Sunday, March 10, 2013

Worms and IBD


Hemlinth Therapy


One of the more radical therapies being investigated as a treatment for IBD is worm therapy.  When most developed nations think of worms, the earthworm comes to mind.  In developing nations, worms evoke a different picture – endemic parasites that are present in undercooked food, contaminated water, and soil that can be transmitted by ingestion, through mosquito bites, or during sexual intercourse.  These worms, belonging to the family of helminths, are parasites that live off the largess of their host – in this case the human body.  They include hookworms, roundworms, pinworms, and tapeworms (amongst others). 

Helminths are the cause of many diseases, the most prevalent being the compromise of the immune system and malnutrition due to a hookworm, roundworm, or whipworm infection in the intestines.  Anemia, nausea, malabsorption, and intestinal blockages are all common side effects of helminthes infection.   Intestinal worms generate an immune response when they lay eggs, and they release toxins as a byproduct of their own digestive process, causing further systemic disturbance.(1)  Given their negative impact on intestinal functioning, why are the proposed as a treatment for IBD?

One of the postulated mechanisms of inflammation in IBD is the Th1 response goes out of control.  Th1, a cytokine producing helper T-cell, is believed to be the cause of autoimmune responses and is a generator of inflammation in the body.*  The corresponding Th2 cytokine producer modulates the Th1 response, reducing inflammation.  Both exist in relative homeostatis in a normal functioning human body.  Crohn’s disease is believed to be a Th1-mediated disease and Ulcerative Colitis a Th2-mediated disease, with some evidence of associated causality.(2)

Hemolinth parasite infection rates have been shown to be inversely proportional to allergy rates in many locations.  The inverse mapping applies to IBD infection rates as well.  Places in Asia and Africa with high infestation rates also show the lowest IBD infection rates.  There is additional support from studies involving children who grew up in high parasite areas then moved to low parasite areas having a lower incidence of IBD.  There are many other factors co-incident with poor sanitation and hemolinth infection, and there have been no studies that have conclusively isolated hemolinth infection and IBD prevention.  Though there is some correlation, there is no evidence of a causal relationship, though one has been postulated. 

Specifically related to immune response in an allergic sense, the chronic infection with hemolinth parasites has been shown to regulate Immunoglobulin E (IgE) response.(3,4)  IgE has been shown to assist in perpetuating a Th2 response.  Because Crohns is believed to be Th1 mediated disease and the Th1 response is inactivated by the presence of Th2, there is a theoretical basis that parasite infection may have a positive modulatory effect on the disease.  This is a simplistic explanation, but the actual relationship between the cytokines is significantly more complex and not completely understood.

Hemolinth studies have occurred (and are still occurring) in humans for treating IBD.  The initial animal studies showed promise, but I will focus here on the human studies.  Some of the most promising studies involve Trichuris suis, or pig worm.  The initial work by Weinstock had three Crohns patients consume Trichuris suis eggs (or ova).  All three had objective improvements in their disease with no side effects.  Smaller follow-on studies showed similar results, as did studies involving UC patients (the mechanism for action on UC is less clear if the Th2 modulation model holds).(5,6)  Though the IBD treatments showed no major side effects, the largest study of T. Suis ingestion for allergic rhinitis did show significant side effects in the form of moderate to severe gastrointestinal issues lasting up to two weeks during the early ingestion stages, with continuing adverse reactions in a subclinical form for the mid-term use (long term data is not yet available).  While there is some speculation, there is no good data available right now on why there was a major discrepancy between the trials.(7)

The trials related to the use of T. Suis to treat IBD is promising, but not yet convincing for a few reasons:
1.        The sample sizes to-data have been small.  This is not unusual in pilot studies, it just shows the need for additional work.
2.       The majority of work has been done by the same group of researchers.  It would be beneficial to see repeatable results confirmed by other research teams to avoid potential issues with protocols or results reporting that may not be readily apparent. 
3.       There are known side effects of parasitic worm infection ranging from GI problems to malabsorption to increased susceptibility to bacterial infection.  The studies using T. Suis have conflicting information on adverse events and this needs to be resolved.
4.       While there was a clinical improvement in the trials against placebo, the treatment would still need to be compared to the current best treatment options in terms of both efficacy and side effects.  The efficacy cannot be adequately benchmarked given the small sample size of the previous trials.
5.       As with all similar treatments, if there is a secretion or other chemical action caused by T. Suis that leads to the postulated modulation, isolation of that mechanism and a more controlled implementation of just the active chemical action would be the most advantageous.

Hemolinth therapy shows promise for IBD, and the current recommendation would be to do larger, longer term trials in comparison to current gold standard treatment.  Given the potential for side effects, individuals not enrolled in trials should be taking a wait-and-see approach.

Bottom Line


·         T. Suis showed efficacy in reducing symptoms (objective and subjecting) v. placebo in pilot trials.
·         Adverse event activity associated with T. Suis has conflicting reports.  The potential for serious adverse effects exists, and needs to be quantified.
·         The evidence does not yet support implementation of T. Suis therapy for IBD patients outside of a clinical trial setting.

* Amongst other things, Th1 is responsible for the production of TNF-alpha. The biological treatments for IBD are thought to operate on this mechanism to interrupt the inflammatory response chain.

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1.       World Health Organization. "Prevention and control of intestinal parasitic infections." Report of a WHO Expert Committee. Ginebra: WHO (1987).
2.       Bouma, Gerd, and Warren Strober. "The immunological and genetic basis of inflammatory bowel disease." Nature Reviews Immunology 3.7 (2003): 521-533.
3.       Yazdanbakhsh, Maria, Anita van den Biggelaar, and Rick M. Maizels. "Th2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease." Trends in immunology 22.7 (2001): 372-377.
4.       Bashir, Mohamed Elfatih H., et al. "An enteric helminth infection protects against an allergic response to dietary antigen." The Journal of Immunology169.6 (2002): 3284-3292.
5.       Hunter, M. M., and D. M. McKay. "Helminths as therapeutic agents for inflammatory bowel disease." Alimentary pharmacology & therapeutics 19.2 (2004): 167-177.
6.       Summers, Robert W., et al. "Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease." The American journal of gastroenterology 98.9 (2003): 2034-2041.
7.       Bager, Peter, et al. "Symptoms after ingestion of pig whipworm Trichuris suis eggs in a randomized placebo-controlled double-blind clinical trial." PloS one6.8 (2011): e22346.

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