Interplay of androgens, microbiota and immunoregulation in lupus

狼疮中雄激素、微生物群和免疫调节的相互作用

基本信息

批准号：
8969464
负责人：
MICHELE M KOSIEWICZ
金额：
$ 41.26万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969464
关键词：
Address Affect Agonist Androgen Receptor Androgens Autoimmune Diseases Castration Cell physiology Complex Cytoprotection Data Defect Dendritic Cells Development Diabetes Mellitus Disease Environment Estrogens Exhibits Feces Female Gonadal Steroid Hormones Health Human Immune response Immune system In Vitro Inbred NOD Mice Incidence Inflammatory Insulin-Dependent Diabetes Mellitus Intestines Knowledge Lead Link Lupus Mediating Men&apos s Role Microbiological Techniques Modeling Mus Pathogenesis Phytol Play Prevention strategy Production Property Puberty RXR Receptor Signaling Regulatory T-Lymphocyte Role Severity of illness Sex Characteristics Systemic Lupus Erythematosus Techniques Therapeutic Transplantation Treatment Protocols Tretinoin Volatile Fatty Acids Woman base commensal microbes disorder prevention gut microbiota immunoregulation imprint in vivo innovation male men metabolomics mortality mouse model next generation sequencing novel novel therapeutics public health relevance sex

项目摘要

DESCRIPTION (provided by applicant): Resubmission Systemic lupus erythematosus (SLE) is much more prevalent in females than males in humans, and in the (NZBxNZW)F1 (BWF1) mouse model of lupus. Although estrogens can exacerbate disease in females, considerable evidence suggests that androgens play a critical role in protecting males from lupus in both humans and mice. The gut microbiota is now thought to play a major role in host health and disease, and microbiota dysbiosis is associated with development of autoimmune diseases. Interestingly, androgens can have a significant impact on the microbiota and vice versa. Recent studies in a mouse model of type 1 diabetes (T1D) suggest that the microbiota and androgens collaborate, in what is now being referred to as the "microgenderome", to protect male mice from disease via currently unknown mechanisms. However, little is known about the relationship between androgens and the microbiota in lupus. In preliminary studies, we have found that both the microbiota composition and metabolomic profile differ significantly between mature female and male BWF1 mice, and transfer of male microbiota to female BWF1 mice protects female recipients from disease, and significantly enhances survival. These data suggest that the male environment confers protective properties on the microbiota by altering microbiota composition and/or metabolome. Metabolites from commensal bacteria have been found to induce Treg differentiation both directly and through DC. The gut CD103+ dendritic cells (CD103DC) are highly tolerogenic, and generate regulatory T cells in the periphery that can control systemic immune responses. Our preliminary data showing sex-based differences in CD103DC function, and the requirement for CD103+ cells for protection in male BWF1 mice strongly support the notion that CD103DC function as a critical link between the male gut microbiota and the immune response, and may, therefore, play an important role in protecting BWF1 male mice from disease. Moreover, preliminary analysis of the microbiota metabolome has identified a metabolite that is increased in male BWF1 mice that may have an impact CD103DC function. We, therefore, hypothesize that the androgen-modified male microbiota and its metabolites protect against lupus by acting through the gut CD103DC. This novel hypothesis will be addressed in lupus-prone BWF1 mice by 1) examining the impact of androgens on the gut microbiota and its metabolites; 2) exploring the role of male microbiota and its metabolites in protection from disease; and 3) determining the role that CD103DC play in male microbiota- mediated protection from disease. The proposed project will fill the gaps in our knowledge about the role of the androgen-gut microbiota relationship in immunoregulation and lupus, and will lead to the development of novel therapeutic strategies using the microbiota and/or its metabolites for the treatment of lupus and other autoimmune diseases.

描述（由申请人提供）：重新提交系统性红斑狼疮（SLE）在人类中女性比男性更常见，并且在（NZBxNZW）F1（BWF1）狼疮小鼠模型中虽然雌激素可以加剧女性的疾病，但大量证据表明。表明雄激素在预防人类雄性和小鼠狼疮方面发挥着关键作用。肠道微生物群现在被认为在宿主健康和疾病中发挥着重要作用。微生物群失调与自身免疫性疾病的发展相关，雄激素可以对微生物群产生重大影响，反之亦然。最近对 1 型糖尿病 (T1D) 小鼠模型的研究表明，微生物群和雄激素之间存在相互作用。被称为“微性别组”，通过目前未知的机制保护雄性小鼠免受疾病的影响。然而，我们在初步研究中发现，人们对狼疮中雄激素和微生物群之间的关系知之甚少。成熟的雌性和雄性 BWF1 小鼠之间的微生物群组成和代谢组学特征存在显着差异，将雄性微生物群转移到雌性 BWF1 小鼠中可以保护雌性受体免受疾病的侵害，并显着提高存活率。这些数据表明雄性环境赋予了小鼠保护特性。研究发现，通过改变共生细菌的微生物群组成和/或代谢物，微生物群可以直接或通过 DC 诱导 Treg 分化。 (CD103DC) 具有高度耐受性，并在外周生成能够强烈控制全身免疫反应的调节性 T 细胞。我们的初步数据显示 CD103DC 功能存在性别差异，并且雄性 BWF1 小鼠需要 CD103+ 细胞进行保护。 CD103DC 是雄性肠道微生物群和免疫反应之间的关键环节，因此可能在保护 BWF1 雄性小鼠免受疾病侵害方面发挥重要作用。微生物群代谢组鉴定出一种在雄性 BWF1 小鼠中增加的代谢物，该代谢物可能会影响 CD103DC 功能，因此，我们发现雄激素修饰的雄性微生物群及其代谢物通过肠道 CD103DC 发挥作用来预防狼疮。在易患狼疮的 BWF1 小鼠中，可以通过 1) 检查雄激素对肠道微生物群及其代谢物的影响 2) 探索其作用；男性微生物群及其代谢物在预防疾病方面的作用；3) 确定 CD103DC 在男性微生物群介导的疾病预防中所发挥的作用该项目将填补我们关于雄激素-肠道微生物群关系在免疫调节中的作用的知识空白。和狼疮，并将导致使用微生物群和/或其代谢物治疗狼疮和其他自身免疫性疾病的新治疗策略的开发。