Tapeworm Infection Reduces Epithelial Ion Transport Abnormalities in Murine Dextran Sulfate Sodium-Induced Colitis

Abstract

The rat tapeworm Hymenolepis diminuta was used to test the hypothesis that helminth infection could modulate murine colitis. Mice were infected with five H. diminuta cysticercoids, and colitis was evoked via free access to 4% (wt/vol) dextran sulfate sodium (DSS)-containing drinking water for 5 days. BALB/c mice were either infected with H. diminuta and 7 days later exposed to DSS (prophylactic strategy) or started on DSS and infected with H. diminuta 48 h later (treatment strategy). Naive and H. diminuta-only-infected mice served as controls. On autopsy, colonic segments were processed for histological examination and myeloperoxidase (MPO) measurement or mounted in Ussing chambers for assessment of epithelial ion transport. Cytokines (gamma interferon [IFN-␥], interleukin 12 [IL-12], and IL-10) were measured in serum and colonic tissue homogenates. DSS treatment resulted in reduced ion responses (indicated by short-circuit current [Isc]) to electrical nerve stimulation, the cholinergic agonist carbachol, and the adenylate cyclase activator forskolin compared to controls. H. diminuta infection, either prophylactic or therapeutic, caused a significant (P < 0.05) amelioration of these DSS-induced irregularities in stimulated ion transport. In contrast, the histopathology (i.e., mixed immune cell infiltrate, edema, and ulcerative damage) and elevated MPO levels that accompany DSS colitis were unaffected by concomitant H. diminuta infection. Similarly, there were no significant differences in levels of IFN-␥, IL-12, or IL-10 in serum or tissue from any of the treatment groups at the time of autopsy. We suggest that abolishment of colitis-induced epithelial ion transport abnormalities by H. diminuta infection provides proof-of-principle data and speculate that helminth therapy may provide relief of disease symptoms in colitis.The dichotomous split of helper T lymphocytes into type 1 (Th1) or type 2 (Th1) cells, as originally proposed by Mosmann and colleagues (24), has provided a convenient conceptual framework for characterizing T-cell responses and immunological processes. While the Th1-Th2 paradigm does not hold true for all situations and is certainly a simplified view of in vivo T cell responses (23), it has nevertheless had a profound impact on the approach to understanding host responses to antigen, infection, and disease processes in general.The T-cell response of rodents infected with parasitic nematodes is typically skewed towards a Th2-dominated cytokine profile (i.e., elevated levels of interleukin 4 [IL-4], IL-5, and IL-10) (13), and experiments that block or enhance the Th2 response result in predicted increases in susceptibility to or rejection of the helminth parasite, respectively (14). Fewer data are available for cestode infections (28); nevertheless, the increases in mast cells, immunoglobulin E, eosinophils, and goblet cell mucin production are consistent with a Th2 host response (21). The reciprocal cross-regulation between Th2 and Th1 cells suggests that helminth infection could prevent or redu...

Infection with a Helminth Parasite Prevents Experimental Colitis via a Macrophage-Mediated Mechanism

“…In support for no role for Th2 cytokines in protection, worm infection of mice deficient in both IL-4 and IL-13 were refractory to DSS-induced colitis. These findings that a schistosome-induced Th2 response was not protective in this model are consistent with work investigating the effect of another helminth, Hymenolepis diminuta on colitis, which although inducing a robust Th2 response, also did not reduce DSS-induced tissue damage (43). However, other gastrointestinal parasitic worms may induce a regulatory type 2 response that can suppress colon inflammation in different models of colitis.…”

Neutralizing Anti-IL-10 Antibody Blocks the Protective Effect of Tapeworm Infection in a Murine Model of Chemically Induced Colitis

“…However, when using biological organisms, the situation is likely to be more complicated that this. We previously showed that infection with H. diminuta alleviated the electrophysiological abnormalities that characterize murine DSSinduced colitis (7). Using DNBS to evoke what is considered a Th1-driven colitis (24), the present study shows that H. diminuta infection in a prophylactic regimen almost abolished the colitis, as assessed by clinical parameters, histological assessment, and biochemical markers (i.e., MPO).…”

“…It is intuitive to think that this increase in Th2 cytokines will also have the benefit of protecting the host from an unrelated Th1-type disease, such as Crohn's disease, a major form of inflammatory bowel disease (IBD) 3 characterized as having a Th1 profile (6). Previous studies from our laboratory have shown that infection with the tapeworm parasite, Hymenolepis diminuta, given both prophylactically and as a treatment, improved the abnormalities in colonic epithelial ion transport that accompany dextran sodium sulfate (DSS)-induced murine colitis (7). Other studies showed that infection with parasitic helminths can reduce the Th1 response to an unrelated infection (8,9) and have confirmed an anticolitic effect of infection with parasitic helminths (principally nematodes and Schistosoma mansoni) in murine model systems (10 -12).…”

Exacerbation of Oxazolone Colitis by Infection with the Helminth Hymenolepis diminuta

“…This increase in eosinophils in DSS-induced colitis may explain, at least partially, the finding that infection with H. diminuta alleviated the ion transport abnormalities but not the histopathology in this model of colitis. 39 However, colitis in oxazolone and oxazoloneϩ anti-IL-5 AB-treated mice were similar. Thus, while colonic eosinophilia is characteristic of this model of colitis, these cells may play only a small role in the disease such that the normal variation between mice in their response to oxazolone is large enough to mask any role of eosinophils that could potentially be revealed by neutralization of IL-5.…”