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The Hygiene Hypothesis & Helminth Treatments With Parasitic Worms

Parasitic helminth infections continue to be among the most common diseases affecting children from low- and middle-income countries.1 Looking at just one such infection, an estimated 440 million people globally harbor hookworms.2 Why, then, have scientists been purposely infecting patients with these worms in clinical trials?

Some helminths—including Trichuris suis (pig whipworm) and Necator americanus (human hookworm)—are being studied for their potential to treat or cure autoimmune diseases.3 Over the centuries, a variety of helminth parasites have evolved within the human immune system. In order to survive inside of their mammalian hosts, they use sophisticated strategies that render hosts’ defenses futile,4 preventing hosts’ immune system from attacking. What’s intriguing to researchers is that in populations of people with high rates of helminth infections, there are fewer reports of autoimmune diseases.3

Helminths secrete a mixture of proteins, carbohydrates, and lipids into their environment, and these products have been found to exhibit a variety of immunomodulatory activities.3 Pre-clinical trials in humans have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, asthma, and atopy.3 A 2017 study found that in individuals with autoimmune rheumatic diseases, such as rheumatoid arthritis, helminth infection has the potential to alleviate the symptoms and slow disease progression.5

How does it work? With Trichuris suis, the worm egg is swallowed and, once hatched, colonizes the caecum and colon of the human gut for a few weeks; treatments are repeated at intervals to prevent chronic infection.3 Larvae of the human hookworm Necator americanus are administered percutaneously and migrate through the vasculature and lungs to the small intestine where they survive by feeding on blood. At high doses, hookworm causes gastrointestinal symptoms and anemia,3 but in small doses, hookworms modulate the immune response, increasing immune tolerance.

IFM educator Sidney Baker, MD, discusses the vital role of immune tolerance:

Dr. Baker is a Yale medical graduate and former assistant professor of Medical Sciences.

Interestingly, our attempt to eradicate parasitic worms in the developing world over the past 50 years coincides with a rise in allergy, autoimmunity, and obesity.6 Some scientists link this event to the Hygiene Hypothesis, which speculates that reduced exposure to infections in early childhood might result in increased risk of developing allergic disease later in life.3 To restore immune tolerance, managed infections may be useful.

Animal models and clinical studies have shown that helminth infections alter intestinal permeability and provide a potential beneficial action on autoimmune and inflammatory disorders such as inflammatory bowel disease and celiac disease.7 Epidemiologic studies also suggest that hookworm infections may protect against asthma.8

Helminth immunotherapy is also being evaluated as a therapy for MS with varying success.9 Researchers have speculated that for the worms to be successful in controlling inflammation, perhaps patients must be exposed before the onset of the inflammatory condition, or perhaps, they need to be exposed to them at a young age to allow the immune system to co-develop with them.3

The use of helminth therapy is controversial with some scientists questioning the ethics of infecting patients with a parasite known to risk human health. The hookworm parasite, in particular, is a leading cause of iron-deficiency anemia in rural areas of the world’s poorest countries and is considered to be the second most important parasitic infection after malaria.10 Keeping these statistics in mind, scientists have begun studying other ways to use the helminth—as opposed to actual worm therapy. Molecules the worms use to suppress the immune system could potentially be manipulated for drug-based therapeutic purposes3 in the treatment of a vast array of autoimmune diseases.

View the Solving the Puzzle of Autoimmunity: The Interplay of Gut, Genes, and Environment Conference Proceedings to explore clinical topics, like helminth therapy, from IFM’s 2018 Annual International Conference on autoimmunity.

 

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References

  1. Bharti B, Bharti S, Khurana S. Worm infestation: diagnosis, treatment and prevention [published online November 11, 2017]. Indian J Pediatr. doi:10.1007/s12098-017-2505-z.
  2. Bottazzi ME. The human hookworm vaccine: recent updates and prospects for success. J Helminthol. 2015;89(5):540-544. doi:10.1017/S0022149X15000206.
  3. Helmby H. Human helminth therapy to treat inflammatory disorders—where do we stand? BMC Immunol. 2015;16:12. doi:10.1186/s12865-015-0074-3.
  4. Wakelin D. In: Baron S, ed. Medical Microbiology. 4th ed. Galveston, TX: University of Texas Medical Branch at Galveston; 1996: Chapter 87.
  5. Oliveira SM, Gomides APM, Mota LMH, Lima CMBL, Rocha FAC. Intestinal parasites infection: protective effect in rheumatoid arthritis? Rev Bras Reumatol. 2017;57(5):461-465. doi:10.1016/j.rbr.2016.04.002.
  6. Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res. 2017;116(8):2065-2074. doi:10.1007/s00436-017-5544-5.
  7. Sipahi AM, Baptista DM. Helminths as an alternative therapy for intestinal diseases. World J Gastroenterol. 2017;23(33):6009-6015. doi:10.3748/wjg.v23.i33.6009.
  8. Leonardi-Bee J, Pritchard D, Britton J. Asthma and current intestinal parasite infection: systematic review and meta-analyses. Am J Respir Crit Care Med. 2006;174(5):514-523. doi:10.1164/rccm.200603-331OC.
  9. Tanasescu R, Constantinescu CS. Helminth Therapy for MS. Curr Top Behav Neurosci. 2015;26:195-220. doi:10.1007/7854_2014_361.
  10. Hotez PJ, Diemert D, Bacon KM, et al. The human hookworm vaccine. Vaccine. 2013;31(Suppl 2):B227-B232. doi:10.1016/j.vaccine.2012.11.034.