Immunological partners: the gut microbiome in homeostasis and disease

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. 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. 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. 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) 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. 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 b-glucan (YBG), is a prebiotic that Gudi et al. investigate in their original article (Fig. 1 2), and they find that administration of YBG expands FoxP3 IL10 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-a, and IL-17 with a targeted decrease in some cytokines (e.g. interferon-c). 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). 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. 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. Using mice deficient in eosinophils (i.e. DdblGATA-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). Although these investigators did not find that these changes in