Antibody and gut bacteria in 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。流行率 据估计，美国10-19岁人群的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细胞促进肥胖和 T2D。在人类皮下脂肪组织中也发现了B细胞，并且B细胞的功能已经被 在肥胖的受试者中表现为受损。B细胞的主要功能之一是分泌抗体。 然而，抗体在肥胖和T2D中的作用还不是很清楚。在确定因果关系时 和机制，我们将利用激活诱导胞苷脱氨酶缺陷(AID-/-)小鼠。在……里面 这些小鼠，我们能够特异性地研究IgM在免疫代谢中的作用和与IgM相关的 肠道细菌在肥胖的同时不影响B细胞的其他功能，因为B细胞隔间将完好无损。 此外，我们能够确定免疫球蛋白对肥胖后期发展的早期影响。我们的 初步数据显示，IgM会加速小鼠的肥胖。转移粪便肠道微生物区系，我们正在 能够在不到2分钟的时间内将AID-/-小鼠的代谢异常转移到野生型无菌(GF)小鼠 几周。我们还发现，患有T2D的肥胖青少年受试者与IgM结合的肠道增加， 可促进GF小鼠体重增加和糖耐量受损。我们的核心假设是 本课题旨在通过免疫球蛋白M和免疫球蛋白M结合的肠道微生物区系诱导免疫代谢失衡，促进机体免疫功能的恢复。 肥胖和T2D。我们将在小鼠(特定目标1)和人类(特定目标2)身上测试中心假设，在 体外和体内。我们还假设，免疫球蛋白M的免疫致病作用和肠道生物失调 微生物区系协同作用导致肥胖、代谢性炎症和调节失调。我们将对此进行测试 特定目的假说3使用骨髓嵌合小鼠和无菌小鼠。一旦我们确定 因果关系和机制，我们将能够设计出更好的治疗方法来预防和治疗 儿童期、成年期、肥胖症和T2D。

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.