Human helminthic parasites were considered as a therapeutic option. Many could not be used because there are no available sources other than a human carrier. Eggs from such a source would risk inadvertent transmission of pathogenic microbial agents. Also, some human helminths have disease potential or raise public health concerns.
Trichuris species are helminths with favourable characteristics for therapeutic use. Their life cycle minimises the risk of inadvertent colonisation. Trichuris ova mature in the soil and are ingested by the host. Ova hatch in the duodenum, releasing larvae that ultimately grow in 6–8 weeks into adult worms. They migrate to the terminal ileum and colon but do not invade the host. Worms can remain viable for 1–2 years in the natural host. Adult worms release ova that are shed into the stool. These ova are immature and are not capable of colonising another host until they incubate in the soil for several weeks to allow embryonation.
We chose T suis
as the helminth to colonise subjects in this study. T suis
, the porcine whipworm, is genetically related to T trichiura
, the human whipworm. T suis
is not a natural human parasite but it has been shown experimentally to colonise humans briefly without causing disease.8
The ova can be produced using pathogen free pigs, and processed to assure absence of biological contaminants.
Treatment with T suis
ova for 24 weeks yielded a response rate of nearly 80% and a remission rate of nearly 73%, which was much greater than the anticipated placebo effect.11–14
This was particularly notable as many patients had refractory disease. Thus T suis
ova therapy may produce substantial and sustained improvement in active Crohn’s disease. However, the study was open label, and we cannot exclude a high placebo effect. The treatment caused no side effects or complications even in patients receiving multiple immunosuppressants (for example, corticosteroids and azathioprine/6-MP), suggesting a high safety profile.
Subset analysis of the data suggested that patients on immunosuppressive therapy faired better, as did patients with an intact terminal ileum. We can only speculate on the reason for these observations. It is possible that immunosuppressives could have influenced T suis colonisation. Also, there could have been a synergistic interaction between the immunomodulatory effect of the helminths and the immunosuppressive effect of the other drugs. Terminal ileal resection also could have affected worm colonisation, or perhaps residual symptoms from the surgery confounded CDAI scoring. Both of these observations need confirmation in a prospective trial to assure that they were not artefacts.
There is an immunological basis to expect that exposure to helminths such as T suis
will prove beneficial in Crohn’s disease. Crohn’s disease involves over reactive Th1 pathways, and helminths blunt Th1 responses. For example, helminths attenuate intestinal inflammation in animal models of inflammatory bowel disease. Interleukin 10 deficient mice spontaneously develop a Th1-type colitis characterised by infiltration of the lamina propria with interferon γ producing CD4+ T cells.15
Colonisation with T muris
or Heligmosomides polygyrus
retards development of colitis in interleukin 10 deficient mice.1
Mice and rats treated with di- or trinitrobenzene sulphonic acid (DNBS, TNBS) develop a Th1 cytokine driven colitis that shares features with Crohn’s disease.16
Mice and rats exposed to Schistosoma mansoni
are resistant to TNBS colitis.6,7
Colonisation of mice with Trichinella spiralis
diminishes DNBS induced colits.5
This protection is associated with decreased systemic and colonic interferon γ and interleukin 12 expression, which are critically important Th1 cytokines.
Colonisation with helminths augments several immunoregulatory pathways that limit Th1-type inflammation. Helminths induce production of interleukin 4 and interleukin 13, which are Th2 cytokines. This Th2 response inhibits production of Th1 cytokines thereby reducing colitis severity.6
Helminths also induce regulatory T cells and immune regulatory substances such as transforming growth factor β, interleukin 10, and prostaglandin E2
that assist in maintaining host mucosal homeostasis.4
In summary, T suis is well tolerated and appears efficacious for Crohn’s disease in this open label trial. Helminths probably inhibit intestinal inflammation by mechanisms different from current medications. Helminths may offer an easy to administer alternative or supplement to currently available therapeutic agents. These results justify a double blind controlled clinical trial. Furthermore, these results support the hypothesis that helminthic exposure provides protection against some immune mediated inflammatory disease like Crohn’s disease.