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: 10396668
• 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/10396668
• 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.

项目摘要 “衰老的支柱”假设具有慢性未分辨注射的权利，并与代谢相结合 功能障碍和大分子损伤是损害细胞更新和的关键机制之一 导致衰老和慢性疾病的再生过程。炎症是一种保护机制 这已经进化为防止病原体和组织损伤，使宿主能够生存生命 通过恢复体内平衡而面临的挑战。那么，像炎症这样的受保护反应如何变成 慢性，驱动衰老并充当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（营养不良）的改变或衍生型菌群的潜在易位向肝脏 肠系膜和胶质脂肪组织可能有助于与年龄相关的炎症的机理。排队 有了这种可能性，最近的研究表明，与 衰老并暗示微生物组可能在炎症的某些方面起因果作用。我们最近 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样簇（FALC）。与淋巴结不同，FALCS是混乱的 与脂肪细胞相关的非囊化的非经典淋巴组织包含T细胞，B细胞和 巨噬细胞。此外，我们发现B细胞随着Falcs的年龄而扩展并显示出独特的 转录轮廓提醒抗原经验的B细胞。根据我们的原始发现，中央 该应用的假设是肠道微生物向内脏脂肪组织的易位导致FALC 形成和年龄相关的炎症导致代谢功能障碍。我们将测试如何 防止微生物群的易位可以防止FALC形成和炎症。