INFLAMMATORY BOWEL DISEASE
Trichuris suis therapy in Crohn’s disease
R W Summers, D E Elliott, J F Urban Jr, R Thompson, J V Weinstock
See end of article for
Dr R W Summers, James A
Clifton Center for Digestive
Diseases, Department of
University of Iowa Roy J
and Lucille A Carver
College of Medicine, 200
Hawkins Drive, Iowa City,
IA 52242, USA;
Revised version received
28 March 2004
Accepted for publication
9 April 2004
Gut 2005;54:87–90. doi: 10.1136/gut.2004.041749
Background: Crohn’s disease is common in highly industrialised Western countries where helminths are
rare and uncommon in less developed areas of the world where most people carry worms. Helminths
diminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental
colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn’s disease.
Aims: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth
Trichuris suis in the treatment of patients with active Crohn’s disease.
Patients: Twenty nine patients with active Crohn’s disease, defined by a Crohn’s disease activity index
(CDAI) >220 were enrolled in this open label study.
Methods: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity
was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response
was defined as a decrease in CDAI of greater than 100.
Results: At week 24, 23 patients (79.3%) responded (decrease in CDAI .100 points or CDAI ,150) and
21/29 (72.4%) remitted (CDAI ,150). Mean CDAI of responders decreased 177.1 points below
baseline. Analysis at week 12 yielded similar results. There were no adverse events.
Conclusions: This new therapy may offer a unique, safe, and efficacious alternative for Crohn’s disease
management. These findings also support the premise that natural exposure to helminths such as T suis
affords protection from immunological diseases like Crohn’s disease.
helminthic colonisation is rare and uncommon in those
areas where most people carry worms.1It appears to result
from an inappropriate immune response to normal gut flora.
Helminths down-modulate the host immune response to
unrelated antigens,2–4a property that could be beneficial in
Crohn’s disease. Helminths reduce inflammation in experi-
mental murine colitis.1 5–7Trichuris suis, the porcine whip-
worm, is similar to human whipworm T trichiura. Ingestion of
T suis ova results in short term self limited colonisation of
humans.8We therefore conducted a 24 week clinical trial to
evaluate the safety and possible efficacy of live T suis therapy
in Crohn’s disease.
rohn’s disease is a chronic relapsing inflammatory
reaction that may affect any part of the gastrointestinal
tract. It is common in parts of the world where
Patients were enrolled in a 24 week open label study after
giving informed consent. The University of Iowa Institutional
Review Board approved the protocol. Subjects with Crohn’s
disease, as defined by standard clinical, radiological, and
histological criteria, were recruited and followed at the
University of Iowa and clinical practices in the State of
Iowa. Patients 18–72 years old were eligible if they had a
Crohn’s disease activity index (CDAI) between 220 and 450.9
A small bowel series and colonoscopy were required within
the year before enrolment. Patients continued their Crohn’s
disease medications if they met the following enrolment
criteria: (1) mesalamine or derivatives if they had been
receiving it for .8 weeks and the same dose for .4 weeks;
(2) oral prednisone up to 25 mg/day if patients had been
receiving it for .8 weeks and the same dose for .4 weeks;
and (3) azathioprine or 6-mercaptopurine (6-MP) if patients
had been receiving it for .6 months and the same dose for
.8 weeks. Before enrolment, patients had to have a
haemoglobin concentration of .10.0 g/dl, white blood count
of 5000–15 000/mm3, platelet count .150 000/mm3, no iron or
vitamin B12deficiency, total bilirubin ,1.5 mg/dl, aspartate
aminotransferase and alanine aminotransferase ,100 U/dl,
,40 mg/dl, serum creatinine ,2.0 mg/dl, and stool exam-
ination negative for pathogens or Clostridium difficile toxin.
Women had a negative pregnancy test and practised birth
control. Patients withileostomy,
.50 cm, obstructive symptoms, or anticipated need for
surgery were excluded. They were not enrolled if (1)
treatment in the last 12 weeks included cyclosporine,
agents, (2) treatment in the last two weeks included
antibiotics, antifungal, or antiparasitic medications, and (3)
they had other diseases that could interfere with compli-
ance or interpretation of the results.
Specific pathogen free pigs were given T suis ova by gastric
gavage. After allowing time for worm maturation, adult
worms were isolated from the colon and cultured in vitro.
Ova produced in vitro were collected and allowed to
embryonate for 5–6 weeks in phosphate buffered saline
containing penicillin/streptomycin/amphotericin B at 22˚C.
The embryonated ova were then made bacteria free using
0.2% K2Cr2O7, washed with sterile saline, and stored at 5˚C in
phosphate buffered saline. Standard viral and bacterial
cultures were performed on aliquots of ova to assure that
they contained no pathogens. Pigs were inoculated with
stored ova at regular time intervals to assure that the ova
remained infective. This analysis demonstrated that stored
ova retained viability for at least nine months. Eggs were
divided into individual aliquots of 2500. This number of ova
was the same as that used in our earlier pilot study.10Subjects
returned every three weeks to drink the ova suspended in a
commercial drink. The study coordinator witnessed that all of
the subjects consumed the drink.
Abbreviations: CDAI, Crohn’s disease activity index; 6-MP, 6-
mercaptopurine; DNBS, ditrinitrobenzene sulphonic acid; TNBS,
trinitrobenzene sulphonic acid
Patients kept daily diaries of clinical symptoms. Dosing of
all other inflammatory bowel disease medications was held
constant. The following were obtained at entry and every six
weeks: medical history and physical examination, pregnancy
test, complete blood count, liver profile, and stool examina-
tion for ova, pathogens, and C difficile toxin. Means (SD) are
given. Medians are presented with interquartile range. The
two tailed Fisher’s exact test was used to examine patient
characteristics that might predict response or remission.
A total of 29 patients were enrolled and their baseline
characteristics are shown in table 1. Most patients had
longstanding disease (median 3.9 (1.5–6.8) years) and were
refractory to standard inflammatory bowel disease therapy
before enrolment. Fourteen patients were on corticosteroids
and/or azathioprine/6-MP. Only 5/29 (17%) were on no
medications; of these, 10 previously had tried corticosteroids
and/or other immunosuppressants (azathioprine, 6-MP,
infliximab). Mean CDAI was 294, indicating that patients
were moderately ill. The cohort included patients with
anatomical disease distribution similar to that of the
Crohn’s disease population at large.
Patients were compliant with the protocol; all patients
completed their symptom diaries, attended all clinic visits,
and received all doses of the ova. None was lost to follow up.
Four withdrew at or before week 12 because of ongoing
disease activity, and one withdrew between weeks 12 and 24
because of pregnancy. Ongoing disease activity was defined
as failure to respond or achieve remission and these
individuals are included in the analysis. There was no
indication that the ova therapy made any patient more ill,
and there were no side effects or complications attributable to
therapy. Patients developed no new symptoms such as
nausea, vomiting, abdominal pain, or worsening of diar-
rhoea. There was no deterioration in CDAI in the four
patients that withdrew before week 12. Analysis of laboratory
data collected during the study showed no significant
changes in complete blood count or differential, blood urea
nitrogen or creatinine, or aspartate aminotransferase, alanine
aminotransferase, or alkaline phosphatase. All stool speci-
mens were negative for ova and parasites.
At week 12, 22 patients (75.9%) responded (decrease in
CDAI .100 points or CDAI ,150) and 19/29 (65.5%) were in
remission (CDAI ,150). At week 24, 23 patients (79.3%)
experienced a response and 21/29 (72.4%) were in remission
(fig 1A). Mean initial CDAI of responders was 287.1 (47.8). It
decreased to 92.0 (49.2) at week 12 and 99.9 (35.6) at week
24 (fig 1B). Thus the mean improvement in CDAI for these
patients was 195.1 and 187.2 at weeks 12 and 24,
respectively. There were six patients with a baseline CDAI
between 250 and the minimum entry criterion of 220. All six
achieved both a response (improvement in CDAI of .100)
and remission (CDAI ,150).
We performed subset analysis of patient characteristics
looking for predictors of outcomes. Sex, patient age, disease
duration, smoking status, or disease location did not
influence the frequency of response or remission. There was
a trend for patients using immunosuppressive drugs to
improve to a greater degree than those not using these
agents (table 2). Also, patients with a prior history of
terminal ileum resection were less responsive.
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 character-
istics 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.8The 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.11–14This
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,
Baseline characteristics of the patients*
VariableNo of patients (n=29)
Mean age (y)
Smoking status (yes/total)
Median duration of disease (y)
Site of disease
Small bowel only
Small bowel and colon
Medications at entry
13/16 (44.8% M)
CDAI, Crohn’s disease activity index; 6-MP, 6-mercaptopurine.
? ?? ????????
week 12 or 24 after initiating ova therapy. (B) Mean change in Crohn’s
disease activity index (CDAI, mean (SD)) for respondents to ova therapy.
CDAI ,150 is remission. p,0.0001, week 12 or week 24 compared
with baseline (time 0).
(A) Percentage of patients achieving remission or response at
88Summers, Elliott, Urban, et al
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 immuno-
suppressants (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 immuno-
suppressives 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 c producing
CD4+ T cells.15Colonisation with T muris or Heligmosomides
polygyrus retards development of colitis in interleukin 10
deficient mice.1Mice and rats treated with di- or trinitro-
benzene sulphonic acid (DNBS, TNBS) develop a Th1
cytokine driven colitis that shares features with Crohn’s
disease.16Mice and rats exposed to Schistosoma mansoni are
resistant to TNBS colitis.6 7Colonisation of mice with
Trichinella spiralis diminishes DNBS induced colits.5This
protection is associated with decreased systemic and colonic
interferon c and interleukin 12 expression, which are
critically important Th1 cytokines.
Colonisation with helminths augments several immuno-
regulatory 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 b,
interleukin 10, and prostaglandin E2that assist in maintain-
ing 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.
The authors gratefully acknowledge the support of Betty Musgrave,
clinical research coordinator. Drs Miriam B Zimmerman and William
Clarke, Department of Biostatistics provided assistance with study
design, statistical methods, and data analysis. Additional participat-
ing University of Iowa gastroenterologists included Drs Jeffrey Field,
Khurram Qadir, and David Ramkumar. Collaborating gastroenterol-
ogists from the State of Iowa included: Drs Dean Abramson, Nile
Dusdieker, Joseph Ewing, Jon Gibson, Bernard Leman, Randall
Lengeling, Sudhakar Misra, James Piros, Douglas Purdy, Leon Qiao,
Surish Reddy, Robert Silber, Joseph Truszkowski, and Gary
The Crohn’s and Colitis Foundation of America provided the
primary support for this study. The Broad Medical Research Program
of the Eli and Edythe L Broad Foundation, the Ed and Liliane
Schneider Family Foundation, and the Thomas Irwin Memorial Fund
also provided partial support. The study sponsors had no involvement
in the study design, collection, analysis, and interpretation of the
Subset analysis of patient characteristics for response and remission
No% No% No% No%
Current smoking status
Small bowel only
Small bowel and colon
Use of immuosuppressives*
*Immunosuppressives=corticosteroids, azathioprine, or 6-mercaptopurine.
Helminth ova therapy in Crohn’s disease89
data, in the writing of the report; or in the decision to submit the Download full-text
paper for publication.
R W Summers, D E Elliott, R Thompson, J V Weinstock, James A Clifton
Center for Digestive Diseases, Department of Internal Medicine,
University of Iowa Roy J and Lucille Carver College of Medicine,
University of Iowa, Iowa City, Iowa, USA
J F UrbanJr, Nutrient Requirements and Functions Laboratory, Beltsville
Human Nutrition Research Center, Agricultural Research Service, United
States Department of Agriculture, Beltsville, Maryland, USA
Conflict of interest: None declared.
1 Elliott DE, Urban JF Jr, Argo CK, et al. Does the failure to acquire helminthic
parasites predispose to Crohn’s disease? FASEB J 2000;14:1848–55.
2 Sabin EA, Araujo MI, Carvalho EM, et al. Impairment of tetanus toxoid-
specific Th1-like immune responses in humans infected with Schistosoma
mansoni. J Infect Dis 1996;173:269–72.
3 Borkow G, Leng Q, Weisman Z, et al. Chronic immune activation associated
with intestinal helminth infections results in impaired signal transduction and
anergy. J Clin Invest 2000;106:1053–60.
4 Weinstock JV, Summers R, Elliott DE. Helminths and harmony. Gut
5 Khan WI, Blennerhasset PA, Varghese AK, et al. Intestinal nematode infection
ameliorates experimental colitis in mice. Infect Immun 2002;70:5931–7.
6 Elliott DE, Li J, Blum A, et al. Exposure to schistosome eggs protects mice from
TNBS colitis. Am J Physiol 2003;284:G385–91.
7 Moreels TG, Nieuwendijk RJ, De Man JG, et al. Concurrent infection with
Schistosoma mansoni attenuates inflammation induced changes in colonic
morphology, cytokine levels, and smooth muscle contractility of
trinitrobenzene sulphonic acid induced colitis in rats. Gut 2004;53:99–107.
8 Beer RJ. The relationship between Trichuris trichiura (Linnaeus 1758)
of man and Trichuris suis (Schrank 1788) of the pig. Res Vet Sci
9 Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease
activity index. National Coorperative Crohn’s Disease Study.
10 Summers RW, Elliott DE, Qadir K, et al. Trichuris suis seems to be safe and
possibly effective in the treatment of inflammatory bowel disease.
Am J Gastroenterol 2003;98:2034–41.
11 Sands BE, Winston BD, Salzberg B, et al. Randomized, controlled trial of
recombinant human interleukin-11 in patients with active Crohn’s disease.
Aliment Pharm Ther 2002;16:399–406.
12 Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human
antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-
blind placebo-controlled trial. Gastroenterology 2001;120:1330–8.
13 Panaccione R, Canadian Consensus Group on the use of infliximab in Crohn’s
disease. Infliximab for the treatment of Crohn’s disease: review and
indications for clinical use in Canada. Can J Gastroenterol 2001;15:371–5.
14 Feagan B. Infliximab in the treatment of Crohn’s disease. Can J Gastroenterol
15 Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in
interleukin-10-deficient mice are associated with aberrant cytokine production
and CD4(+) TH1-like responses. J Clin Invest 1996;98:1010–20.
16 Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to interleukin 12 abrogate
established experimental colitis in mice. J Exp Med 1995;182:1281–90.
EDITOR’S QUIZ: GI SNAPSHOT ..................................................................
Robin Spiller, Editor
Vomiting in the recently anticoagulated patient
A 42 year old previously healthy man presented with an eight
hour history of retrosternal tightness. While clinical exam-
ination was unremarkable, his cardiac enzymes were raised
and his electrocardiogram showed ST segment elevation in
leads II, III, and aVf. He was diagnosed with an acute inferior
myocardial infarction and received 1.5 million units of
streptokinase over the next hour. His pain settled and he
was comfortable overnight.
The following morning he developed epigastric pain and
tenderness and vomited twice. His haemoglobin level
dropped to 12 g/dl (15 g/dl on admission). Although overall
he improved over the next 48 hours, he continued to vomit
even though fasting. An upper gastrointestinal endoscopy
was preformed and demonstrated the duodenal abnormality
shown in fig 1.
What is the abnormality shown (fig 1) and what is the most
appropriate course of subsequent treatment?
See page 102 for answer
This case is submitted by:
R A Cahill, S Siddique, J O’Connor
Department of General Surgery, Waterford Regional Hospital, Waterford,
Correspondence to: Mr R Cahill, Department of General Surgery, Waterford
Regional Hospital, Waterford, Ireland; firstname.lastname@example.org
Upper gastrointestinal endoscopy.
90Summers, Elliott, Urban, et al