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Gut dysbiosis induces lupus

肠道菌群失调诱发狼疮

基本信息

批准号：
9199844
负责人：
Laurence Morel
金额：
$ 18.64万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-04 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199844
关键词：
Age Androgens Antinuclear Antibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Bacteria Biological Markers Butyrates Collaborations Congenic Mice DNA Data Development Disease Disease Progression Experimental Models Feces Future Genes Genome Germ-Free Health Homeostasis Immune Immune response Immune system Immunoglobulin G Immunology Immunophenotyping Inflammation Institution Intestines Knowledge Lactobacillus acidophilus Lupus Lymphocyte Lymphocyte Activation Maps Microbe Modeling Mus Pathogenesis Pathology Pathway interactions Phenotype Play Production Property Rag1 Mouse Regulatory T-Lymphocyte Research Personnel Role SLEB1 gene SLEB2 gene SLEB3 gene Secondary to Shapes System Testing Therapeutic Time Transplantation Variant Work attenuation autoreactivity base cohort commensal microbes congenic design ds-DNA follow-up gut microbiota immune activation immunoregulation metabolomics microbial microbiome microbiota mouse model novel public health relevance

项目摘要

DESCRIPTION (provided by applicant): It is increasingly accepted that gut commensal bacteria play a major role in regulating the immune system in health and disease. An important break-through was achieved with the discovery of the ability of TH17 and regulatory T cells to modify the composition of the gut microbiota, including segmented filamentous bacteria and genetically modified L. acidophilus to shape the local and systemic immune responses, which have been followed up with studies of the role of the microbiota in all major autoimmune diseases. These studies have shown that dysbiosis is associated with disease progression, as well as identify pathways, including MyD88- deficiency or androgen exposure resulting in disease attenuation through the microbiome. Accordingly, we have used a mouse model of lupus, the B6.Sle1.Sle2.Sle3 strain, called TC (triple congenic) for short, which shares >95% of its genome with B6, to show that autoimmunity was associated with a distinct intestinal microbiota that is normalized by a treatment that reversed the disease. Importantly, we demonstrated that microbiota for autoimmune TC mice was sufficient for inducing the production of anti-dsDNA IgG and also caused a strong immune activation in germ free (GF) B6 mice. To the best of our knowledge, this is the first demonstration that the autoimmune phenotype can be induced by microbial dysbiosis in an autoimmune mouse model. Based on these novel preliminary data and on the work of others on the immunoregulatory role of microbiota, we hypothesize that a dysregulated gut microbiota contributes to lupus pathogenesis either directly or indirectly, through the production of critical metabolites (e.g., butyrate). In the former case, variations in immune related genes or others intrinsically change the composition of the microbiota, independently from the ongoing autoimmune response. In the latter case, the inflammation and autoimmune activation that develops with lupus leads to gut dysbiosis, which in turn, promotes inflammation resulting in dysfunctional immune homeostasis. To test this hypothesis and to delineate the relationship between dysbiosis and autoreactivity, we propose two specific aims. 1. To elucidate the autoimmune responses induced by microbial dysbiosis from lupus-prone TC mice. We will expand our initial findings that TC microbiota induces autoAb production and immune activation in a larger cohort of GF B6 mice, with a characterization of the fecal microbiota and microbiome of the donors and the GF recipients 4 wks post transfer. We will also investigate whether we can sustain the immunophenotypes and induce autoimmune pathology with multiple fecal transfers. Finally, we will test whether the expression of the Sle1 locus is sufficient to confer immune activation to the microbiota. 2. To Test the mechanisms of TC dysbiosis relative to the development of systemic autoimmunity. Based on the experimental setting developed in Aim 1, determine whether the autoimmune-inducing properties of TC microbiota are intrinsic or secondary to TC autoimmunity. An answer to this fundamental question is required to direct any future mechanistic studies of the interplay between systemic autoimmunity and dysbiosis. Analyzing the microbiota of TC mice that have already reverted disease also offers the possibility of identifying microbial species or products that can be used as disease biomarkers. The body of knowledge that will be generated from this exploratory proposal will launch future studies that define how specific bacteria and their metabolites promote systemic autoimmunity, as well as to assess the potential value of the microbiota in generating biomarkers of disease activity.