Multiple Sclerosis-Associated Changes in the Composition and Immune Functions of Spore-Forming Bacteria.
Multiple Sclerosis-Associated Changes in the Composition and Immune Functions of Spore-Forming Bacteria.
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多发性硬化症相关的形成细菌的组成和免疫功能的变化。
DOI：
10.1128/msystems.00083-18
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发表时间：
2018-11
期刊：
影响因子：
6.4
通讯作者：
Baranzini SE
中科院分区：
文献类型：
--
作者：
Cekanaviciute E;Pröbstel AK;Thomann A;Runia TF;Casaccia P;Katz Sand I;Crabtree E;Singh S;Morrissey J;Barba P;Gomez R;Knight R;Mazmanian S;Graves J;Cree BAC;Zamvil SS;Baranzini SE
为了解决微生物组对疾病发展的影响，有必要超越描述性研究并评估微生物组变化的生理重要性。我们的研究将计算分析与孢子形成微生物群落炎症特性的体外和体内探索相结合，揭示了新的功能相关性。我们特别表明，虽然多发性硬化症患者和健康受试者的微生物组之间存在微小差异，但这些差异在氯仿抗性部分中加剧。我们进一步证明，当从多发性硬化症患者中纯化时，该部分与体外免疫调节反应受损相关。多发性硬化症（MS）是一种中枢神经系统自身免疫性疾病，其特征是适应性和先天免疫系统失调。最近的研究揭示了多发性硬化症受试者和实验诱导模型中肠道微生物群落的适度改变。然而，仍然缺乏将观察到的微生物群变化与疾病存在联系起来的机制理解。耐氯仿、孢子形成细菌主要属于厚壁菌门中的芽孢杆菌和梭状芽胞杆菌，已被证明在体外和体内表现出免疫调节特性，但尚未在人类疾病中对其进行表征。这项研究探讨了多发性硬化症中该细菌部分的群落组成和免疫功能。我们鉴定了与 MS 相关的孢子形成类群（主要属于梭菌纲），并表明它们的存在与体外分泌 IL-10 的调节性 T 淋巴细胞分化受损相关。在经过抗生素处理的小鼠中定植孢子形成细菌，使我们能够鉴定出一些有利于 IL-10+ 淋巴细胞分化的细菌分类群，以及其他诱导促炎性 IFN-γ+ T 淋巴细胞分化的细菌分类群。然而，当喂食抗生素治疗的小鼠时，MS 和对照来源的孢子形成细菌都能够诱导类似的表达 IL-10 的 Treg 免疫调节反应，从而改善实验性过敏性脑脊髓炎 (EAE) 的症状。我们的分析还发现，Akkermansia muciniphila 是一种关键微生物，它可能直接或间接与孢子形成细菌相互作用，从而加剧 MS 相关肠道微生物群的炎症效应。因此，孢子形成分数的变化可能会影响多发性硬化症中T淋巴细胞介导的炎症。这种根据功能特征分离微生物群子集的实验方法可能有助于更深入地研究其他微生物组分。重要性 为了解决微生物组对疾病发展的影响，有必要超越描述性研究并评估微生物组变化的生理重要性。我们的研究将计算分析与孢子形成微生物群落炎症特性的体外和体内探索相结合，揭示了新的功能相关性。我们特别表明，虽然多发性硬化症患者和健康受试者的微生物组之间存在微小差异，但这些差异在氯仿抗性部分中加剧。我们进一步证明，当从多发性硬化症患者中纯化时，该部分与体外免疫调节反应受损相关。作者视频：提供本文的作者视频摘要。
To address the impact of microbiome on disease development, it is essential to go beyond a descriptive study and evaluate the physiological importance of microbiome changes. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of spore-forming microbial communities, revealing novel functional correlations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform-resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is correlated with impaired immunomodulatory responses in vitro. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria, which primarily belong to the classes Bacilli and Clostridia in the phylum Firmicutes, have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa (primarily in the class Clostridia) and show that their presence correlates with impaired differentiation of IL-10-secreting, regulatory T lymphocytes in vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of proinflammatory, IFN-γ+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control-derived spore-forming bacteria were able to induce similar IL-10-expressing Treg immunoregulatory responses, thus ameliorating symptoms of experimental allergic encephalomyelitis (EAE). Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth. IMPORTANCE To address the impact of microbiome on disease development, it is essential to go beyond a descriptive study and evaluate the physiological importance of microbiome changes. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of spore-forming microbial communities, revealing novel functional correlations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform-resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is correlated with impaired immunomodulatory responses in vitro. Author Video: An author video summary of this article is available.