The microbiome and regulation of mucosal immunity

Abstract

The gastrointestinal tract is a mucosal surface constantly exposed to foreign antigens and microbes, and is protected by a vast array of immunologically active structures and cells. Epithelial cells directly participate in immunological surveillance and direction of host responses in the gut and can express numerous pattern recognition receptors, including Toll-like receptor 5 (TLR5), TLR1, TLR2, TLR3, TLR9, and nucleotide oligomerization domain 2, as well as produce chemotactic factors for both myeloid and lymphoid cells following inflammatory stimulation. Within the epithelium and in the underlying lamina propria resides a population of innate lymphoid cells that, following stimulation, can become activated and produce effector cytokines and exert both protective and pathogenic roles during inflammation. Lamina propria dendritic cells play a large role in determining whether the response to a particular antigen will be inflammatory or anti-inflammatory. It is becoming clear that the composition and metabolic activity of the intestinal microbiome, as a whole community, exerts a profound influence on mucosal immune regulation. The microbiome produces short-chain fatty acids, polysaccharide A, α-galactosylceramide and tryptophan metabolites, which can induce interleukin-22, Reg3γ, IgA and interleukin-17 responses. However, much of what is known about microbiome-host immune interactions has come from the study of single bacterial members of the gastrointestinal microbiome and their impact on intestinal mucosal immunity. Additionally, evidence continues to accumulate that alterations of the intestinal microbiome can impact not only gastrointestinal immunity but also immune regulation at distal mucosal sites.

Keywords: immunity; inflammation; intestinal; microbiome; mucosal.

Figure 1

The cellular and structural composition of the small and large intestinal epithelium. (a) Organization of the small intestinal epithelium. Intestinal epithelial cells and a mucus layer separate the intestinal lumen from the underlying tissue. Lymphocytes beneath the intestinal epithelium are found in either inductive and effector sites. Inductive sites, such as Peyer's patches, generate mature lymphocytes that then migrate to effector sites, such as the lamina propria, to respond to microbial stimulation. (b) Organization of the large intestinal epithelium. The organization of the large intestinal epithelium is very similar to that of the small intestine, excepting the lack of Peyer's patches and a predominance of B cells instead of T cells in the underlying lamina propria. IEL, intraepithelial lymphocyte.

Figure 2

Microbial modulation of mucosal immunity. The intestinal microbiome generates numerous signals, which impact the regulation of intestinal mucosal immunity. The microbiome produces metabolic by-products, such as butyrate and tryptophan catabolites, which can enhance intestinal integrity and stimulate IL-22 production by group 3 ILCs, respectively. Certain members of the microbiome are known to activate specific arms of intestinal immunity. SFB colonization of the small bowel enhances Th17-mediated immunity, while colonization by Clostridia from clusters IV and XIVa promotes the development of regulatory T cells. Polysaccharide A, generated by Bacteroides fragilis, is also capable of enhancing regulatory T-cell activity in the gut. SFB, segmented filamentous bacteria; PSA, polysaccharide A; SCFAs, short-chain fatty acids; AHR, aryl hydrocarbon receptor; ILC, innate lymphoid cell; IL-17, interleukin-17.