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Will worms really cure Crohn’s disease?
  1. G L Radford-Smith
  1. Correspondence to:
    Dr G Radford-Smith
    Department of Gastroenterology, Level 9A, Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Herston 4029, Australia; graham_radford-smithhealth.qld.gov.au

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Treatment of Crohn’s disease patients with the intestinal helminth Trichuris suis appears safe and effective in the short term, even with concurrent immunosuppressive therapy

HELMINTHS AND IBD EPIDEMIOLOGY

There are a wealth of data that support an immunoregulatory role for helminth infection in animal models and the human host.1–3 Recently, this concept has been utilised therapeutically for the treatment of patients with inflammatory bowel disease (IBD). Specifically, Summers and colleagues4 report the results of their open study of live Trichuris suis ova therapy in 29 patients with Crohn’s disease (CD) in this issue of Gut(see page 87).4 Treatment with T suis appears safe and effective in the short term, even with concurrent immunosuppressive therapy. Extension of this concept into the “hygiene hypothesis”5 may seem increasingly attractive in terms of an explanation for some epidemiological observations in patients with IBD, in particular the north-south gradient for IBD prevalence in both North America and Europe, and the lack of IBD in developing nations.6–8 However, some of these epidemiological observations should be viewed with caution. Studies that find a north-south gradient are limited to determining incidence rates and do not attempt to tackle the more difficult task of finding epidemiological reasons behind the gradient. In addition, the stringent “rules” that are now being applied to replication of genetic association and linkage studies have not been applied to all epidemiological studies in IBD. Recent data on paediatric IBD and twin studies would support an increasingly important role for environmental factors over genetics. Specifically, paediatric IBD has increased in frequency in the recent past (1990–2001), is becoming increasingly multi-ethnic, and less often familial, and repeat twin studies from Scandinavia using a new (younger) cohort show reduced concordance rates for CD.9–11 Multiple environmental factors, including pathogen exposure, diet, and lifestyle, are likely to contribute to these observations. However, the role of helminth infection is questionable here given the age of these cohorts, their geography, and the switch from ulcerative colitis (UC) to CD as the leading cause of IBD seen in at least two studies.9,12

IS INTESTINAL IMMUNOREGULATION THE EXPLANATION?

Chronic helminth infection affects over one billion people worldwide, and although these individuals may suffer subsequent nutritional and growth deficiencies, they rarely develop allergic or chronic autoimmune disease.5 Immunologically, this is thought to relate to two major processes. Firstly, helminthic infection is associated with a strong Th2 response, which opposes the Th1 response associated with autoimmune disease and CD.1–3 Secondly, chronic infection with these organisms may generate a network of regulatory T (Treg) cells that secrete transforming growth factor (TGF)-β and interleukin (IL)-10.2,13 These cytokines may not only regulate aggressive Th1 responses but also control heightened Th2 responses that contribute to chronic allergic diseases. The data supporting these pathways come from both human and animal studies, with IL-10 levels elevated in chronic schistosome infection and reduced in patients with chronic allergic diseases from industrialised countries.14,15 However, there are limited data to confirm the role of these pathways in the human gut. Animal models of IBD such as the trinitrobenzene sulphonic acid colitis murine model have indicated that resolution of inflammation in animals infected with S mansoni eggs is associated with increased mucosal IL-10 and reduced interferon-γ (IFN-γ) mRNA, while IL-4 levels are increased in the mesenteric lymph nodes.16 These results are in contrast to those of Moreels et al who used the same model to demonstrate significant attenuation of colitis in animals with helminth infection, but were unable to confirm the Th1 to Th2 switch.17 Data presented recently in abstract form by Elliott et al indicate that helminth infection (H polygyrus) in the proximal small bowel is able to influence immunoregulatory cytokines downstream in the Peyer’s patches of the terminal ileum. Infection is associated with downregulation of IFN-γ, upregulation of IL-4, IL-5, and IL-10, and a switch in lipopolysaccharide induced cytokine synthesis, from IL-12 to TGF-β18,19 All of these experiments have the limitations of being carried out in the highly controlled environment of animal models, and some also involve a cell isolation step. No similar human data are available. However, experience has taught us that human IBD is not as simple as Th1 versus Th2,20 and therefore other “anticolitis” mechanisms of protection and repair may be in place during helminth infection. It is not so long ago that the concept of a breakdown in oral tolerance was put forward as a potential mechanism for human chronic inflammatory disorders, including IBD. This hypothesis has a very similar cast of cytokines, including IFN-γ, IL-2, IL-4, IL-10, and TGF-β. Successful trials of promoting oral tolerance in animal models are yet to realise their potential in patients.21

OTHER PROTECTIVE MECHANISMS

Helminth infection may bring other anticolitis mechanisms into play, including increases in mucus and water secretion into the gut lumen via effects on goblet cells and mast cell activation.22,23 This may influence the interaction between gut bacteria, their products, and a diseased epithelium, as well as impacting on intestinal motility. Helminths may also influence the microbial ecology of the gut24 and the neuroendocrine response, with an increase in neurotransmitters such as vasoactive intestinal polypeptide.25 None of these factors has been assessed in human studies.

WIDENING THE CONCEPT OF PATHOGEN EXPOSURE IN IBD

There are other “pathogens” that may give us clues to a more complex interplay between the environment and the human host in IBD. A number of studies show a reciprocal relationship between exposure to Helicobacter pylori and IBD, particularly CD.26,27 At least two studies have gone on to demonstrate that H pylori exposure may be associated with subtle changes in disease course, including a delay in CD presentation28 and a reduction in relapses in non-smokers with CD,29 despite the known mucosal Th1 response associated with H pylori infection.30 These studies have thus far been relatively small and some of the results may be due to a cohort effect. However, the results are consistent with increased levels of domestic hygiene in CD patients, and H pylori in this situation may be a surrogate marker of the spectrum of environmental exposures in infancy and childhood. Similar exposure data are not available for helminth infection in the IBD population. Data are available for allergic disease and exposure to Enterobius vermicularis within a similar “developed world” population, and do not show any protective effect of infection over allergy.31 However, “infection turnover”, as opposed to specific infections, may also play an important role in the development of a balanced immune system by generation of increased regulatory T cells. An example of this may be childhood/adolescent appendicitis and its potentially protective role against the development of UC.32 There are two further pieces of recent evidence that indirectly support the concept of reduced pathogen exposure in childhood as a risk factor for IBD. Baron et al identified breast feeding as being an independent risk factor for the development of paediatric CD.33 This may work in a number of ways, one of which is to provide the infant with blocking antibody to an array of dietary and microbial antigens and thus reduce both oral tolerance and pathogen exposure at a critical stage of immunological development. Secondly, analysis of the mucosa associated bacteria of patients with active IBD and controls suggests that patients have a reduction in the diversity of intestinal bacteria compared with the control group.34 However, this may be confounded by a greater uptake of antibiotics in patients with CD, as recently reported in Gut.35 Both of these studies33,34 need to be replicated by independent investigators. These observations together with the results of helminth infection suggest that the microbial environment of the entire gut may have an influence on the development of intestinal inflammation. Further work on the epidemiology of these early exposures and the microbial ecology of the whole gut are essential in identifying key environmental risk and protective factors for IBD.

IS THERAPEUTIC HELMINTH INFECTION SAFE?

Complications related to therapeutic helminth infection have not arisen thus far. However, there is evidence that coinfection with other known pathogens such as Campylobacter jejuni may result in serious infection, including septicaemia.36 A recent case report indicates that this coinfection and its serious consequences may also occur in patients.37 Another potentially serious coinfection is S mansoni with Toxoplasma gondii, which leads to a significant increase in circulating tumour necrosis factor α, severe liver pathology, and death in a murine model.38 These reports indicate that patients being considered for helminth therapy may require screening for carriage of other potential pathogens prior to initiation of treatment. Other issues related to this that need to be addressed by future studies are the choice of organism and the type of infection. Both human and animal studies indicate that a heavy helminth burden is associated with a greater immunoregulatory environment, while a light burden may be associated with an increased risk of allergic disease.5 The current human trials in IBD patients use a transient infection and, despite this, demonstrate clinical efficacy and no significant allergic disease post-infection.4 Long term data, particularly after repeated exposure, will provide further reassurance.

SUMMARY

In conclusion, helminth infection provides us with an excellent model of a successful parasite which is able to manipulate its environment within the host to its advantage. Summers and colleagues4 have now taken that further by using helminths to gain an advantage for the host. It is too early to determine whether this form of treatment will be safe and effective for larger numbers of patients with IBD—further controlled randomised studies will be required to answer this. However, what these important and innovative studies demonstrate is the need for a greater understanding of the helminth-host relationship. This is slowly being addressed but almost exclusively in animal models. Of special interest will be identification of antigens or epitopes responsible for the generation of a tolerant environment, and recent work indicates that one candidate is the schistosome oligosaccharide lacto-N-neotetraose.39 This molecule, which is also present in human milk, stimulates the expansion of a Gr1+ cell population, which creates a Th2 biased immune environment by increased production of IL-10 and TGF-β, and by directing naïve CD4+ T cells down the Th2 path. Molecules such as this may represent potentially novel therapeutic agents for chronic inflammatory disorders such as IBD, and thus bypass the need for helminth inoculation and infection.

Treatment of Crohn’s disease patients with the intestinal helminth Trichuris suis appears safe and effective in the short term, even with concurrent immunosuppressive therapy

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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