ABSTRACTEXAMINATION OF PARASITES AS A TREATMENT FOR INFLAMMATORY BOWEL DISEASE USING MURINE MODELSByJamie Jennifer Kopper Inflammatory Bowel Disease (IBD) is a serious, life-threatening chronic inflammatory disease of the gastro-intestinal tract that has been reported to affect 1.1 million adults in the US. Patients with IBD often become refractory to traditional treatments which include antibiotics, immune modulators and corticosteroids. IBD can result in a life-threatening condition and lead to the necessitation of surgical interventions such as for bowel resections. In 2003 Dr. Joel Weinstock proposed using Trichuris suis as a treatment for inflammatory bowel disease in patients who were otherwise refractory to standard treatments and subsequently published the results of two small-scale clinical trials. Here, he reported that T. suis resulted in amelioration of clinical signs of disease in many patients and no adverse side effects. Despite these positive results, the mechanism(s) by which T. suis improved patient outcomes remains unknown. In this work we set forth to address possible mechanisms, and to investigate the possibility of adverse side effects due to T. muris infections in a murine model. We addressed the hypothesis that infections with T. muris alters the colonic microbiota in mice, which may serve as one mechanism to explain the improvement observed in the human patients treated with this worm. We found that C57 BL/6 IL-10-/- mice infected with T. muris had sex and dose dependent morbidity and mortality. Additionally, these infections resulted in severe peritonitis with or without gastrointestinal perforations in some mice. In a subsequent experiment C57 BL/6 IL-10-/- mice infected with T. muris were concurrently treated with prednisolone or metronidazole, neither of which resulted in a significant decrease in mortality when compared to the untreated infected mice. Finally we infected C3H/HeJ and C3Bir IL-10-/- mice, which are predisposed to developing a spontaneous colitis, with T. muris to test our hypothesis that infections with T. muris would change the colonic microbiota. Using Terminal Restriction Fragment Length Polymorphisms (TRFLPs) we determined that mice infected with T. muris had significantly different proximal colon microbial microbiota when compared to uninfected mice. To further assess the effects of colitis without T. muris infections on proximal colon microbiota we obtained samples from C3Bir IL-10-/- mice within our breeding colony who developed spontaneous colitis and compared them to C3Bir IL-10-/- mice without colitis. From this study we found that overall there were no differences, as assessed using TRFLP, between the two groups. From the entirety of this work we conclude that T. muris has the possibility of causing adverse side effects in some individuals, which could include gastrointestinal perforations and peritonitis, particularly those who are deficient in IL-10. Additionally, we concluded that T. muris does result in changes in the structure of the proximal colon microbiota, which may be one mechanism through which it worked as a treatment for IBD in human patients.
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