Regulation of the immune system by the resident intestinal bacteria

Abstract

The microbiota is an important factor in the development of the immune response. The interaction between the gastrointestinal tract and resident microbiota is well balanced in healthy individuals, but its breakdown can lead to intestinal and extraintestinal disease. We review current knowledge about the mechanisms that regulate the interaction between the immune system and the microbiota, focusing on the role of resident intestinal bacteria in the development of immune responses. We also discuss mechanisms that prevent immune responses against resident bacteria, and how the indigenous bacteria stimulate the immune system to protect against commensal pathobionts and exogenous pathogens. Unraveling the complex interactions between resident intestinal bacteria and the immune system could improve our understanding of disease pathogenesis and lead to new therapeutic approaches.

Keywords: IgA; Innate Lymphoid Cells; Microbiota; Regulatory T Cell; Th17.

Figure 1. Multiple Firewalls Limit Immune Responses Against Resident Intestinal Bacteria

The intestine has firewalls that limit inappropriate immune responses against commensal bacteria. One mechanism involves compartmentalization of the resident bacteria by a thick mucus layer, anti-microbial peptides (such as RegIIIγ), or secreted IgA, which all prevent access of the resident bacteria to the epithelium. Neutrophils can migrate out to the intestinal lumen and build intraluminal cellular casts that encapsulate commensals, limiting the penetration of luminal microbes. A second mechanism involves microbial hyporesponsiveness of resident intestinal macrophages. In contrast to monocytes and macrophages in systemic tissues, intestinal macrophages are hypo-responsive to microbial stimuli and produce only limited amounts of inflammatory cytokines such as TNFα or IL12. Furthermore, resident phagocytes spontaneously produce anti-inflammatory cytokines, such as IL10. A third mechanism involves active suppression of microbe-reactive effector T cell responses by Foxp3⁺ iTreg cells and Foxp3⁻ Tr1 cells via production of IL10. In addition, MHC-II⁺ ILCs present bacterial antigens, which limits activation of commensal-reactive CD4⁺ T cells.

Figure 2. Regulation of the Resident Intestinal Bacteria by the Immune System

Direct binding of IgA to the commensal B thetaiotaomicron regulates bacterial gene expression. IgA also regulates the composition of the commensal bacterial community. IL22 produced by RORgt⁺ group 3 ILCs induces production of RegIIIγ by IECs, which limits the growth of SFB. Overgrowth of SFB increases numbers of Th17 cells and Th17-cell–mediated intestinal inflammation. RORγt⁺ ILCs limit expansion of the commensal pathobiont A xylosoxidians in PPs. Expression of T-bet by ILCs limits the accumulation of certain commensal pathobionts, such as K pneumoniae, P mirabilis, or H typhlonius. IL18 is induced by the intestinal epithelium via a NLRP3-dependent pathway. IL18 limits the overgrowth of the pathobionts Prevotellaceae and TM7 via unidentified mechanisms.