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EDITORIAL
Probiotic Therapy for Ulcerative Colitis
Martin H. Floch, MD
I
n 2009, 2 manuscripts were added to the literature that demonstrated the effectiveness of
probiotics in inducing remission in patients with ulcerative colitis. The first manuscript was
published by Miele and colleagues.1 Twenty-nine newly diagnosed ulcerative colitis patients
were randomized to receive either VSL#3 on a weight-based dose or a placebo in conjunction
with concomitant steroid induction and mesalamine maintenance treatment. The subjects were
children with a mean age of 9.8 years ranging from 1.7 to 16.1 years. There were 13 females
and 16 males. The subjects were thoroughly evaluated at 1 month, 2 months, 6 months, and 1
year after the diagnosis or at the time of relapse. All 29 patients responded at the induction of
therapy, and remission was achieved in 13 patients (92.8%) treated with VSL#3 and
inflammatory bowel disease therapy and in 4 patients treated with placebo and inflammatory
bowel disease therapy. This gave a clear statistical result of effectiveness of the probiotics with
a P level of less than 0.001. At 1 year, 3 of the 14 patients treated with the probiotics relapsed,
whereas 11 of 15 on the placebo relapsed, again giving a significant P value of less than 0.014.
The authors concluded that their randomized, placebo-controlled trial suggested the efficacy
and safety of a high concentrated mixture of probiotic bacteria, VSL#3, in active ulcerative
colitis and demonstrated its role in maintenance of remission. The study carried out in Italy
included both endoscopic and histologic evaluations.
The second study was carried out in India by Sood and colleagues2 and again revealed
that VSL#3 was safe and effective in achieving clinical responses and remissions in patients
with mild-to-moderately active ulcerative colitis. They had randomized adult patients to
groups that were given VSL#3 (n = 77) or placebo (n = 70) twice daily for 12 weeks. Their end
point was a 50% decrease in the ulcerative colitis disease activity index at 6 weeks, and
a secondary end point included remission at 12 weeks and reduction in total individual
Ulcerative Colitis Disease Activity Index parameters. Comparing the probiotic treatment
group to the placebo gave a clear P value of less than 0.001, and at 12 weeks there were 33
patients on the probiotics which achieved remission, whereas only 11 patients given placebo
had a remission, again with a P value of less than 0.0001.
These 2 reports seem to tip the scale in favor of recommending probiotic therapy for
ulcerative colitis. The dose in the first article was weight-related, but in the second article it was
3.6 ! 1012 colony forming units twice daily (4 sachets).
By definition, probiotics are live human bacteria when fed in either pills, tablets, or
foods that benefit the host. The first clinical study on the use of a probiotic in ulcerative colitis
was reported by Rembacken and colleagues in 1999.3 They randomized patients with active
ulcerative colitis to either mesalamine 800 mL three times daily or Escherichia coli Nissle 1917
strain for up to 3 months of therapy. Remission had been induced with the use of
corticosteroids. Remission was obtained in 75% of patients treated with the mesalamine and
68% treated with the probiotics. There is difficulty in interpreting this study because of the
small differences in the time to remission, 42 days for the probiotics patients and 44 days for
the mesalamine. Some interpreted this as meaning that they both work but, in contrast, the use
of the mesalamine was at a very low dose. Nevertheless, this was the first study that gave some
indication that probiotics may work.
In 2007, a Yale University Workshop was held to review the medical literature on the
use of probiotics in ulcerative colitis. This review was carried out by Fedorak and Dieleman4
which revealed that there were 15 controlled studies reported since 1980, and induction of
remission was noted in 7 studies evaluating 350 patients. It seemed that induction of remission
did occur but that the results varied. The most effective probiotics used were E. coli Nissle
strain and VSL#3. A detailed review on maintenance of remission by these same authors
revealed that there were 8 studies using 775 patients. Four showed clear maintenance
remission and 4 did not. Again, the most effective organisms were E. coli Nissle and VSL#3.
In the most recent review of the literature by Kroeker and Dieleman,5 their
recommendation for probiotic use in ulcerative colitis, quoting an update in the Yale review,6
From the Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
No funding.
No conflict of interest.
Reprints: Martin H. Floch, MD, Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 40 Temple
Street, Suite 1A, New Haven, CT 06510 (e-mail: [email protected]).
Copyright r 2010 by Lippincott Williams & Wilkins
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Volume 44, Number 4, April 2010
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Floch
is that probiotic therapy can be given a level B recommendation for both inducing remission and maintenance of
therapy.
It seems from the literature that the organisms that
have been most effective are E. coli Nissle strain 1917,
which is available in Europe but not in North America, or
VSL#3. The mechanism by which the probiotic is effective
is not yet clearly defined. One could assume that it is
through stimulation of an immune process, as probiotics
are now well established to be effective in stimulating
cytokines and the immune response.7 Of interest is the fact
that the 2 most effective probiotics are so different. E. coli
Nissle strain is a single organism and one could theorize
that it has its effect directly. However, VSL#3 contains 8
organisms. Four strains of Lactobacillus (L. paracasei,
L. plantarum, L. acidophilus, and L. delbreueckii) and
3 strains of Bifidobacteria (B. longum, B. breve, and
B. infantis) as well as Streptococcus thermophilus. There is
an extensive literature on VSL#3. However, which organisms
are effective and which are not in this conglomeration is
unknown. Nevertheless, they are given in high doses and do
seem to be effective as reported in the 2 studies in this
manuscript and in several other studies in the literature.
Therefore, the question has to be asked now, should
we recommend the use of probiotics for the treatment of
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Volume 44, Number 4, April 2010
ulcerative colitis? The scale certainly seems to be tipped to
the side of yes. As with all therapies, it should be used in the
correct approach. The literature does indicate that it is
good for mild cases. As there is little or no complication
from these organisms should it be added to armamentarium
of all patients with ulcerative colitis? These questions
remain to be answered.
REFERENCES
1. Miele E, Pascarella F, Giannetti E, et al. Effect of a probiotic
preparation (VSL#3) on induction and maintenance of remission
in children with ulcerative colitis. Am J Gastroenterol. 2009;104:
437–443.
2. Sood A, Midha V, Makharia GK, et al. The probiotic preparation,
VSL#3 induces remission in patients with mild-to-moderately active
ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7:1202–1209.
3. Rembacken BJ, Snelling AM, Hawkey PH, et al. Non-pathogenic
Escherichia coli versus mesalazine for the treatment of ulcerative
colitis: a randomized trial. Lancet. 1999;354:635–639.
4. Fedorak RN, Dieleman LA. Probiotics in the treatment of human
inflammatory bowel diseases: update 2008. J Clin Gastroenterol.
2008;42:S97–S103.
5. Kroeker K, Dieleman LA. Treatment of ulcerative colitis in probiotics:
a clinical guide. In: Floch MH, Kim A, Slack KA, eds. Probiotics:
A Clinical Guide. Thorofare NJ: Publisher Slack. 2010. In press.
6. Floch MH, Walker WA, Guandalini S, et al. Recommendations for
probiotic use – 2008. J Clin Gastroenterol. 2008;42:S104–S108.
7. Madsen K. Probiotics and the immune response. J Clin Gastroenterol. 2006;40:232–234.
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2010 Lippincott Williams & Wilkins