaging. We recently discovered that aging is associated with formation of tertiary lymphoid structures, called Fat-associated lymphoid clusters (FALCs), in the visceral adipose tissue. The FALCs, unlike lymph nodes are disorganized non-encapsulated non-classical lymphoid tissues associated to adipocytes contain T cells, B cell and macrophages. Moreover, we found that B cells expand with age in the FALCs and display a unique transcriptional profile reminiscent of antigen-experienced B cells. Based on our original findings, the central hypothesis of this application is that translocation of gut microbes to visceral adipose tissue results in FALC formation and age-related inflammation leading to metabolic dysfunction. We will test the mechanism of how preventing the translocation of microbiota protects against FALC formation and inflammaging.

项目概要 “衰老支柱”假说认为，慢性未解决的炎症，加上代谢 功能障碍和大分子损伤是损害细胞更新和恢复的关键机制之一。 导致衰老和慢性疾病的再生过程是一种保护机制。 其进化目的是防止病原体和组织损伤，使宿主能够在危及生命的情况下生存 那么，保护性反应如何变成炎症呢？ 慢性，导致衰老并成为慢性疾病的触发因素？在没有明显的衰老感染的情况下， 肠道微生物群的改变（生态失调）或微生物群衍生的 PAMP 可能易位至肝脏， 肠系膜和网膜脂肪组织可能有助于年龄相关炎症的机制。 考虑到这种可能性，最近的研究表明，与以下疾病相关的微生物组发生了深刻的变化： 衰老并表明微生物组可能在炎症的某些方面发挥因果作用。 发现衰老与三级淋巴结构的形成有关，称为脂肪相关 内脏脂肪组织中的淋巴簇（FALC）。 与脂肪细胞相关的非包膜非经典淋巴组织含有 T 细胞、B 细胞和 此外，我们发现 FALC 中的 B 细胞随着年龄的增长而扩张，并表现出独特的特征。 根据我们最初的发现，转录谱让人想起经历过抗原的 B 细胞。 该应用的假设是肠道微生物易位至内脏脂肪组织导致 FALC 我们将测试导致代谢功能障碍的机制。 防止微生物群移位，防止 FALC 形成和炎症。