Our world is changing fast. Microbes, once considered our adversaries, are now recognized as partners. Well, not all microbes, but a vast number that live in the unique niches of our bodies and, in particular, the gut. Recently, we have come to appreciate how our normal microbiota contribute to our health, and how disruption of this partnership can open the way for disease (both infectious and non‐infectious). This Joint Virtual Issue on ‘Immunology and the Microbiome’ celebrates this partnership and is a joint initiative by the immunological societies of Australia and New Zealand (ASI) and Britain (BSI) and their journals, Immunology & Cell Biology and Immunology, respectively. This collection contains six recent articles from each journal (three reviews and three original research articles) that highlight specific aspects of the microbiome–immune partnership.

Focusing on the articles from Immunology, there are key central themes that arise: the changing nature of this relationship over time, how diet influences the microbiota and consequently the immune system, and how individual components of the innate and adaptive immune systems interact with the gut microbiome to regulate and balance the complex network. To start this collection off, Zhao et al.1 begin at the beginning – the education of the adaptive immune system by gut microbial antigens (Fig. 1 ①). This education starts at birth with the first major seeding of flora from the mother; colonization begins and so does the development of adaptive cells. Zhao et al.1 detail how these processes are intertwined with the neonate’s immune system regulating the microbial community and the microbes shaping the developing immune cells. This period is a critical ‘window of opportunity’, which impacts one’s health and homeostasis throughout life. Within the large community of microbes, specific microbes can support the differentiation or expansion of different functional immune subsets such as the support of regulatory T (Treg) cell expansion by specific Clostridium clusters and Bacteroides fragilis or the induction of T helper type 17 cells by epithelial‐adhesive bacteria like Escherichia coli O157.1 Zhao et al. conclude by discussing how the mis‐education of adaptive immune cells during this critical period promotes the development of chronic inflammatory diseases such as Crohn’s disease and multiple sclerosis (MS)1 and end by highlighting how the potential of probiotics or prebiotics to ‘normalize’ the gut microbiota presents an attractive therapeutic strategy.

Partnerships take a lot of work; they need the right fuel to keep them alive and to enable both partners to benefit. That is how probiotics and prebiotics work – seeding the right microbes and then providing the right nutrients to fuel them. Gudi et al. and Haase et al.2, 3 investigate how specific microbial partnerships are fueled and sustained such that their metabolites can regulate chronic inflammatory diseases such as MS. The complex dietary polysaccharide, yeast β‐glucan (YBG), is a prebiotic that Gudi et al.2 investigate in their original article (Fig. 1 ②), and they find that administration of YBG expands FoxP3⁺ IL‐10⁺ IL‐17⁺ T cells ex vivo and modulates the T‐cell compartment in vivo, leading to suppression of type 1 diabetes in non‐obese diabetic mice. Key to this effect is the finding that YBG enhances, not suppresses, local cytokine production including interleukin (IL)‐10, tumor necrosis factor‐α, and IL‐17 with a targeted decrease in some cytokines (e.g. interferon‐γ).2

Promoting the growth of the ‘right’ kind of bacteria has flow‐on effects not only locally but also systemically, by the production of immune‐modifying microbial metabolites as discussed by Haase et al. (Fig. 1 ③).3 In particular, the ability of these microbially produced compounds such as short‐chain fatty acids or tryptophan metabolites to alter neuroinflammation in diseases such as MS speaks to the importance of the microbiota–gut–brain axis in maintaining health and homeostasis throughout the body. This axis involves not just the immune system but is a complex network encompassing enteroendocrine cells, vagal nerve signals, as well as astrocytes and microglia within the brain with short‐chain fatty acids exerting their effects through stimulation of retinoic acid production, histone deacetylase inhibition and direct activation of free fatty acid receptors like GPR43, GPR41 and GPR109A.3 This review centers on the specific benefits of short‐chain fatty acids and tryptophan metabolites, but these microbially‐derived products are only subset of metabolites that contributes to immune homeostasis and the development of a beneficial microbial partnership.

Immune control of the microbial populations in the gut is essential to the maintenance of a healthy gut microbiome, and control of gut microbes by gut eosinophils and secretory IgA (sIgA) are the focus of the articles by Singh et al. and Hoces et al.4, 5 Using mice deficient in eosinophils (i.e. ΔdblGATA‐1^−/− mice), Singh and his colleagues report that an absence of eosinophils did not alter gut architecture, barrier integrity or sIgA levels; however, the loss of eosinophils significantly changed microbial diversity with the greatest effects found in the mucus‐associated communities (Fig. 1 ④).4 Although these investigators did not find that these changes in microbial communities resulted in any apparent negative health effects in this controlled experimental system, it remains to be seen whether a loss or impairment of eosinophil function in a more complex and chaotic environment that more closely parallels real life would reveal a role for these innate cells in maintaining gut health.

Looking in more detail into how sIgA regulates microbial colonization, Hoces et al.5 not only discuss the direct interaction between sIgA and gut microbes but also consider the contributions of gut physiology and environment into the seemingly contradictory actions of sIgA in preventing disease but promoting colonization (Fig. 1 ⑤). They discuss the function of sIgA in the context of the changing gut environment, which is promoted by the high flow rate through the gastrointestinal system, as well as the constant molecular evolution that microbes undergo in adapting to this changing environment. Specifically, they propose a model whereby high microbial densities lead to classical agglutination by sIgA, whereas low bacterial densities promote ‘enchained’ clonal growth.5 This enchained growth or clumping provides specific benefits including selective clonal growth and extinction as well as reducing horizontal gene transfer, suggesting an impact on local microbial evolution.5 By understanding how sIgA regulates microbial communities in the gut, we can better design vaccines or targeted therapeutics that harness the complex activities of sIgA to regulate gut health.

The last Immunology article in this Joint Virtual issue highlights how sustaining a beneficial partnership requires constant work and effort. In the context of gut health, Kehrmann et al.6 investigate the involvement of Treg cells in shaping the microbial communities in the gut (Fig. 1 ⑥). While Treg cells are critical regulators of immune cells, this original article looks at how a loss of Treg cells, using DEpletion of REGulatory T cells (DEREG) mice, changes the microbiota. One of the key findings of this study was the increase in abundance of bacteria from the phylum Firmicutes; however, underscoring this finding was recognition of the contribution of inter‐subject variability influenced by cage, breeding, sex and experiment to even this controlled experimental system.6

To complement these articles from Immunology, are six from Immunology & Cell Biology that investigate and discuss the involvement of immune factors (interferon inducible transmembrane genes)7 or immune cells (MAIT cells)8 in regulating the local gut environment to maintain epithelial homeostasis and immune–microbial balance. The benefit of a balanced and regulated microbiota is also discussed by Malone et al. in the context of how the gut–brain axis influences stroke outcomes9 and by McCoy et al.10 in how the microbiome shapes immune memory. These reviews highlight the potential of targeted microbiome interventions in the treatment of stroke or to maximize vaccine efficacy. Finally, studies by Poyntz et al. and Mullaney et al. examine the individual contributions of genetic factors versus microbiota in experimental models of antibody responsiveness11 or autoimmunity,12 and find that in these instances, the microbiome cannot overcome genetic susceptibility.

Taken together, this collection of articles and editorials from Immunology1-6 and Immunology & Cell Biology7-13 begin to dissect the complex partnership that has evolved, and continues to evolve, between microbes and humans. The consequences of an unhealthy relationship (i.e. dysbiosis) are far‐reaching, as shown by the effects of the gut microbiome on chronic inflammatory (e.g. Crohn's disease) or autoimmune (type 1 diabetes, MS) diseases, but by understanding this complex network, we can design interventions (diet, vaccines, therapeutics) to prevent disease and promote a healthy homeostasis.

我们的世界正在快速变化。微生物曾经被认为是我们的对手，现在被认为是我们的伙伴。嗯，并不是所有微生物，而是大量生活在我们身体，特别是肠道的独特环境中的微生物。最近，我们开始认识到我们的正常微生物群如何对我们的健康做出贡献，以及这种伙伴关系的破坏如何为疾病（传染性和非传染性）开辟道路。这期关于“免疫学和微生物组”的联合虚拟期刊庆祝了这种伙伴关系，是由澳大利亚和新西兰免疫学会 (ASI) 和英国 (BSI) 及其期刊《免疫学与细胞生物学》和《免疫学》联合发起的。该合集包含各期刊最近发表的六篇文章（三篇评论和三篇原创研究文章），重点介绍了微生物组与免疫伙伴关系的具体方面。

关注免疫学的文章，出现了一些关键的中心主题：这种关系随着时间的推移而变化的性质，饮食如何影响微生物群进而影响免疫系统，以及先天性和适应性免疫系统的各个组成部分如何与肠道相互作用微生物组调节和平衡复杂的网络。为了开始这个系列，赵等人。 1从头开始​​——通过肠道微生物抗原对适应性免疫系统进行教育（图1①）。这种教育从出生时就开始了，从母亲那里播下了第一批主要的植物种子。定植开始，适应性细胞的发育也开始。赵等人。 1详细介绍了这些过程如何与新生儿的免疫系统交织在一起，从而调节微生物群落以及塑造发育中的免疫细胞的微生物。这一时期是一个关键的“机会之窗”，会影响一个人一生的健康和体内平衡。在大型微生物群落中，特定微生物可以支持不同功能性免疫亚群的分化或扩增，例如通过特定梭状芽胞杆菌簇和脆弱拟杆菌支持调节性 T (Treg) 细胞扩增，或通过上皮细胞诱导 17 型辅助 T 细胞‐粘附细菌，如大肠杆菌O157。 1赵等人。最后讨论了在这一关键时期对适应性免疫细胞的错误教育如何促进克罗恩病和多发性硬化症 (MS) 等慢性炎症性疾病的发展1 ，最后强调益生菌或益生元如何使免疫系统“正常化”肠道微生物群提出了一种有吸引力的治疗策略。

建立伙伴关系需要做很多工作；他们需要合适的燃料来维持生命并使合作伙伴双方都能受益。这就是益生菌和益生元的工作原理——播种正确的微生物，然后提供正确的营养物质来为它们提供能量。古迪等人。和哈斯等人。 2, 3研究了特定的微生物伙伴关系如何被促进和维持，以便它们的代谢物可以调节慢性炎症性疾病，例如多发性硬化症。复杂的膳食多糖，酵母β-葡聚糖（YBG），是一种益生元，Gudi等人。 2在他们的原始文章中进行了研究（图 1 ②），他们发现 YBG 的施用会在体外扩增 FoxP3 ⁺ IL-10 ⁺ IL-17 ⁺ T 细胞，并在体内调节 T 细胞区室，从而抑制类型1 非肥胖糖尿病小鼠的糖尿病。这种作用的关键是发现 YBG 增强而不是抑制局部细胞因子的产生，包括白细胞介素 (IL)-10、肿瘤坏死因子-α和 IL-17，并有针对性地减少某些细胞因子（例如干扰素-γ ）。 2

正如 Haase等人所讨论的，通过产生免疫修饰微生物代谢物，促进“正确”细菌的生长不仅在局部而且在全身都有流动效应。 （图1③）。 3特别是，这些微生物产生的化合物（例如短链脂肪酸或色氨酸代谢物）能够改变多发性硬化症等疾病中的神经炎症，这说明了微生物群-肠-脑轴在维持全身健康和体内平衡方面的重要性。该轴不仅涉及免疫系统，而且是一个复杂的网络，包括肠内分泌细胞、迷走神经信号以及大脑内的星形胶质细胞和小胶质细胞，短链脂肪酸通过刺激视黄酸产生、组蛋白脱乙酰酶抑制和直接激活游离脂肪酸受体，如 GPR43、GPR41 和 GPR109A。 3本综述的重点是短链脂肪酸和色氨酸代谢物的具体益处，但这些微生物衍生产品只是有助于免疫稳态和有益微生物伙伴关系发展的代谢物的子集。

对肠道微生物群的免疫控制对于维持健康的肠道微生物组至关重要，而肠道嗜酸性粒细胞和分泌性 IgA (sIgA) 对肠道微生物的控制是 Singh等人文章的重点。和霍斯等人。 4, 5 Singh 和他的同事使用缺乏嗜酸性粒细胞的小鼠（即Δ dblGATA-1 ^−/−小鼠）报告说，缺乏嗜酸性粒细胞不会改变肠道结构、屏障完整性或 sIgA 水平；然而，嗜酸性粒细胞的丧失显着改变了微生物多样性，其中在粘液相关群落中影响最大（图 1 ④）。 4虽然这些研究人员没有发现微生物群落的这些变化在这个受控实验系统中导致任何明显的负面健康影响，但在更复杂和混乱的环境中，嗜酸性粒细胞功能的丧失或损害是否会导致嗜酸性粒细胞功能的丧失或损害，还有待观察。现实生活将揭示这些先天细胞在维持肠道健康中的作用。

Hoces等人更详细地研究了 sIgA 如何调节微生物定植。图5不仅讨论了sIgA与肠道微生物之间的直接相互作用，还考虑了肠道生理和环境对sIgA预防疾病但促进定植看似矛盾的作用的贡献（图1⑤）。他们讨论了 sIgA 在不断变化的肠道环境中的功能，这是由胃肠道系统的高流速以及微生物为适应这种不断变化的环境而经历的不断的分子进化所促进的。具体来说，他们提出了一个模型，其中高微生物密度导致 sIgA 的经典凝集，而低细菌密度则促进“链式”克隆生长。 5这种链式生长或聚集提供了特定的好处，包括选择性克隆生长和灭绝以及减少水平基因转移，这表明对当地微生物进化的影响。 5通过了解 sIgA 如何调节肠道微生物群落，我们可以更好地设计疫苗或靶向疗法，利用 sIgA 的复杂活性来调节肠道健康。

本期联合虚拟期刊中的最后一篇免疫学文章强调了维持有益的伙伴关系如何需要不断的工作和努力。在肠道健康方面，Kehrmann等人。 6研究了 Treg 细胞在塑造肠道微生物群落中的作用（图 1 ⑥）。虽然 Treg 细胞是免疫细胞的关键调节因子，但这篇原创文章通过使用调节性 T 细胞耗竭 (DEREG) 小鼠来研究 Treg 细胞的损失如何改变微生物群。这项研究的主要发现之一是厚壁菌门细菌丰度的增加。然而，强调这一发现的是认识到受笼子、繁殖、性别和实验影响的受试者间变异性对这一受控实验系统的影响。 6

为了补充这些来自免疫学的文章，来自免疫学和细胞生物学的六篇文章研究和讨论了免疫因子（干扰素诱导跨膜基因） 7或免疫细胞（MAIT 细胞） 8在调节局部肠道环境以维持上皮稳态和免疫方面的作用–微生物平衡。 Malone等人还讨论了平衡和受调节的微生物群的好处。在肠-脑轴如何影响中风结果的背景下9和 McCoy等人。 10微生物组如何塑造免疫记忆。这些评论强调了有针对性的微生物组干预在治疗中风或最大限度地提高疫苗功效方面的潜力。最后，Poyntz等人的研究。和穆拉尼等人。在抗体反应性11或自身免疫12的实验模型中检查遗传因素与微生物群的个体贡献，发现在这些情况下，微生物组无法克服遗传易感性。

总而言之，这本来自《免疫学》第 1-6 期和《免疫学与细胞生物学》第 7-13 期的文章和社论合集开始剖析微生物与人类之间已经进化并将继续进化的复杂伙伴关系。不健康的关系（即生态失调）的后果是深远的，正如肠道微生物组对慢性炎症（例如克罗恩病）或自身免疫（1 型糖尿病，MS）疾病的影响所表明的那样，但通过了解这个复杂的网络，我们可以设计干预措施（饮食、疫苗、疗法）来预防疾病并促进健康的体内平衡。