Professional Documents
Culture Documents
Probiotic Therapy
David R. Mack∗
Introduction
The term probiotic was first used to describe substances produced by a microorganism to promote
the growth of another microorganism [1] but the definition has evolved to that espoused by the
joint task force of the FAO/WHO, which is ‘live microorganisms that confer a health benefit
when administered in adequate amounts’ [2]. Most microorganisms used as probiotics are bacteria
that have been derived from human, animal and food sources. Most species of probiotics belong
to the Lactobacillus and Bifidobacterium Genus but other bacterial strains within the Genus’
Enterococcus, Streptococcus and Escherichia have variously been used. The most common non-
bacterial probiotic is the fungus Saccharomyces boulardii that is derived from the lychee fruit.
Although not normally an inhabitant of the human intestinal tract as are some of the human
and food derived bacterial strains, S. boulardii has gained consideration as a probiotic because it
grows at normal body temperature and is intrinsically resistant to antibiotics.
The use of probiotics has been proposed for providing benefits to human health for a long time
but in recent years there has been increased interest for their use in a number of gastrointestinal
conditions including inflammatory bowel disease [3]. In part, this has been the result of animal
studies that have yielded provocative information regarding the importance of intestinal microbiota
in stabilization and regeneration of the intestinal mucosa in the presence of inflammation [4]
and that intestinal microbes can be involved in the development and chronicity of inflammation
in various animal models of inflammatory bowel disease [5]. Probiotics are being ingested by
patients with IBD sometimes through the advice of the physician but mostly self-prescribed as a
form of alternative medicine [6, 7]. The interest in adults ingesting probiotics for their IBD has
crossed over into probiotic usage in children and adolescents despite a significant lack of studies
in younger aged IBD patients [8, 9]. Recent reports compared to even a few years ago would
suggest increase in the use such that up to 50% of patients with IBD at least are trying probiotics
if not taking them on a regular basis [7–11]. However, this must also be taken into the context
of a 10-fold increase in information being published on medical journals cited by Medline in
recent years available to the general public. As a measure of this increased information, a count
of citations for a Medline search for probiotics and Crohn’s disease yields 9 citations prior to
2001 but 94 citations during the period from 2001 through 2005. Similarly, 14 citations are listed
for ulcerative colitis and probiotics prior to 2001 but 137 from 2001 through 2005. The reasons
351
352 David R. Mack
people are using probiotics is most often related to worse disease severity, adverse side effects of
traditional treatments and health beliefs [6–8].
Probiotics are available as single microbes or as blends of microbes and are generally combined
with other prescription medicines. Although certain segments within healthcare provision have
adopted probiotics for use in IBD without critical appraisal, it is important that we use the same
principles as applied to pharmaceuticals in treating a disease condition as with probiotics for use
in IBD. The aim of this chapter is to review the clinical trial data with respect to specific aspects
of ulcerative colitis and Crohn’s disease care that is currently available.
Ulcerative Colitis
Treatment of Active Inflammation
Very small trials with approximately 10–35 participants in treatment arms have now been reported
using probiotics as therapy for mild to moderate active colitis in adults (Table 27.1). The trials
have included probiotics as sole therapy [12–15] with one of these trials combining the probiotic
with a low dose of the prebiotic (i.e. a food ingredient, that is usually a non-digestible oligosac-
charide, that allows for selective microbial growth in order to enhance the health of the host)
fructooligosaccharide/inulin [15] or as therapy combined with a conventional medicine [16] in
either open label trials (n = 3) or double-blind, placebo controlled (n = 2). The probiotics have
either been a blend of several different strains (VSL#3® , Yakult® ) or single strain studies (Saccha-
romyces boulardii, Bifidobacterium longum no strain specified).
Rates of inducing remission and response are reported in the 70–80% range for those reporting
successful intervention [12–14, 16] but one negative trial was reported without clinical benefit of
the 8 participants in the treatment group compared to the 8 participants receiving placebo over
the 4-week intervention period [15]. As comparison, in a trial of 268 UC patients with moderate
severity of disease 4.8 grams of delayed release oral mesalamine was found to have clinical
benefit in 70% and superior to a response rate of 59% for those using a lower dose of 2.4 grams
of a delayed release oral mesalamine for moderate UC [17].
Maintenance Therapy
Only a few probiotic products either combined as blends (n = 2) or administered as single strain
monotherapy (n = 4) have been studied in adult UC maintenance trials. Indeed, 3 of the trials have
utilized E. coli strain Nissle 1917 however; these trials have included larger numbers of participants
DBPC: double-blind randomized placebo-controlled; R: randomized; Blend: combination of two or more probiotic
organisms
Chapter 27 Probiotic Therapy 353
Table 27.2. Trials of probiotics used as maintenance therapy for ulcerative colitis.
Total Trial Design Probiotic (Strains) Daily Dosing Trial Length Reference
Participants (CFU) (Months)
(# Treated)
DBPC: double-blind randomized placebo-controlled; R: randomized; Blend: combination of two or more probiotic
organisms
than in studies evaluating treatment of active disease (See Table 27.2). With a background of
up to a 70% relapse rate over a 1-year period for those with ulcerative colitis not taking any
form of maintenance therapy [18], many of the trials have been for one year (Table 27.2) and
studied remission rates in comparison with 5-aminosalicylate products [20, 23, 24]. One of these
12-month probiotic versus 5-aminosalicylate trials was initiated with active UC patients [20] and
followed those achieving remission for a 12-month period. In this study the relapse rates were high
in both the group maintained with E. coli Nissle 1917 and those maintained on 1.5 grams of daily
mesalazine (67% and 72%, respectively). The other 12-month trials were initiated in participants
with quiescent disease. In these studies, maintenance of remission rates varied between 45%
and 75% [22–24] and studies in those receiving 5-aminosalicylates as a control group had a
similar maintenance of remission rate as the probiotic intervention group [23, 24]. Interestingly in
the trial comparing monotherapy L. rhamnosus strain GG, monotherapy mesalamine (2.4 grams
per day) and combination probiotic and mesalamine, no synergistic benefit was derived form
combination therapy but all three groups had equivalent rates for maintenance of remission [24].
The studies comparing probiotic with 5-aminosalicylates have used different total daily amounts
(1.5–2.4 grams per day). Nevertheless, currently there is not clinical evidence of a direct dose-
dependent maintenance benefit above 1.6 grams daily dosing of 5-aminosalicylate but lower
doses are not as effective [25]. It is not obvious from the trials done to date that there is any
advantage to blends of probiotics as compared to single probiotics and there are no comparative
trials to answer this question.
Pouchitis
Pouchitis is the most common long-term complication following ileal pouch-anal anastomosis
(See Chapter on Pouchitis). Most patients will develop this problem in their first year following
the surgery and luminal flora play a prominent role in the pathogenesis of this problem. Antibiotics
can be an effective form of therapy in many but in some discontinuation of the antibiotics can lead
to recurrence of symptomatology, so called chronic relapsing antibiotic dependent pouchitis. As
antibiotics can provide relief for most with pouchitis, a basic assumption has been the importance
of the microbiota of the pouch in the development and chronicity of pouchitis. Thus, consideration
of probiotics to alter the pouch microbiota as a form of treatment, prevent the onset of pouchitis
immediately following surgery prior to the colonization with a deleterious microbiota and provide
354 David R. Mack
Probiotics as Treatment
Trials for treating mild/moderate pouchitis are few and involve small numbers of participants.
Kuisma et al. [26] recruited 20 patients (10 in the intervention arm) for a DBRPC trial of LGG
2 × 1010 CFU/day × 3 months. In contrast to the studies on prevention of recurrence of pouchitis,
participants in this trial were excluded if they had received antibiotics in the previous month. As
well, those with evidence of active proctitis were excluded. The Pouchitis Disease Activity Index
[27] was utilized for evaluation of clinical effect. Prior to study entry, the mean PDAI was in the
mild range (8.0 ± 0.8). There was no difference following the intervention period [26]. A lack of
improvement of clinical scores was also reported on interviewing patients in an open-label trial of
51 UC patients post ileal pouch-anal anastomosis using a fermented milk product with a blend of
probiotic strains (L. acidophilus strain La5 + B. lactis strain Bb12) containing 5 × 1010 CFU/day
however, there was a reported improvement in endoscopic evaluation [28].
Thus, there is not evidence for a role of probiotics as monotherapy for mild/moderate pouchitis
at the present time. Limiting access of microbiota to the mucosa of the pouch and subsequent
development of inflammation may be a key mechanism whereby probiotics provide benefit, thus it
may not be surprising that once the deleterious microbiota have colonized within the pouch there
is little a probiotic as monotherapy can do to alter the situation. A somewhat analogous situation
exists for use of probiotics as monotherapy in treating Helicobacter pylori. The eradication rate of
probiotic monotherapy was very poor compared to standard triple therapy (a proton pump inhibitor
+ 2 antibiotics) in children colonized with H. pylori [29]. Interestingly, a number of studies have
reported indirect evidence suggesting reduced H. pylori colonization with probiotic monotherapy
even though eradication rate is poor [30] and one study suggested reduced gastritis on biopsy
[31]. The increased eradication rates of H. pylori using combined probiotic and antibiotic may
take advantage of lower levels of pathogen in the stomach and/or decreased adverse effects of the
antibiotics. Thus, if there is an analogy to be drawn it would be interesting in future studies of
patients with pouchitis requiring continuous antibiotics or very frequent use of antibiotics whether
probiotics had a role following short antibiotic courses of therapy.
DBPC: Double-blind randomized placebo-controlled; Blend: combination of two or more probiotic organisms
Chapter 27 Probiotic Therapy 355
a blend probiotic (VSL# 3™) had developed colitis as determined using the Pouchitis Disease
Activity Index (PDAI) with endoscopy compared to 8 of 20 (40%) of the control arm participants
(p < 0.05). For the open label trial with a 3-year follow-up period, 7% receiving the L. rhamnosus
strain GG immediately post-ileal pouch-anal anastomosis developed pouchitis as compared to
29% (p=0.011) of those with ileal pouch-anal anastomosis performed between 1989–1996 that
did not receive probiotic in the immediate post-operative period and served as historical controls.
Thus, both trials showed benefit regardless of whether a single strain or a blend probiotic was
administered.
Crohn’s Disease
Maintenance Therapy
Initial trials (See Table 27.4) in Crohn’s disease were done in diverse clinical protocols including
being used as sole maintenance therapy following corticosteroid therapy to treat active disease
[39], in combination with lower does of 5-aminosalicylate therapy compared to controls for
356 David R. Mack
maintenance therapy in those already in remission [40], or as additional therapy in those that had
not reached remission despite other therapies [41]. There were suggestions that benefit could be
obtained with these approaches [39, 41] and greater benefit with the combination therapy [40].
Subsequent trials have focused on L. rhamnosus strain GG for maintenance therapy following
induction of remission with corticosteroids [42] and maintenance of remission with probiotic
used as additional maintenance therapy. In contrast to the earlier studies, neither a statistical
benefit nor even a trend to benefit was recognized in these more recent trials. In the largest
maintenance trial to date and one of the very few trials in children and adolescents, Bousvaros
et al. [43] reported no difference in the proportion of those developing relapse on L. rhamnosus
strain GG 2 × 1010 CFU/day (31%; 12 of 39) or placebo (17%; 6 of 36, p=0.18). The time
to relapse is shown in Figure 27.1, and although the placebo arm had a longer time to relapse,
comparison between it and the intervention group taking the probiotic was not statistically different
(p=0.10).
Figure 27.1. Kaplan-Meier Survival Curves showing probability of staying relapse free during the study
treatment duration for participants administered Lactobacillus rhamnosus GG or placebo.
Source: (Figure reproduced from Inflamm Bowel Dis 2005;11:833–839 with permission from Dr. A Bousvaros and
Lippincott, Williams & Wilkins).
Associated Conditions
Arthralgia
In an open label trial with a drop-out rate of 45%, 16 patients with either Crohn’s disease or
ulcerative colitis completed a 3-month trial of ingesting 9 × 1011 CFU/day of a blend probiotic
(VSL# 3™) to assess whether there was a clinical improvement in arthralgia [48]. Patients had
quiescent IBD and no clinical or laboratory evidence of arthritis, were not taking non-steroidal anti-
inflammatory medications and other medications were unchanged. An improvement in peripheral
but not axial arthralgia was reported using an articular index score but no improvement was
reported using a patient-completed visual analog scoring system used for subjective joint pain.
Summary
Our current knowledge regarding the use of probiotics is limited with small studies, control drug
dosing issues and delineating effects of probiotics from combination probiotic and prescription
medication studies as outlined in this chapter and by others [49, 50]. That being said, specific
probiotic products might have more potential for modest effect in maintenance of remission of
ulcerative colitis especially for those unable to use 5-aminsalicylate products. Whether there is
efficacy in active mild to moderate disease remains to be determined. Clinical practice for use in
chronic relapsing pouchitis demonstrates that far fewer patients benefit from probiotics than some
of the early small trials and there is a lack of evidence for their use as sole treatment in active
pouchitis. There is little persuasive evidence that patients with Crohn’s disease should ingest
probiotics. A deleterious effect in those taking specific strains for maintenance or prevention of
358 David R. Mack
post-operative recurrence has not been statistically demonstrated but it seems a prudent course
at the present time to discourage their use until there are further studies to ensure no trends are
developing that may not be uncovered, except in large trials or meta-analysis of smaller trials.
As well, at this point in time understanding what sub-groups of patients (i.e. specific genotype,
specific phenotype, specific age group) do demonstrate benefit require study before advocacy of
probiotics in Crohn’s disease.
It is important to not generalize reports of positive benefit from specific strain studies to either
Genus or Species effects and it is equally as important not to generalize negative reports of a
specific strain to a Genus or Species effect. Clearly there is a need for knowledge with regards to
dosing, duration of therapy, delivery methods and whether blends of different strains of probiotics
offer any benefit over single strains. As well, without significant regulatory controls quality
control, viability and the potential for differences of microbe phenotype expression between
studied probiotic products and commercially available products has led to debatable results [51, 52]
and ones that make it difficult for health care providers and consumers to discern.
Given the current situation of parental and self-prescribing of alternative care products including
those described as probiotics for IBD, it behooves those providing care for IBD patients to
know exactly all prescription and non-prescription items being administered to the children and
adolescents with IBD so when problems in care are occurring comprehensive strategization of care
can be co-coordinated. There are a number of clinical situations in which this could potentially
be important. Among the most serious clinical scenarios to consider is that in which a patient
is initiating immunosuppressive therapy. While most patients undergo the initiation of immune
altering medications without incident, immunosuppression is a possibility. There is no evidence
for the efficacy of probiotics in any form of severe IBD and in general, there is little clinical
experience in the use of probiotics administration to severely immunocompromised IBD patients.
However, in ill patients in ICU settings fungemia has developed from the use of S. boulardii as
probiotic [53] and sepsis from a Lactobacillus strain has also been reported in an ulcerative colitis
patient [54]. Another reason it would be good to know if patients are ingesting probiotics is related
to the reported link to gastrointestinal side effects following ingestion of heat-killed probiotics. In
a clinical trial evaluating the benefits of heat-killed, non-viable L. rhamnosus GG with live, viable
L. rhamnosus GG for atopic dermatitis, increased gastrointestinal side effects in those administered
the non-viable microbes lead to premature termination of the study [55]. Viability is affected by
a number of issues that include practices of retailers (i.e. shelf time, product storage), distributors
(warehouse storage, distribution) and manufacturers [56]. Poor practices at any level will lead to
loss of viable microorganisms in a probiotic product with potential for problems associated with
ingestion of non-viable probiotics as reported by Kirjavainen et al. [55] the symptoms of which
may be mistaken for active IBD. Ingestion of S. boulardii has also been linked to worsening of
diarrhea in two patients with ulcerative colitis [57]. Although the commercialization of probiotics
is ahead of scientific and clinical investigation, as practitioners we should demand that the various
aspects of IBD care are critically appraised before encouraging patients to ingest undocumented
probiotic products as therapy in IBD.
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