Antibody and gut bacteria in obesity and T2D

肥胖和 T2D 中的抗体和肠道细菌

• 批准号: 10599318
• 负责人: Li Wen
• 金额: $ 44.19万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599318
• 关键词: Acceleration; Address; Adipose tissue; Adolescent; Adolescent obesity; Adult; Anti-Inflammatory Agents; Antibodies; B-Lymphocytes; Binding; Bone Marrow; Cell Compartmentation; Cell physiology; Cells; Childhood; Circulation; Crowns; Data; Endotoxins; Essential Fatty Acids; Etiology; Fatty acid glycerol esters; Germ-Free; Health; Human; Immune; Immune response; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Memory; Impairment; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Intestinal permeability; Knowledge; Life; Lymphoid Cell; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Molecular; Mucous Membrane; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathogenicity; Patients; Persons; Play; Prevalence; Prevention therapy; Production; Role; Silver; Structure; Study models; T cell regulation; T-Lymphocyte; Testing; Tissues; Weight Gain; activation-induced cytidine deaminase; adolescent patient; aged; cytokine; design; gut bacteria; gut dysbiosis; gut microbiota; humoral immunity deficiency; impaired glucose tolerance; in vivo; influenza infection; man; mouse model; obese patients; obese person; obesity development; small molecule; subcutaneous; type 2 diabetes in children

Abstract Obesity and type 2 diabetes (T2D) in children and adolescents are serious health problems. Prevalence estimates a 31% increase in T2D among people aged 10-19 years in US. A body of evidence suggests that immune cells play an important role in obesity and T2D, and this has led to the new but fast growing field of “immunometabolism”. Studies in humans have suggested that B cells promote inflammation in obesity and T2D. B cells were also found in human subcutaneous adipose tissue and the function of B cells has been shown to be impaired in obese subjects. One of the major functions of B cells is to secrete antibodies. However, not much is known about the role of antibodies in obesity and T2D. In determining the causality and mechanism, we will take advantage of activation-induced cytidine deaminase deficient (AID-/-) mice. In these mice, we are able to specifically investigate the role of IgM in immune-metabolism and IgM-associated gut bacteria in obesity, while not affecting other functions of B cells, as the B cell compartment will be intact. Moreover, we are able to determine the early-life effects of IgG on later development of obesity. Our preliminary data suggest that IgM accelerates obesity in mice. Transferring fecal gut microbiota, we are able to transfer the metabolic abnormalities in AID-/- mice to wild type germ free (GF) mice in less than 2 weeks. We have also discovered that obese adolescent subjects with T2D have increased IgM-bound gut , which promote body weight gain and impaired glucose tolerance in GF mice. Our central hypothesis of this project is that IgM and IgM-bound gut microbiota induce imbalance of immune-metabolism and promote obesity and T2D. We will test the central hypothesis in mouse (Specific Aim 1) and man (Specific Aim 2), in vitro and in vivo. We also hypothesize that the immune-pathogenic role of IgM and dysbiosis of gut microbiota synergistically contribute to obesity, metabolic inflammation and dysregulation. We will test this hypothesis in Specific Aim 3 using bone marrow chimeric mice and germ-free mice. Once we establish causality and the mechanism, we will be able to design better therapy for the prevention and treatment of childhood, as well as adult, obesity and T2D.

摘要 儿童和青少年的肥胖和2型糖尿病（T2D）是严重的健康问题。患病率 据估计，在美国10 - 19岁的人群中，T2D增加了31%。大量证据表明， 免疫细胞在肥胖和T2D中起着重要作用，这导致了新的但快速增长的领域， "免疫代谢"。对人类的研究表明，B细胞促进肥胖症的炎症， 2型糖尿病B细胞也存在于人皮下脂肪组织中，并且B细胞的功能已被证实。 在肥胖的受试者中表现出受损。B细胞的主要功能之一是分泌抗体。 然而，关于抗体在肥胖和T2D中的作用知之甚少。在确定因果关系时 和机制，我们将利用激活诱导的胞苷脱氨酶缺陷（AID-/-）小鼠。在 在这些小鼠中，我们能够特异性地研究IgM在免疫代谢和IgM相关的 肠道细菌的肥胖，而不影响其他功能的B细胞，因为B细胞区室将是完整的。 此外，我们能够确定IgG对以后肥胖发展的早期影响。我们 初步数据表明IgM加速了小鼠的肥胖。转移粪便肠道微生物群， 能够将AID-/-小鼠中的代谢异常转移到野生型无菌（GF）小鼠中， 周我们还发现患有T2D的肥胖青少年受试者具有增加的IgM结合肠道， 其促进GF小鼠的体重增加和葡萄糖耐量受损。我们的核心假设是 该项目是IgM和IgM结合的肠道微生物群诱导免疫代谢失衡，并促进 肥胖和T2D。我们将在小鼠（特定目标1）和人（特定目标2）中检验中心假设， 体外和体内。我们还假设IgM的免疫致病作用和肠道生态失调 微生物群协同地促成肥胖、代谢炎症和失调。我们将测试这个 使用骨髓嵌合小鼠和无菌小鼠，在特异性目标3中进行了假设。一旦我们确定 因果关系和机制，我们将能够设计更好的治疗方法来预防和治疗 儿童以及成人、肥胖和T2 D。