Helminths and Inflammatory Bowel Disease: Animal Studies

In addition to altering systemic immune responses, helminths can change mucosal immune responses in mice. Heligmosomoides polygyrus is a murine roundworm that only colonizes the duodenum of its host. Intestinal lamina propria mononuclear cells from H. polygyrus -colonized mice make less IL-12 and IFN-γ but more IL-4, IL-13, and IL-10 than lamina propria mononuclear cells from worm-free mice (Elliott et al., submitted, 2004). This ability to influence mucosal immune responses may permit helminths to inhibit excessive intestinal inflammation. Indeed, this effect is demonstrated with various helminths in several different colitis models.

Some strains of mice and rats develop severe colitis after transrectal challenge with trinitrobenzene sulfonic (TNBS) or dinitrobenzene sulfonic (DNBS) acid. The mucosa of challenged animals is infiltrated with CD4+ IFN-γ-producing T cells.[52] Treatment of mice with anti-IL-12,[52] anti-tumor necrosis factor a[53] monoclonal antibodies, or with recombinant IL-10[54] inhibits TNBS colitis. This suggests that the colitis results from a dysregulated immune response. We and others showed that exposure to helminths prevents TNBS[55**] and DNBS[56,57] colitis. Mice exposed to Trichinella spiralis or Schistosoma mansoni eggs made less IL-12 and IFN-γ but more IL-4 and immunoregulatory IL-10.[55**,56] The protection afforded by schistosome egg exposure required intact IL-4 and Stat6 signaling.[55**] Exposure of mice to Trichuris muris or H. polygyrus also protects mice from developing TNBS colitis (Elliott, unpublished observation, May 2004).[58]

IL-10-deficient mice have a dysregulated immune system that causes fatal colitis in response to normal gut flora. The colitis is characterized by infiltration of the mucosa with CD4+ IFN-γ-producing T cells.[4] Previous colonization of IL-10-deficient mice with T. muris or H. polygyrus reduces spontaneous colitis.[35] In addition to protecting from developing colitis, helminths can treat ongoing active colitis in this model. It is well established that IL-10-deficient mice that receive H. polygyrus after colitis improve dramatically.[59**] The reduction in colitis is associated with inhibition of IFN-γ and IL-12p40 production by intestinal lamina propria mononuclear cells. Importantly, transfer of mesenteric lymph node T cells from H. polygyrus -colonized IL-10-deficient mice to colitic IL-10-deficient mice also reverses intestinal inflammation. This suggests that helminths activate regulatory T cells even in the absence of IL-10. Indeed, worm colonization enhances expression of mRNA for a transcription factor that drives regulatory T-cell activity (Foxp3) in mesenteric lymph node T cells. Exposure to S. mansoni eggs also inhibits previously established colitis in IL-10-deficient mice (Elliott, unpublished observation, May 2004).

Worms may alter other "nonimmunologic" reactions in the gut. For example, mice develop intestinal epithelial cell injury in response to dextran sodium sulfate ingestion.[60] Colonization with Hymenolepis diminuta reduced the abnormal epithelial ion transport evoked by dextran sodium sulfate without grossly changing the toxin-induced histopathology.[61] In individuals, these types of changes may decrease symptoms from intestinal inflammation.