Immunological design of commensal communities to treat intestinal infection and inflammation.
Immunological design of commensal communities to treat intestinal infection and inflammation.
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DOI：
10.1371/journal.ppat.1009191
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发表时间：
2021-01
期刊：
影响因子：
6.7
通讯作者：
Clarke TB
中科院分区：
文献类型：
--
作者：
Brown RL;Larkinson MLY;Clarke TB
对微生物群中的单个益生菌物种的免疫学影响知之甚少，限制了益生菌治疗疾病的使用。在这里，我们系统地分析了人类肠道主要门（放线菌门，拟杆菌门，厚壁菌门和变形菌门）的细菌的免疫指纹，以揭示免疫激活的分类模式，并利用这些信息合理设计细菌群落，以增强抗菌防御和对抗肠道炎症。我们揭示拟杆菌和厚壁菌门通过差异诱导初级和次级应答基因对肠道免疫有不同的影响。在这些门中，拟杆菌纲（拟杆菌门）共生体的免疫刺激能力反映了它们TLR 4激活的稳健性，而拟杆菌群落仅依赖于该受体来影响肠道免疫。相比之下，在梭菌纲（厚壁菌门）中，它反映了TLR 2和TLR 4活化的程度，梭菌群落通过这两种受体发出信号，对肠道免疫发挥作用。通过分析受体、细胞内信号成分和转录因子，我们发现典型的NF-κB信号是决定免疫刺激程度的重要调节器。在这种免疫学分析的指导下，我们构建了一个跨门的共生菌（单形拟杆菌、卵形拟杆菌、厌氧消化链霉菌和溶组织梭菌），其增强了先天TLR、IL 6和巨噬细胞依赖性防御万古霉素耐药肠球菌的肠道定植，并通过相同的途径增强了病理性肠道炎症期间的粘膜屏障功能。重要的是，由该联合体建立的肠道免疫的设定点由经典NF-κB信号传导校准。因此，通过分析主要人类肠道物种的免疫学影响，我们的工作为合理的微生物群重建铺平了道路，以防止抗生素耐药性感染和治疗肠道炎症。寄生在人体肠道中的共生细菌是免疫系统的主要调节者。虽然这些生物体塑造免疫功能的集体能力是明确的，但不同共生体对免疫力的个体影响却很难描述。为了解决这一问题，我们系统地表征了来自人类肠道微生物群中主要类群的广泛的一组细菌的免疫学特性。我们已经发现了模式识别受体，细胞内信号传导成分和转录因子的独特互补，通过这些互补，每个共生物种对先天免疫系统发挥作用。这使我们能够第一次确定免疫的神经调节的分类模式，并揭示典型NF-κB信号传导在充当校准共生体引起的免疫刺激程度的变阻器中的独特作用。我们使用这些共生体的免疫学特征来指导治疗性共生体群落的构建，以对抗AMR感染和病理性肠道炎症。以前，利用共生微生物的力量来对抗疾病在很大程度上是一个试错过程，预测微生物群组成的变化将如何影响免疫力几乎是不可能的。我们的研究解决了这两个挑战，并提供了一个独特的科学资源，以指导共生微生物群落的合理设计，以治疗各种疾病，并揭示了不同共生体的损失将如何影响宿主健康。
The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-κB signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-κB signaling. Thus, by profiling the immunological impact of major human commensal species our work paves the way for rational microbiota reengineering to protect against antibiotic resistant infections and to treat intestinal inflammation. The symbiotic bacteria that colonize the human intestine are major regulators of the immune system. While the collective ability of these organisms to shape immune function is clear the individual impact of different symbionts on immunity is poorly delineated. To address this, we have systematically characterized the immunological properties of an extensive panel of commensals from the major taxa in the human intestinal microbiota. We have uncovered the unique complement of pattern recognition receptors, intracellular signaling components and transcription factors through which each symbiotic species exerts their effect on the innate immune system. This allowed us to identify, for the first time, taxonomic patterns of commensal regulation of immunity and uncover a unique role for canonical NF-κB signaling in acting as a rheostat calibrating the degree of immune stimulation symbionts elicit. We used the immunological profiles of these symbionts to guide the construction of therapeutic symbiont communities to combat both AMR infection and pathological intestinal inflammation. Previously, harnessing the power of symbiotic microbes to combat disease was largely a trial-and-error process, and predicting how changes in microbiota composition will impact immunity was almost impossible. Our study addresses both of these challenges and provides a unique scientific resource to guide the rational design of symbiotic microbial communities to treat myriad diseases and reveals how loss of different symbionts will impact host health.
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影响因子：
64.8
作者：
Brandl, Katharina;Plitas, George;Mihu, Coralia N.;Ubeda, Carles;Jia, Ting;Fleisher, Martin;Schnabl, Bernd;DeMatteo, Ronald P.;Pamer, Eric G.
通讯作者：
Pamer, Eric G.
影响因子：
30.3
作者：
Caballero S;Kim S;Carter RA;Leiner IM;Sušac B;Miller L;Kim GJ;Ling L;Pamer EG
通讯作者：
Pamer EG
影响因子：
3.9
作者：
Clark, Kristopher
通讯作者：
Clark, Kristopher
上皮TNF受体信号传导促进炎症性肠病的粘膜修复。
DOI：
10.4049/jimmunol.1601066
发表时间：
2017-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bradford EM;Ryu SH;Singh AP;Lee G;Goretsky T;Sinh P;Williams DB;Cloud AL;Gounaris E;Patel V;Lamping OF;Lynch EB;Moyer MP;De Plaen IG;Shealy DJ;Yang GY;Barrett TA
通讯作者：
Barrett TA
影响因子：
8.7
作者：
Bain CC;Mowat AM
通讯作者：
Mowat AM