Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05401.
Medical Systems Biology Group, Lübeck Institute of Experimental Dermatology, University of Lübeck, 23562 Lübeck, Germany.
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27516-27527. doi: 10.1073/pnas.2002817117. Epub 2020 Oct 19.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome. However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. In parallel, we used a reductionist approach focused on two of the most disparate phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to modulate EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified as a commensal species unexpectedly associated with exacerbation of EAE in a genetically susceptible host, which was functionally confirmed by bacterial isolation and commensal colonization studies. These results reveal complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmunity, providing insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease and underscoring the need to consider host genetics and baseline gut microbiome composition.
多发性硬化症（MS）是一种中枢神经系统自身免疫性疾病。MS 的病因是多因素的，疾病风险由遗传和环境因素决定。肠道微生物组失衡是免疫介导性疾病的一个新出现的危险因素。然而，与疾病风险相关的肠道微生物的特征、它们的作用机制以及与宿主遗传的相互作用仍然不清楚。为了解决这些问题，我们利用多发性硬化症的主要自身免疫模型，实验性自身免疫性脑脊髓炎（EAE），以及代表 29 种独特宿主基因型的遗传多样化小鼠模型，通过微生物组测序和靶向微生物组操作进行研究。我们确定了与 EAE 易感性相关的特定肠道细菌及其代谢功能，表明短链脂肪酸代谢是跨越多个宿主基因型的一个关键元素。同时，我们使用一种简化的方法，专注于我们筛选中确定的两种最不同的表型。通过移植和共住房来操纵肠道微生物组，证明将这些微生物组转移到遗传上相同的宿主中足以调节 EAE 的易感性和系统代谢物谱。平行的生物信息学方法确定 作为一种共生种，出乎意料地与遗传易感宿主的 EAE 恶化有关，这通过细菌分离和共生定植研究得到了功能上的证实。这些结果揭示了宿主遗传和肠道微生物组之间复杂的相互作用，调节了对中枢神经系统自身免疫的易感性，为针对微生物组的策略提供了见解，旨在降低自身免疫性疾病的风险，并强调了需要考虑宿主遗传和基线肠道微生物组组成的必要性。
