The Hygiene Hypothesis: Intestinal Parasites and Immune System Regulation

1. The Hygiene Hypothesis:  Intestinal Parasites and Immune System Regulation Judy Chinitz, M.S., M.S., New Star Nutritional Consulting Allan Goldblatt, P.A., Autism Associates of New York

2. The Year Was 1998 Dr. Sudhir Gupta had just published his paper, Th1- and Th2-like Cytokines in CD4+ and CD8+ Cells in Autism - Journal of Neuroimmunology, May 1, 1998 “These data suggest that an imbalance of Th1- and Th2-like cytokines in autism may play a role in the pathogenesis of autism.”

3. Also in 1998… Dr. Andrew Wakefield said, at his first Defeat Autism Now! conference, that the pathology he had found in the intestines of children with autism was “a subtle variation on Crohn’s Disease.”

4. NY Times, August 31, 1999 “IN PURSUIT OF AUTOIMMUNE WORM CURE” “For most of Western history, the average child walked around with a bellyful of parasitic worms: pinworms, tapeworms, hookworms. Then modern civilization came along, put shoes on the children’s feet, installed sewers and stopped using human waste as fertilizer, and the worms mostly disappeared.”

5. More from the Times article… “But there may be a downside to all this hygiene. Children in industrialized countries, which are relatively worm-free, have a much greater tendency than those in other countries to grow into adults with autoimmune disorders (in which the body is attacked by its own immune system), like rheumatoid arthritis, multiple sclerosis, lupus and inflammatory bowel disease.”

6. “Recently, researchers at the University of Iowa gave a drink containing the eggs of half-inch-long parasitic worms to six people suffering from acute, chronic inflammatory bowel disease. Five went into remission and the sixth improved substantially.”

7. “He [Dr. Joel Weinstock] and his colleagues began wondering about worms called helminths, which have been with humans for thousands of years….Dr. Weinstock thinks inflammatory bowel diseases develop when the body overreacts to the normal bacteria in the digestive tract, unleashing a salvo of Th1 cells that end up damaging the colon and bowel themselves. Helminths, he says, trigger a Th2 response, which dampens the Th1 response.”

8. Parasitic Worms and Inflammatory Diseases - Parasite Immunology, October, 2006 Drs. Zaccone, Fehervari, Phillips, Dunne, Cooke “Worm parasites have co-evolved with the mammalian immune system for many millions of years and during this time, they have developed extremely effective strategies to modulate and evade host defenses and so maintain their evolutionary fitness. It is therefore reasonable to conclude that the human immune system has been shaped by its relationship with parasitic worms and this may be a necessary requirement for maintaining our immunologicial health.

9. YEAR BY YEAR, THE DATA GROWS…

10. 2000 “Does the Failure to Acquire Helminthic Parasites Predispose to Crohn’s Disease?” • Journal of The Federation of American Societies for Experimental Biology, Drs. Elliott, Urban, Argo and Weinstock

11. “Lymphocytes from inflamed intestine due to Crohn’s disease secrete a Th1- pattern of cytokines….Helminths and their eggs probably are the most potent stimulators of mucosal Th2 responses. The Th2 response provoked by parasitic worms can modulate immune reactions to unrelated parasitic, bacterial and viral infections….Perhaps failure to acquire these parasites and experience mucosal Th2 conditioning predisposes to Crohn’s disease, which is an overly active Th1 inflammation.”

12. 2001 Th2 responses without atopy [allergy]: immunoregulation in chronic helminth infections and reduced allergic diseases - Trends in Immunology, Drs. Yazdanbakhsh, van den Biggelaar, Maizels “It is suggested that down-regulatory immune mechanism, which dampen the anti-parasite response, might benefit the host by blocking progression to atopic reactions.”

13. 2002 An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigens - Journal of Immunology, Drs. Bashir, Andersen, Fuss, Shi, Nagler-Anderson “Our results demonstrate that, in a murine [rodent] model, helminth infection protects against the development of allergy.”

14. 2004 Increased Incidence of Inflammatory Bowel Disease: the price of the decline of Infectious Burden? - Current Opinion in Gastroenterology, Drs. Feillet, Bach “Converging clinical and experimental data strongly suggest the protective nonspecific role of infections on inflammatory bowel disease….The extension to inflammatory bowel disease of the hygiene hypothesis opens new therapeutic perspectives including the revisiting of probiotics and other forms of exposure to bacteria or parasite components.”

15. ALSO IN 2004 Can Helminth Antigens be Exploited Therapeutically to Downregulate Pathological Th1 Responses? • Current Opinion in Investigational Drugs, Drs. Raine, Zaccone, Dunne,Cooke “In developing countries where helminth infections are highly prevalent, Th1 autoimmune diseases are almost never reported.”

16. 2005 Trichuris Suis Therapy for Active Ulcerative Colitis: A Randomized Controlled Trial - Gastroenterology, Drs. Summers, Elliott, Urban, Thompson, Weinstock “Conclusions: Ova therapy seems safe and effective in patients with active colitis.”

17. 2006 The Use of Trichuris Suis and Other Helminth Therapies to Treat Crohn’s Disease - Parasitology Research, Drs. Reddy and Fried “GI nematodes [family of worms, including hook worm] are powerful modulators of the immune response, and as such, they may have the potential to affect the outcome of concurrent infections with other parasites, bacteria, or viruses….If harboring helminths protects against immune-mediated disease, then these animals must be viewed as useful animals that may produce important compounds helpful for therapy for human disease.”

18. 2007 Helminths as Governors of Immune-Mediated Inflammation - International Journal of Parasitology, Drs. Elliott, Summers, Weinstock “Immune-mediated diseases (e.g. inflammatory bowel disease, asthma, multiple sclerosis and autoimmune diabetes) are increasing in prevalence and emerge as populations adopt meticulously hygienic lifestyles…Loss of natural helminth exposure removes a previously universal Th2 and regulatory immune biasing imparted by these organisms….”

19. October 19, 2007 – two friends email me a link to this site: www.autismtso.com – thank you, Stewart Johnson! Porcine whip worms now available commercially! www.ovamed.org

21. The Increasing Incidence of Immune Regulatory Disorders From Bach J-F., (2002) 347:911-920

23. POOR SANITATION, IMPURE FOOD AND CROWDED LIVING CONDITIONS Viral, bacterial and protozoan infections Helminthic infections Regulatory T Cell Conditioning Excess Immune reactivity Inhibits Excess Reactivity Crohn’s disease and other diseases (Prevents) GENETIC PREDISPOSITION

24. Helminths Modulate Immune Responses in Rodents • Modulate responses to unrelated Ag (Kullberg, J. Immunol. 148:3264) • Delayed graft rejection (Ledingham, Transplantation 61:184) • M- TNF and IL12; IL10 and TGF (Kuroda, Parasite Immunol. 23:305)

25. Helminths Modulate Immune Responses in People • Th2 response to tetanus toxoid (Sabin, J. Infect. Dis. 173:269) • Children have reduced atopy (Yazdanbakhsh, Science 296:490) • PBMC IL10 and TGF production (Doetze, Int. Immuol. 12:623)

26. Trichuris suis(Porcine whipworm) • Self-limited colonization • No multiplication in host • No direct transmission • Eggs stable and easy to produce

27. Trichuris suis Therapy in Active Ulcerative Colitis

28. Overall Response • No side effects, complications

29. Time to Response

30. How do worms in the duodenum regulate the ileum and colon?

31. CD25 CD8 Treg Tr1 Th3 Th2 FoxP3 TGFb IL10 TGFb IL4, IL5 IL13, IL10 TGFb IL10 Mostly CD4 Regulatory T Cells

32. Prevent/reverse inflammation No contact required LPS TLR4 CD4 Regulatory T cells CD4 CD8 TGFb Th2 cytokines (IL4, IL13) IL10 IL12 @ @ T Cell Proliferation IFNg Th1 Th1 / Th2 Effector T cells Helminths

33. Judy Chinitz New Star Nutritional Consulting www.newstarnutrion.com (914) 244-3646 Allan Goldblatt Autism Associates of New York www.autismny.com (516) 921-3456