Regulation of innate and adaptive immunity by the commensal microbiota
Highlights
► The microbiota contributes to the maintenance of immune homeostasis in the intestine. ► The host must remain tolerant of commensals and able to mount protective immune responses against pathogenic microbes. ► Specific bacteria promote lymphocyte differentiation and help establish innate immune defense. ► Some members of the intestinal microbiota can provoke aberrant immune responses that extend beyond the gut.
Introduction
The mammalian intestinal tract is colonized by an estimated 1013–1014 bacteria. These microbes aid the host by breaking down food into absorbable products in exchange for an environment with a constant influx of nutrients necessary for their survival. Thus, the microbial communities that inhabit the mammalian intestine, termed the intestinal microbiota, maintain a symbiotic relationship with their host. Because the gut is open to the environment, the risk of infection with exogenous pathogenic organisms is real. The immune system must be both tolerant to the microbial communities it contains and able to efficiently respond to infection. The microbiota itself plays a crucial role in preventing the outgrowth of pathogenic organisms. This ‘colonization resistance’ can be disrupted by changes in the complexity and density of the microbiota. Germ-free (GF) mice or mice carrying a low complexity microbiota, in addition to being highly susceptible to a variety of intestinal pathogens, also have altered mucosal immune responses [1, 2••].
The scale of current efforts to understand the composition and dynamics of the microbiota reflects the growing understanding of its crucial role in whole organism homeostasis. It is now recognized that changes in the composition and density of the gut flora can have profound effects on the development of not only inflammatory bowel disease, but also autoimmunity in tissues that are not in direct contact with the microbiota. This review will address the role of the intestinal microbiota in host defense and in shaping immune compartments that contribute to inflammatory responses and autoimmunity.
Section snippets
The complex microbiota protects against infection
The intestinal tract of mammals harbors many bacterial species that have not been cultured in the laboratory. This has limited our understanding of the complexity of the intestinal microbiota until recent years, when cultivation-independent 16S rRNA gene sequencing techniques began to be employed more widely for this purpose. We now know that following antibiotic treatment, the density and composition of the intestinal microbiota is severely affected [3••, 4, 5]. Further, lasting changes in the
Immune activation elicits host defense
The importance of the microbiota in driving protective immune responses during intestinal infection is best illustrated by the finding that restoring signaling through innate immune receptors in antibiotic-treated mice can protect from intestinal infections. Many TLRs are expressed in the murine and human intestine, but their expression by the specific cell lineages of the gut is not fully elucidated. Toll-like receptor (TLR) 9 stimulation of antibiotic-treated mice by DNA derived from gut
Microbiota and B cell responses
Given the important role of innate immune receptors in intestinal immune homeostasis and host defense, it is interesting to note that MyD88-deficient mice keep the microbiota at bay and prevent bacteremia. In a recent study, Slack and colleagues demonstrated the crucial role of T-cell dependent IgG production in the context of severe innate immune deficiency [24••]. Mice lacking the signaling mediators MyD88 and TRIF have elevated serum levels of IgG specific for microbiota components,
Role of the microbiota in directing T cell responses
Th17 cells are important mediators of immune defenses in the gut and are induced by the microbiota through several mechanisms (Figure 2). Induction of Th17 cells in the small intestinal lamina propria by SFB appears to be mediated partly by the production of serum amyloid A, which is upregulated upon SFB colonization and can induce Th17 cell differentiation in vitro [21••]. Phagocytosis of infected apoptotic cells by DC induces Th17 cells via production of IL-6 and TGFβ following recognition of
Inflammation and the microbiota
While microbiota-induced Th17 cytokines in the lamina propria can be crucial for protection against intestinal pathogens [18, 21••], they can also contribute to inflammation in the colon [35], and IL-23-responsive innate lymphoid cells in the lamina propria contribute to colitis in Rag−/− mice by producing IL-17 and IFNγ [45]. RORγt-deficient mice lack Th17 cells and lymphoid tissue inducer cells, resulting in an absence of lymph nodes, Peyer's patches, and isolated lymphoid follicles. RORγt−/−
Autoimmunity
While shifts in microbiota composition and density affect immune responses locally, it is now recognized that changes in bacterial species in the gut can also result in altered immunity in organs that are not in direct contact with the intestinal microbiota. Mice lacking an intestinal microbiota develop attenuated disease in models of autoimmune arthritis and autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Colonization with SFB promotes progression to autoimmune
Concluding remarks
Our appreciation for the role of the microbiota in shaping host innate and adaptive immunity has increased greatly in the past decade. These insights have established that changes in the density and composition of the intestinal microbiota should be considered when inflammatory processes are under investigation, including metabolic syndrome and chronic inflammatory responses. This is highlighted by the fact that C57BL/6 mice from different providers harbor distinct microbiotas that shape the
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Supported by NIH grants R01AI042135 and R37AI039031 to E.G. Pamer.
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