Trichuris suis therapy in Crohn's disease
R W Summers, D E Elliott, J F Urban, Jr, R Thompson and J V Weinstock
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INFLAMMATORY BOWEL DISEASE
Gut 2005;54:87–90. doi: 10.1136/gut.2004.041749
See end of article for
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. Helminthsdiminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental
Dr R W Summers, James A
colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease.
Clifton Center for Digestive
Aims: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth
Diseases, Department of
Trichuris suis in the treatment of patients with active Crohn's disease.
University of Iowa Roy J
Patients: Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index
and Lucille A Carver
(CDAI) >220 were enrolled in this open label study.
College of Medicine, 200
Methods: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity
Hawkins Drive, Iowa City,
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) and21/29 (72.4%) remitted (CDAI ,150). Mean CDAI of responders decreased 177.1 points below
Revised version received
baseline. Analysis at week 12 yielded similar results. There were no adverse events.
Accepted for publication
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.
Crohn's disease is a chronic relapsing inflammatory aminotransferase and alanine aminotransferase ,100U/dl,
reaction that may affect any part of the gastrointestinal
tract. It is common in parts of the world where
,40 mg/dl, serum creatinine ,2.0 mg/dl, and stool exam-
helminthic colonisation is rare and uncommon in those
ination negative for pathogens or Clostridium difficile toxin.
areas where most people carry worms.1 It appears to result
Women had a negative pregnancy test and practised birth
from an inappropriate immune response to normal gut flora.
Helminths down-modulate the host immune response to
.50 cm, obstructive symptoms, or anticipated need for
unrelated antigens,2–4 a property that could be beneficial in
surgery were excluded. They were not enrolled if (1)
Crohn's disease. Helminths reduce inflammation in experi-
treatment in the last 12 weeks included cyclosporine,
mental murine colitis.1 5–7 Trichuris suis, the porcine whip-
worm, is similar to human whipworm T trichiura. Ingestion of
agents, (2) treatment in the last two weeks included
T suis ova results in short term self limited colonisation of
antibiotics, antifungal, or antiparasitic medications, and (3)
humans.8 We therefore conducted a 24 week clinical trial to
they had other diseases that could interfere with compli-
evaluate the safety and possible efficacy of live T suis therapy
ance or interpretation of the results.
in Crohn's disease.
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.
Patients were enrolled in a 24 week open label study after
Ova produced in vitro were collected and allowed to
giving informed consent. The University of Iowa Institutional
embryonate for 5–6 weeks in phosphate buffered saline
Review Board approved the protocol. Subjects with Crohn's
containing penicillin/streptomycin/amphotericin B at 22˚C.
disease, as defined by standard clinical, radiological, and
The embryonated ova were then made bacteria free using
histological criteria, were recruited and followed at the
0.2% K2Cr2O7, washed with sterile saline, and stored at 5˚C in
University of Iowa and clinical practices in the State of
phosphate buffered saline. Standard viral and bacterial
Iowa. Patients 18–72 years old were eligible if they had a
cultures were performed on aliquots of ova to assure that
Crohn's disease activity index (CDAI) between 220 and 450.9
they contained no pathogens. Pigs were inoculated with
A small bowel series and colonoscopy were required within
stored ova at regular time intervals to assure that the ova
the year before enrolment. Patients continued their Crohn's
remained infective. This analysis demonstrated that stored
disease medications if they met the following enrolment
ova retained viability for at least nine months. Eggs were
criteria: (1) mesalamine or derivatives if they had been
divided into individual aliquots of 2500. This number of ova
receiving it for .8 weeks and the same dose for .4 weeks;
was the same as that used in our earlier pilot study.10 Subjects
(2) oral prednisone up to 25 mg/day if patients had been
returned every three weeks to drink the ova suspended in a
receiving it for .8 weeks and the same dose for .4 weeks;
commercial drink. The study coordinator witnessed that all of
and (3) azathioprine or 6-mercaptopurine (6-MP) if patients
the subjects consumed the drink.
had been receiving it for .6 months and the same dose for.8 weeks. Before enrolment, patients had to have ahaemoglobin concentration of .10.0 g/dl, white blood count
Abbreviations: CDAI, Crohn's disease activity index; 6-MP, 6-
of 5000–15 000/mm3, platelet count .150 000/mm3, no iron or
mercaptopurine; DNBS, ditrinitrobenzene sulphonic acid; TNBS,
vitamin B12 deficiency, total bilirubin ,1.5 mg/dl, aspartate
trinitrobenzene sulphonic acid
Summers, Elliott, Urban, et al
Table 1 Baseline characteristics of the patients*
No of patients (n = 29)
Smoking status (yes/total)
Median duration of disease (y)
Small bowel and colon
Medications at entry
Figure 1 (A) Percentage of patients achieving remission or response at
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).
CDAI, Crohn's disease activity index; 6-MP, 6-mercaptopurine.
(fig 1A). Mean initial CDAI of responders was 287.1 (47.8). Itdecreased to 92.0 (49.2) at week 12 and 99.9 (35.6) at week
Patients kept daily diaries of clinical symptoms. Dosing of
24 (fig 1B). Thus the mean improvement in CDAI for these
all other inflammatory bowel disease medications was held
patients was 195.1 and 187.2 at weeks 12 and 24,
constant. The following were obtained at entry and every six
respectively. There were six patients with a baseline CDAI
weeks: medical history and physical examination, pregnancy
between 250 and the minimum entry criterion of 220. All six
test, complete blood count, liver profile, and stool examina-
achieved both a response (improvement in CDAI of .100)
tion for ova, pathogens, and C difficile toxin. Means (SD) are
and remission (CDAI ,150).
given. Medians are presented with interquartile range. The
We performed subset analysis of patient characteristics
two tailed Fisher's exact test was used to examine patient
looking for predictors of outcomes. Sex, patient age, disease
characteristics that might predict response or remission.
duration, smoking status, or disease location did notinfluence the frequency of response or remission. There was
a trend for patients using immunosuppressive drugs toimprove to a greater degree than those not using these
A total of 29 patients were enrolled and their baseline
agents (table 2). Also, patients with a prior history of
characteristics are shown in table 1. Most patients had
terminal ileum resection were less responsive.
longstanding disease (median 3.9 (1.5–6.8) years) and wererefractory to standard inflammatory bowel disease therapybefore enrolment. Fourteen patients were on corticosteroids
and/or azathioprine/6-MP. Only 5/29 (17%) were on no
Human helminthic parasites were considered as a therapeutic
medications; of these, 10 previously had tried corticosteroids
option. Many could not be used because there are no
and/or other immunosuppressants (azathioprine, 6-MP,
available sources other than a human carrier. Eggs from
infliximab). Mean CDAI was 294, indicating that patients
such a source would risk inadvertent transmission of
were moderately ill. The cohort included patients with
pathogenic microbial agents. Also, some human helminths
anatomical disease distribution similar to that of the
have disease potential or raise public health concerns.
Crohn's disease population at large.
Trichuris species are helminths with favourable character-
Patients were compliant with the protocol; all patients
istics for therapeutic use. Their life cycle minimises the risk of
completed their symptom diaries, attended all clinic visits,
inadvertent colonisation. Trichuris ova mature in the soil and
and received all doses of the ova. None was lost to follow up.
are ingested by the host. Ova hatch in the duodenum,
Four withdrew at or before week 12 because of ongoing
releasing larvae that ultimately grow in 6–8 weeks into adult
disease activity, and one withdrew between weeks 12 and 24
worms. They migrate to the terminal ileum and colon but do
because of pregnancy. Ongoing disease activity was defined
not invade the host. Worms can remain viable for 1–2 years
as failure to respond or achieve remission and these
in the natural host. Adult worms release ova that are shed
individuals are included in the analysis. There was no
into the stool. These ova are immature and are not capable of
indication that the ova therapy made any patient more ill,
colonising another host until they incubate in the soil for
and there were no side effects or complications attributable to
several weeks to allow embryonation.
therapy. Patients developed no new symptoms such as
We chose T suis as the helminth to colonise subjects in this
nausea, vomiting, abdominal pain, or worsening of diar-
study. T suis, the porcine whipworm, is genetically related to T
rhoea. There was no deterioration in CDAI in the four
trichiura, the human whipworm. T suis is not a natural human
patients that withdrew before week 12. Analysis of laboratory
parasite but it has been shown experimentally to colonise
data collected during the study showed no significant
humans briefly without causing disease.8 The ova can be
changes in complete blood count or differential, blood urea
produced using pathogen free pigs, and processed to assure
nitrogen or creatinine, or aspartate aminotransferase, alanine
absence of biological contaminants.
aminotransferase, or alkaline phosphatase. All stool speci-
Treatment with T suis ova for 24 weeks yielded a response
mens were negative for ova and parasites.
rate of nearly 80% and a remission rate of nearly 73%, which
At week 12, 22 patients (75.9%) responded (decrease in
was much greater than the anticipated placebo effect.11–14 This
CDAI .100 points or CDAI ,150) and 19/29 (65.5%) were in
was particularly notable as many patients had refractory
remission (CDAI ,150). At week 24, 23 patients (79.3%)
disease. Thus T suis ova therapy may produce substantial and
experienced a response and 21/29 (72.4%) were in remission
sustained improvement in active Crohn's disease. However,
Helminth ova therapy in Crohn's disease
Table 2 Subset analysis of patient characteristics for response and remission
Current smoking status
Small bowel and colon
Use of immuosuppressives*
*Immunosuppressives = corticosteroids, azathioprine, or 6-mercaptopurine.
the study was open label, and we cannot exclude a high
Colonisation with helminths augments several immuno-
placebo effect. The treatment caused no side effects or
regulatory pathways that limit Th1-type inflammation.
complications even in patients receiving multiple immuno-
Helminths induce production of interleukin 4 and interleukin
suppressants (for example, corticosteroids and azathioprine/
13, which are Th2 cytokines. This Th2 response inhibits
6-MP), suggesting a high safety profile.
production of Th1 cytokines thereby reducing colitis severity.6
Subset analysis of the data suggested that patients on
Helminths also induce regulatory T cells and immune
immunosuppressive therapy faired better, as did patients
regulatory substances such as transforming growth factor b,
with an intact terminal ileum. We can only speculate on the
interleukin 10, and prostaglandin E2 that assist in maintain-
reason for these observations. It is possible that immuno-
ing host mucosal homeostasis.4
suppressives could have influenced T suis colonisation. Also,
In summary, T suis is well tolerated and appears efficacious
there could have been a synergistic interaction between
for Crohn's disease in this open label trial. Helminths
the immunomodulatory effect of the helminths and the
probably inhibit intestinal inflammation by mechanisms
immunosuppressive effect of the other drugs. Terminal ileal
different from current medications. Helminths may offer an
resection also could have affected worm colonisation, or
easy to administer alternative or supplement to currently
perhaps residual symptoms from the surgery confounded
available therapeutic agents. These results justify a double
CDAI scoring. Both of these observations need confirmation
blind controlled clinical trial. Furthermore, these results
in a prospective trial to assure that they were not artefacts.
support the hypothesis that helminthic exposure provides
There is an immunological basis to expect that exposure to
protection against some immune mediated inflammatory
helminths such as T suis will prove beneficial in Crohn's
disease like Crohn's disease.
disease. Crohn's disease involves over reactive Th1 pathways,and helminths blunt Th1 responses. For example, helminths
attenuate intestinal inflammation in animal models of
The authors gratefully acknowledge the support of Betty Musgrave,
inflammatory bowel disease. Interleukin 10 deficient mice
clinical research coordinator. Drs Miriam B Zimmerman and William
spontaneously develop a Th1-type colitis characterised by
Clarke, Department of Biostatistics provided assistance with studydesign, statistical methods, and data analysis. Additional participat-
infiltration of the lamina propria with interferon c producing
ing University of Iowa gastroenterologists included Drs Jeffrey Field,
CD4+ T cells.15 Colonisation with T muris or Heligmosomides
Khurram Qadir, and David Ramkumar. Collaborating gastroenterol-
polygyrus retards development of colitis in interleukin 10
ogists from the State of Iowa included: Drs Dean Abramson, Nile
deficient mice.1 Mice and rats treated with di- or trinitro-
Dusdieker, Joseph Ewing, Jon Gibson, Bernard Leman, Randall
benzene sulphonic acid (DNBS, TNBS) develop a Th1
Lengeling, Sudhakar Misra, James Piros, Douglas Purdy, Leon Qiao,
cytokine driven colitis that shares features with Crohn's
Surish Reddy, Robert Silber, Joseph Truszkowski, and Gary
disease.16 Mice and rats exposed to Schistosoma mansoni are
resistant to TNBS colitis.6 7 Colonisation of mice with
The Crohn's and Colitis Foundation of America provided the
primary support for this study. The Broad Medical Research Program
Trichinella spiralis diminishes DNBS induced colits.5 This
of the Eli and Edythe L Broad Foundation, the Ed and Liliane
protection is associated with decreased systemic and colonic
Schneider Family Foundation, and the Thomas Irwin Memorial Fund
interferon c and interleukin 12 expression, which are
also provided partial support. The study sponsors had no involvement
critically important Th1 cytokines.
in the study design, collection, analysis, and interpretation of the
Summers, Elliott, Urban, et al
data, in the writing of the report; or in the decision to submit the
6 Elliott DE, Li J, Blum A, et al. Exposure to schistosome eggs protects mice from
paper for publication.
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 colonicmorphology, cytokine levels, and smooth muscle contractility of
trinitrobenzene sulphonic acid induced colitis in rats. Gut 2004;53:99–107.
R W Summers, D E Elliott, R Thompson, J V Weinstock, James A Clifton
8 Beer RJ. The relationship between Trichuris trichiura (Linnaeus 1758)
Center for Digestive Diseases, Department of Internal Medicine,
of man and Trichuris suis (Schrank 1788) of the pig. Res Vet Sci
University of Iowa Roy J and Lucille Carver College of Medicine,
9 Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease
University of Iowa, Iowa City, Iowa, USA
activity index. National Coorperative Crohn's Disease Study.
J F UrbanJr, Nutrient Requirements and Functions Laboratory, Beltsville
Human Nutrition Research Center, Agricultural Research Service, United
10 Summers RW, Elliott DE, Qadir K, et al. Trichuris suis seems to be safe and
States Department of Agriculture, Beltsville, Maryland, USA
possibly effective in the treatment of inflammatory bowel disease.
Am J Gastroenterol 2003;98:2034–41.
Conflict of interest: None declared.
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
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antibody to TNF (CDP571) for active Crohn's disease: a randomized double-
parasites predispose to Crohn's disease? FASEB J 2000;14:1848–55.
blind placebo-controlled trial. Gastroenterology 2001;120:1330–8.
2 Sabin EA, Araujo MI, Carvalho EM, et al. Impairment of tetanus toxoid-
13 Panaccione R, Canadian Consensus Group on the use of infliximab in Crohn's
specific Th1-like immune responses in humans infected with Schistosoma
disease. Infliximab for the treatment of Crohn's disease: review and
mansoni. J Infect Dis 1996;173:269–72.
indications for clinical use in Canada. Can J Gastroenterol 2001;15:371–5.
3 Borkow G, Leng Q, Weisman Z, et al. Chronic immune activation associated
14 Feagan B. Infliximab in the treatment of Crohn's disease. Can J Gastroenterol
with intestinal helminth infections results in impaired signal transduction and
anergy. J Clin Invest 2000;106:1053–60.
15 Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in
4 Weinstock JV, Summers R, Elliott DE. Helminths and harmony. Gut
interleukin-10-deficient mice are associated with aberrant cytokine production
and CD4(+) TH1-like responses. J Clin Invest 1996;98:1010–20.
5 Khan WI, Blennerhasset PA, Varghese AK, et al. Intestinal nematode infection
16 Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to interleukin 12 abrogate
ameliorates experimental colitis in mice. Infect Immun 2002;70:5931–7.
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 patientClinical presentationA 42 year old previously healthy man presented with an eighthour history of retrosternal tightness. While clinical exam-ination was unremarkable, his cardiac enzymes were raisedand his electrocardiogram showed ST segment elevation inleads II, III, and aVf. He was diagnosed with an acute inferiormyocardial infarction and received 1.5 million units ofstreptokinase over the next hour. His pain settled and hewas comfortable overnight.
The following morning he developed epigastric pain and
tenderness and vomited twice. His haemoglobin leveldropped to 12 g/dl (15 g/dl on admission). Although overallhe improved over the next 48 hours, he continued to vomiteven though fasting. An upper gastrointestinal endoscopywas preformed and demonstrated the duodenal abnormalityshown in fig 1.
QuestionWhat is the abnormality shown (fig 1) and what is the mostappropriate course of subsequent treatment?See page 102 for answerThis case is submitted by:
R A Cahill, S Siddique, J O'Connor
Department of General Surgery, Waterford Regional Hospital, Waterford,
Figure 1 Upper gastrointestinal endoscopy.
Correspondence to: Mr R Cahill, Department of General Surgery, Waterford
Regional Hospital, Waterford, Ireland; [email protected]
Asian consensus on irritable bowel syndromeKok-Ann Gwee,1 Young-Tae Bak,2 Uday Chand Ghoshal,3 Sutep Gonlachanvit,4 Oh Young Lee,5Kwong Ming Fock,6 Andrew Seng Boon Chua,7 Ching-Liang Lu,8 Khean-Lee Goh,9Chomsri Kositchaiwat,10 Govind Makharia,11 Hyo-Jin Park,12 Full-Young Chang,13 Shin Fukudo,14Myung-Gyu Choi,15 Shobna Bhatia,16 Meiyun Ke,17 Xiaohua Hou18 and Michio Hongo19
Journal of Antimicrobial Chemotherapy (1997) 40, 622–630 Antibiotic susceptibilities of mycoplasmas and treatment of David Taylor-Robinsona and Christiane Bébéarb aMRC Sexually Transmitted Diseases Research Group, Department of Genitourinary Medicine, the Jefferiss Wing, Imperial College School of Medicine at St Mary's, Paddington, London W2 1NY, UK;b