These are Trichuris suis eggs shown at the life stage that was given to human patients. (Courtesy of Linda Mansfield, VMD, Ph.D.) Inflammatory bowel disease, or IBD, affects more than 1 million people nationally. Now a Michigan veterinarian has introduced a parasite to help end the plague. Linda Mansfield, VMD, Ph.D., a parasitologist in the College of Veterinary Medicine at Michigan State University, is leading a team of researchers in a study of immune responses to parasites, specifically using the pig whipworm Trichuris suis in an effort to help ulcerative colitis and Crohn’s disease patients. Dr. Mansfield is the only veterinarian in the U.S. working to create a marketed treatment for IBD using parasitic nematodes, and the first in the world to use T. suis. “IBD diseases are chronic, and occur when the bowel becomes irritated and congested with inflammatory cells,” Mansfield says. “This condition can affect people’s ability to work and have a normal life. Evidence from this research could change that.” In June 2006, Mansfield was awarded a five-year, $500,000 grant to conduct a project to identify new molecules and compounds from the whipworm that could be used in patients with IBD, in lieu of patients consuming the parasite’s eggs, which is the current experimental treatment method. While working with the U.S. Department of Agriculture, Mansfield’s chance observation of sick whipworm- and Campylobactor jejuni-infected pigs led to a discovery that could translate to a useful IBD treatment for humans. “The pigs did not succumb to whipworms, but the combination of heavy parasite infections and bacteria created a pathogenic situation,” says Joseph Urban, Ph.D., of the USDA. “Not all of the pigs had heavy worm infections. Those who carried the bacteria with a whipworm infection that did not go to maturity had the best outcomes. We wanted to transfer these benefits to people.” There is no good way to quantitate how long the worm lives within the human intestine, says Urban, which is another facet of the ongoing research. Urban is also trying to determine why some pigs have an increased infection than others when given the same number of eggs. “It is believed that genetics play a role in the inconsistency of infection,” Urban adds. “I am collaborating with Ovamed, a German company that specializes in the development of new treatments using biological organisms.” As a side note, Ovamed markets a product called TSO, Trichuris suis ova, which contains in-vitro cultivated eggs from adult worms grown in monitored pigs. The product is sold online for human use, but does not have Federal Drug Administration approval. Some patients suffering from IBD are willing to chance an unregulated product in hopes of stabilizing effects of IBD. Mansfield says European countries have been considering the use of parasites for homeopathic health solutions for decades. “While I was on sabbatical in Copenhagen, Denmark, we started larger scale collaborative research using parasites to modulate the immune system in animal models,” Mansfield says. “Once the body recognizes the whipworm infection, it produces strong antibody and anti-inflammatory responses. This anti-inflammatory response is responsible for eliminating or reducing IBD symptoms. ” The theory behind developed countries’ prevalence of IBD is attributed to one key factor: good hygiene. “Society’s improved hygiene may account for IBD and a range of other autoimmune disorders,” Mansfield says. “Dubbed the hygiene hypothesis, the theory suggests that human and animal immune systems require exposure to helminth infections early in life in order to develop properly. IBD is almost non-existent in third-world countries where the average child has had at least one parasitic infection by his/her second birthday.” The presence of parasites educates the immune system, Mansfield says. Alternative administrative methods of parasite products are being investigated since whole parasites have a detrimental component, with the possibility of spurring a secondary infection. “T. suis is specifically being used because the parasite lives its entire life in the gastrointestinal tract and does not migrate. Also, since humans are not a natural host, the parasite often does not complete its lifecycle,” Mansfield says. “The desired immune response is achieved within a few weeks.” Mansfield is working with University of Iowa researchers Robert W. Summers, Ph.D., and David E. Elliott, Ph.D., along with Joel V. Weinstock, Ph.D., of Tufts University and Urban. The researchers are exploring ways intestinal parasites benefit and adversely affect an immune system. FDA-approved human trials at Iowa using 24 IBD patients concluded with all patients showing significant improvement, Mansfield says. “Although the FDA has stymied additional human trials for now, there are compelling reasons to continue basic research into the underlying mechanisms,” Mansfield adds. “In animal trials, side effects of a whipworm infection varied with the mouse’s genetic makeup and the bacteria they had in their bowel.” Iowa Drs. Summers, Elliott and Weinstock conducted a statewide double blind trial in patients with Crohn’s disease. Twenty-nine people with Crohn’s disease were invited to consume 2,500 worm eggs every three weeks for six months. Study volunteers drank a whipworm/Gatorade or a Gatorade solution. Four patients withdrew before the halfway mark, and a fifth volunteer stopped taking the worms when she became pregnant, according to study results. Of the 24 who stayed in the experiment, 22 experienced significant improvement in IBD symptoms after three months and 19 had no symptoms at all. At the study’s conclusion, 23 out of 24 participants showed significant improvement, while 21 of the 23 were symptom-free. None of the volunteers reported any worsening of their symptoms, and there were no side effects, according to Dr. Elliott. “This human research is going forward on two fronts, investigator initiated drug licences and with multiple sclerosis patients,” Elliott adds. “The MS study interest is to note if a parasitic infection correlates with exacerbations and altered immune reactivity in patients with the disease.” If successful in treating IBD, the benefits of T. suis could be used on a variety of autoimmune disorders, such as rheumatoid arthritis, collagen vascular diseases, allergic diseases such as asthma and multiple sclerosis. Veterinary Benefit “Whereas the initial push is to aid in human relief, the research could benefit dogs and cats that can have inflammatory bowel disease,” Mansfield says. Mansfield says the human treatment outcomes can be used as comparative medicine for animals. “There is little financing available for studies to aid animals,” Mansfield says. “However, this research can still benefit veterinary medicine in the long run.” Urban is also exploring the possibility of using T. suis to treat primates with colitis. “A zoo veterinarian recently inquired about the use of T. suis to help colitis in primates,” Urban notes. “Discussions about the feasibility of primate treatment is still under consideration.” The USDA is contracting with a medical company to produce an antigen test to diagnose canine whipworm, using information gathered in part by Mansfield’s research. “This assay production could benefit humans and swine also,” Urban says. Urban additionally investigated the use of A. suum, a large pig roundworm, to determine its effect on vaccinating swine against enzootic pneumonia or mycoplasmal pneumonia of swine. Since M. pneumonia is a chronic disease with a high morbidity and a low mortality, veterinary knowledge of a negative reaction with a whipworm infection and vaccine is imperative, Urban says. “M. pneumonia is caused by Mycoplasma hyopneumonia. The clinical signs include a chronic non-productive cough, retarded growth, slow onset spread and repeated occurrence of the disease,” Urban says. Results of research led by Urban showed vaccinated pigs with an A. suum infection had more lung pathology following an infection of M. hyopneumonia. The parasite infection significantly compromised the vaccine’s efficacy. Pigs not exposed to the parasite showed 100 percent serum-conversion after three weeks. “Research that investigates ways to use parasites as a medical benefit and research that identifies potential interference is necessary to advance human and veterinary medicine in these sectors,” Urban says. Multiple Sclerosis Research Researchers Jorge Correale, MD, and Mauricio Farez, MD, conducted a double-cohort study to assess the clinical course in 12 multiple sclerosis patients presenting associated eosinophilia. During a 4.6-year follow up period, T. suis-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores and fewer magnetic resonance imaging changes when compared with uninfected MS patients. The study’s conclusion states that increased production of IL-10 and TGF-_, together with induction of CD25_CD4_ FoxP3_ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS. A full report of this study was published in Annals of Neurology in February 2007. <HOME>
