An Active Role for Microorganisms in Controlling Intestinal Inflammation

The innate and adaptive immune systems in the intestines are uniquely adapted to a milieu that occurs nowhere else in the body. Microorganisms within the intestines are said to outnumber cells in the body by 10-100 fold.¹ These organisms present the problem of how to discriminate between commensals (to which there should be no immune response) and pathogens (to which there should be an immediate immune response).¹ When discrimination between these microbes breaks down, inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis occur. The incidence of IBD has increased over the past 30 years, especially in developed countries. One attractive theory to explain the increase is the "hygiene hypothesis", which postulates that increased antibiotic use and cleaner home environments may promote over­reaction to certain commensals, sometimes called pathobionts, and result in inflammatory diseases such as IBD.² It is said that immune responses in the normal intestine are in a constant state of controlled inflammation. New evidence suggests that, while pathobionts may overwhelm control mechanisms, other commensals, called symbionts, may be active partners in establishing and maintaining this control.^{2, 3}

Normal mice maintained from birth in a germ-free environment are systemically deficient in CD4⁺ CD45^low T lymphocytes, which are known to include regulatory T cells critical in controlling intestinal inflammation.^{2, 3} Colonization with Bacteroides fragilis, a prominent component of mammalian intestinal flora, is by itself able to correct this deficiency as well as promote balance between Th1 and Th2 populations.^{2, 4} Surprisingly, the benefit of B. fragilis relies on, and can be substituted by, the zwitterionic capsular polysaccharide PSA.^{2, 4} Previous data has shown that dendritic cells (DC), which can extend processes from the lamina propria to the intestinal lumen,¹ can take up PSA by a TLR2-dependent mechanism, then process and present it on MHC Class II molecules.⁵ Its presentation pro­motes T cell production of IL-10, a key anti-inflammatory molecule in the intestinal immune system that can be produced by regulatory T cells.² PSA promotes control over production of critical cytokines in the pathogenesis of human IBD, including TNF-alpha and IL-23, as well as amelioration of IBD symptoms such as colonic epithelial hyperplasia, leukocyte infiltration, inflammation, and wasting. Either of two commonly used mouse models supports these findings. In the first model, the chemical TNBS was used to induce a Th17 cell-mediated inflammatory disease. IL-17 and TNF-alpha were elevated in these diseased animals, but not in PSA-protected animals, which also showed less intestinal pathology and inflammation.² In the second model, inflammation was promoted by a pathobiont (Helicobacter hepaticus) in a host predisposed to colitis. PSA provided protection from inflammatory reactions and a decrease in TNF-alpha.² The ability of T cells to produce IL-10 was critical for the reduced inflammatory effect of PSA.²

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Polysaccharide A (PSA) is taken up by lamina propria dendritic cells, processed, and presented to naïve CD4+ T cells. In the presence of activated TGF-beta, these cells can become induced regulatory T cells (iTreg). Production of IL-10 by these and other T-lineage cells promotes control of immune activation. IL-23 inhibits control by Treg, and promotes expansion of inflammatory Th17 cells. For simplicity, many other pro- and anti-inflammatory mechanisms present in the intestines are not shown. (Figure adapted from reference #10)

Other intestinal microorganisms also appear to have a positive effect on the intestinal immune system and have been proposed as probiotic treatments for human IBD.⁶ In vitro studies indicate that their modes of action might be similar to B. fragilis. Cells from hu­man mesenteric lymph nodes that drain inflamed intestines secrete more anti-inflam­matory cytokines (IL-10, TGF-beta) when stimulated with pro­biotic variants of Bifido­bacterium or Lactobacillus but more pro-inflammatory cytokines (TNF-alpha, IL-12) when stimulated with patho­genic Salmonella.⁷ Specific IL-10 secretion is also seen upon stimulation of peripheral blood mononuclear cells from ulcerative colitis patients with heat-killed variants of Bifidobacterium sp.⁸ Early clinical trials of these and other potential probiotics have been encouraging.⁶ Since Bacteroides and Lactobacillus are genera that show decreased representation in the intestines of many IBD patients,⁹ it is intriguing to speculate that symbiont colonization may be deficient in these patients. It will also be interesting to see whether, like PSA, poly­saccharides expressed by other probiotics play an active role in controlling intestinal immune responses.

^References

1. Artis, D. (2008) Nat. Rev. Immunol. 8:411.
2. Mazmanian, S.K. et al. (2008) Nature 453:620.
3. Makita, S. et al. (2007) J. Immunol. 178:4937.
4. Mazmanian, S.K. et al. (2005) Cell 122:107.
5. Wang, Q. et al. (2006) J. Exp. Med. 203:2853.
6. Ewaschuk, J.B. and L.A. Dieleman (2006) World J. Gastroenterol. 12:5941.
7. O'Mahony, L. et al. (2006) Am. J. Physiol. Gastrointest. Liver Physiol. 290:G839.
8. Imaoka, A. et al. (2008) World J. Gastroenterol. 14:2511.
9. Ott, S.J. et al. (2004) Gut 53:685.
10. Mazmanian, S.K. and D.L. Kasper (2006) Nat. Rev. Immunol. 6:849.

^{This symbol denotes references that cite the use of R&D Systems products.}