Beneficial effects of Bacteroides fragilis polysaccharides on the immune system

Abstract

Bacterial colonization of the intestine is critical for the normal function of the mammalian immune system. However, the specific molecules produced by commensal bacteria that contribute to the modulation of the host immune system are largely uncharacterized. Polysaccharide A (PSA) produced by the ubiquitous human commensal, Bacteroides fragilis is a model symbiosis factor. PSA is capable of activating T cell-dependent immune responses that can affect both the development and homeostasis of the host immune system. Colonization of previously germ-free mice with B. fragilis alone is sufficient to correct the splenic Th1/Th2 imbalance found in germ-free mice. In addition, PSA can provide protection in animal models of colitis through repression of pro-inflammatory cytokines associated with the Th17 lineage. This review provides an overview of the immunologic properties of PSA including the mechanisms of immune system activation and the resulting immunomodulatory effects.

Figure 1

Impact of B. fragilis PSA on the development of the immune system. The immune system of GF mice is skewed towards Th2 immune responses. Colonizing GF mice with a PSA-producing strain of B. fragilis corrects this defect and restores a Th1/Th2 balance in the spleen. PSA produced by the intestinal bacteria is most likely sampled from the intestine by DCs, which then migrate to the MLNs. Within the APC, PSA is processed and presented to T cells. Recognition of PSA in the context of MHCII by the TCR triggers a CD4⁺ T cell immune response. PSA stimulates TLR2 signaling and IL-12 production by dendritic cells. The IL-12 produced by the APC binds to the IL-12 receptor on T cells and activates the Th1 transcription factor, Stat-4. In response to IL-12 and Stat-4, Th1 cells are generated that produce IFN-gamma. This process is dependent on PSA; colonization of GF mice with B. fragilis that lacks PSA production does not correct the Th1/Th2 imbalance found in the absence of bacterial colonization.

Figure 2

PSA mediated protection from inflammatory disease in experimental models of colitis. Transfer of CD4⁺CD45Rb^high T cells into Rag^−/− mice colonized with Helicobacter hepaticus induces colitis. Rag^−/− mice co-colonized with H. hepaticus and B. fragilis expressing PSA, but not B. fragilis lacking PSA expression, do not develop colitis. PSA mediated protection against colitis results from decreased levels of cytokines associated with the Th17 lineage including IL-1beta, IL-23, and TNF-alpha. Suppression of the inflammatory cytokines is dependent on IL-10. In the absence of IL-10, PSA cannot prevent colitis in co-colonized mice.