Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Probiotics and prebiotics in Crohn's disease

therapies
Lev Lichtenstein, MD a, b, *, Irit Avni-Biron, MD a, b,
Ofer Ben-Bassat, MD a, b
a
Rabin Medical Center, Petah Tikva, Israel
b
Sackler Faculty of Medicine, University of Tel Aviv, Israel

a b s t r a c t
Keywords:
Probiotics Therapeutic manipulation of gut microbiota has proven valuable in
Prebiotics the management of ulcerative colitis and pouchitis. Despite some
Synbiotics similarities among the various inflammatory bowel conditions, the
Inflammatory bowel disease probiotics investigated thus far seem to confer little benefit in
Crohn's disease Crohn's disease. In this review, we aim to bring together the evi-
VSL#3
dence available on the clinical effect of probiotics and prebioltics in
Sacchromyces boullardi
Bifidobacterium
Crohn's disease patients, and to clarify the place of probiotic
Lactobacillus treatment in current Crohn's therapeutic regimens.
© 2016 Elsevier Ltd. All rights reserved.

Introduction

A variety of in vitro experiments and animal models show that probiotic strains could reshape gut
immune parameters [1e4]. Correlation of these findings with physiological events taking place within
the human body, however, is far from unequivocal [5]. Results from controlled clinical trials are not
always consistent with preclinical findings, especially in the immunologically diverse field of inflam-
matory bowel disease: for example, though probiotics have proven to be fairly advantageous in pou-
chitis and UC, those investigated thus far seem to confer little benefit in Crohn's disease.
In this review, we aim to clarify the evidence available on the clinical effect of probiotics and
prebiotics in current therapeutic regimens for Crohn's disease. In doing so, we take into consideration
different treatment endpoints (induction of remission vs. prevention of relapses), anatomical nuances

* Corresponding author. Gastroenterology Institute, Rabin Medical Center, Derech Jabotinsky 39 Petah Tikva 4941492, Israel.
E-mail address: levl@clalit.org.il (L. Lichtenstein).

http://dx.doi.org/10.1016/j.bpg.2016.02.002
1521-6918/© 2016 Elsevier Ltd. All rights reserved.
82 L. Lichtenstein et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88

(ileal vs. colonic disease), choice of specific microorganism(s), dosages, modes of administration, and
duration of therapy.

Induction of clinical remission

Four relatively small studies [6e9] examined the use of probiotics as an adjunct therapy to con-
ventional treatments, in the induction of clinical remission in Crohn's patients (Table 1).
In a pioneering study by Plein and Hotz in 1993 [6], 20 Crohn's patients treated conventionally, yet
with some residual diarrhea (bowel movements 5.0 ± 1.4 evacuations/day) and moderate complaints
(CDAI 193 ± 32), were also administered the yeast preparation Saccharomyces boulardii for two weeks.
A modest yet statistically significant reduction in the frequency of bowel movements (5.0 ± 1.4 vs.
4.1 ± 2.3 evacuations/day; p < 0.01) and in CDAI (193 ± 32 vs. 168 ± 59; p < 0.05) was reported in the
open-labeled, uncontrolled induction phase of the study.
In a small (4 patients) open-label uncontrolled pilot by Gupta et al. [10], a lactic acid-producing
Lactobacillus rhamnosus GG (previously known as L. acidophilus GG) administered for 6 months was
observed to ameliorate clinical activity in children with mildly to moderately active Crohn's disease.
These results were challenged by a subsequent study by Schultz et al. [7], where 11 adult patients with
active Crohn's disease were treated with a combination of corticosteroids (60 mg/day) and antibiotics,
and then randomized for addition of LGG or placebo to the treatment regimen. No difference in clinical
remission rates was observed during the 6 month-long treatment period.
Steed et al. [8] randomized 35 patients with active Crohn's disease to receive a synbiotic regimen
comprising Bifidobacterium longum, oligofructose and inulin, or placebo, for 6 months, in tandem with
stable doses of conventional medications. Almost half of the patients from both experimental and
control arms were lost to follow-up. Bearing in mind this limitation, significant clinical improvement in
the rest of the synbiotic group was reported, a finding supported by simultaneous improvement in
their histological scores, and reductions in serum levels of pro-inflammatory TNF-a.
In addition to those randomized controlled studies, Fujimori et al. [9] reported results from a small
open-label, uncontrolled trial involving 10 active and steroid-refractory Crohn's patients treated with
psyllium (plantago ovata), and a probiotic preparation consisting of Bifidobacterium breve, Bifido-
bacterium longum, and Lactobacillus casei. Over the 13 months of synbiotic therapy, 7 out of 10 patients
reported symptomatic improvement. However, only 2 of them were able to discontinue corticosteroid
treatment, and laboratory markers of inflammation did not improve.
Overall, there is no convincing evidence that probiotics e either alone, or in combination with
prebiotic preparations e display a significant ability to effectively augment conventional treatments in
inducing clinical remission in Crohn's patients [11e15].

Maintenance of medically induced remission

Nine studies examined the ability of various probiotic regimens to support the maintenance of
medically induced clinical remission in such patients [6,7,16e22] (Table 2).

Table 1
Use of probiotics to induce clinical remission in Crohn's patients.

Study No. of patients Duration Probiotic strain Control Outcome

(months)

Plein, 1993 [6] 17 ½ month S. boulardii Open-labeled; Modest symptomatic

uncontrolled improvement
Schultz et al., 11 6 LGG þ Corticosteroids Placebo þ Corticosteroids No benefit
2004 [7]
Steed et al., 35 (16 lost to 6 B. longum þ “Synergy 1” Placebo Symptomatic
2010 [8] follow- up) improvement
Fujimori et al., 10 13 B. longum, B. breve, L. Open-labeled; Symptomatic
2007 [9] casei þ Plantago ovata uncontrolled improvement
 L. Lichtenstein et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88 83

Table 2
Use of probiotics to maintain medically induced remission in Crohn's patients.

Study No. of Duration Probiotic Control Outcome

patients (months) strain

Plein, 1993 [6] 17 3 S. boulardii Placebo Improvement

Guslandi et al., 2000 [16] 35 6 Pentasa Prevented relapses
Bourreille et al., 2013 [17] 165 12 Placebo No benefit overall; favorable in non-
smokers?
Malchow et al., 1997 [18] 28 Colonic 12 E. coli Nissle Placebo No benefit
Willert et al., 2010 [19] 30 colonic 12 VSL#3 Placebo Deterioration (NS)
(Abstract)
Schultz et al., 2004 [7] 11 6 LGG Placebo No benefit
Zocco et al., 2003 [20] 35 12 Mesalamine No benefit
(Abstract)
Bousvaros et al., 2005 [21] 75 pediatric 42 Inulin Deterioration (NS)
Rutgeerts et al., [22] 63 6 “Synbiotic Placebo No benefit
(Abstract) 2000”

Three trials explored the effect of the probiotic yeast Saccharomyces boulardii on the maintenance of
medically induced remission [6,16,17]. Unlike all the other studies concerning maintenance of medi-
cally induced remission, the results of these trials were not uniformly negative.
In the aforementioned study by Plein and Hotz in 1993 [6], 17 patients e still with some residual
activity after the initial open-labeled induction phase (CDAI 168 ± 59) e were randomized to continue
receiving either S. boulardii or placebo for an additional 10 weeks. While the probiotic group continued
to experience a gradual reduction in the frequency of bowel movements (from 4.1 ± 2.3 to 3.3 ± 1.2
evacuations per day) and in CDAI scores (from 168 ± 59 to 107 ± 85), in the control group, both pa-
rameters eventually returned to their pre-treatment range.
In a trial by Guslandi et al. in 2000 [16], 32 patients in steroid-free remission were randomized to
receive 6 months of maintenance treatment with either Pentasa, or a combination of Pentasa and S.
boulardii. Clinical relapse was reported in 6.25% of patients maintained on the probioticemesalamine
combination, compared to a 37.5% relapse rate in patients maintained on mesalamine alone (p ¼ 0.04).
Lastly, and in the largest study undertaken so far, Bourreille et al. in 2013 [17] randomly assigned
165 patients brought into remission with steroids, to continue treatment with either S. boulardii or
placebo for 52 weeks. The probiotic regimen did not yield a meaningful effect in the entire study
population: 47.5% of patients treated with S. boulardii relapsed during the study period, compared to a
53.2% relapse rate in the placebo arm. However, a post hoc analysis indicated that S. boulardii may exert
some favorable preventive effect in non-smokers.
Two other studies concerned the effect of probiotics on predominantly colonic Crohn's disease
[18,19].
In 1997, Malchow et al. [18] reported data from 28 such Crohn's patients. All were enrolled in the
trial during the active phase of their disease, treated with prednisolone (60 mg/day) for induction of
remission, then randomized to receive maintenance therapy with either E. coli Nissle 1917, or a placebo.
The probiotic did not prove to be superior to placebo in maintaining remission in this 12-month-long,
randomized double blind trial.
In a 2010 study whose results were published as an abstract, Willert et al. [19] randomized 30
patients with predominantly colonic Crohn's disease in steroid-free remission to receive either VSL#3
or placebo for 12 months, both alongside the patient's standard maintenance therapy. VSL#3 was not
effective in maintaining remission in those patients, and was even associated with a greater percentage
of flares (8 of 14 patients who received VSL#3, vs. 1 of 9 who received placebo; p ¼ 0.04).
Three other studies explored the effectiveness of Lactobacillus rhamnosus GG in maintaining
medically induced remission [7,20,21].
In the aforementioned study by Schultz et al. in 2004 [7], patients brought into remission by cor-
ticosteroids, with or without LGG, continued to receive either LGG or placebo as maintenance therapy.
No difference in clinical remission rates was observed, after six months of the treatment.
84 L. Lichtenstein et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88

In another study, whose findings were published as an abstract in 2003, Zocco et al. [20] reported
outcomes in 35 patients with quiescent Crohn's disease, randomized to receive either LGG, mesal-
amine, or a combination of both. After 12 months of such treatment, the groups did not differ with
respect to clinical symptoms (CDAI) or endoscopic features.
In a multi-center trial whose results were summarized by Bousvaros et al. in 2005 [21], 75 children
with quiescent Crohn's disease were randomized to receive LGG plus inulin, or inulin alone, in addition
to their pre-enrollment maintenance regimen. Addition of LGG showed no preventive benefit, and may
even have led to some deterioration (a relapse rate of 31%, vs. 17% in those receiving inulin alone;
p ¼ 0.18). As a consequence, the study was prematurely stopped after 42 months.
In a study published as an abstract in 2004, Rutgeerts et al. [22] reported outcomes of 63 patients
with active Crohn's disease who received on-demand infusions with 5 mg/kg IV infliximab and were
randomized to treatment with a complex synbiotic preparation Synbiotic 2000 (comprised of Pedia-
coccus pentoseceus, Lactobacillus raffinolactis, Lactobacillus paracasei susp paracasei 19, Lactobacillus
plantarum, b-glucans, inulin, pectin, and resistant starch) or to placebo. The patients were followed
until clinical relapse occurred. By the end of this 6 months long trial, the intervention and the placebo
groups did not differ in terms of time to relapse or median interval between demanded infliximab
infusions.
Several attempts to combine and re-analyze the data collected in the aforementioned studies also
resulted in negative conclusions [13e15,23e25]. Overall, with the possible exception of Saccharomyces
boulardii in certain populations (e.g., non-smokers), long-term treatment by probiotic microorganisms
seems to yield no benefit in maintaining remission in patients with either colonic or ileo-colonic
luminal Crohn's disease.

Prevention of post-operative recurrence

Six studies aimed to determine the efficacy of probiotic strains in maintaining surgically induced
remission in Crohn's patients [26e31] (Table 3). The main strength of those studies lies in the fact that
most were uniformly designed, and included meticulous endoscopic assessment reported by means of
Rutgeerts scores.
In a single-blind study published by Campieri et al. as an abstract in 2000 [26], forty post-operative
patients were randomized to receive the complex probiotic preparation VSL#3 (following pre-
treatment with the non-absorbable wide-spectrum antibiotic rifaximin for 3 months), or mesal-
amine. Compared with placebo, the sequential antibiotic-probiotic therapy was associated with a
significantly lower incidence of severe endoscopic recurrence, both at 3 months (10% vs. 40%; p < 0.01)
and at 12 months (20% vs. 40%; p < 0.01).

Table 3
Use of probiotics to prevent post-operative recurrence in Crohn's patients.

Study No. of Duration Probiotic Control Outcome

patients (months) strain

Campieri et al., 40 12 Rifaximin Mesalamine Lower incidence of endoscopic recurrence

2000 [26] eVSL#3
(abstract)
Fedorak et al., 2015 120 12 VSL#3 Placebo No statistically significant benefit short-term
[27] (underpowered).
Lower incidence of severe endoscopic recurrence long-
term if started immediately post-surgery (NS)
Prantera et al., 2002 45 12 LGG Placebo Deterioration (NS)
[28]
Marteau et al., 2006 98 6 L. johnsonii Placebo No benefit
[29]
Van Gossum et al., 70 3 Placebo No benefit
2007 [30]
Chermesh et al., 30 24 “Synbiotic Placebo No benefit
2007 [31] 2000”
 L. Lichtenstein et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88 85

A recent Canadian multi-center randomized, placebo-controlled trial (Fedorak et al., 2015 [27])
involved large number of study participants (n ¼ 120) yet came underpowered due to the lower
than anticipated endoscopic recurrence rate. The results suggested that VSL#3 may exert some
modest protective effect in terms of severe early (day 90) endoscopic recurrence (9.3% vs. 17.5%),
however, the difference failed to reach statistical significance. In accordance with this observed
trend, mucosal pro-inflammatory cytokine expression was significantly lower in the VSL#3 group at
day 90 (p < 0.05). Interestingly, the results also suggested that VLS# may exert 12-months pro-
tective benefit in patients who started the treatment immediately after surgery, as compared to
those who commenced it after 3 months' treatment with placebo (10% vs. 26.7%, p ¼ 0.09).
Four other studies yielded less enthusiastic conclusions [28e31]:
In 2002, Prantera et al. [28] randomized 45 patients to receive either LGG or placebo for 12 months
following ileo-cecal resection. Clinical recurrence was reported in 16.6% of the LGG group, as compared
to 10.5% in the placebo group. In patients in clinical remission, endoscopic recurrence was noted in 60%
of patients in the LGG group, as compared to 35.3% of those receiving placebo (p ¼ 0.297). No signif-
icant differences in the severity of the lesions were observed.
Studies by Marteau of GETAID in 2006 [29] (98 patients; followed for 6 months) and by Van Gos-
sum's group in the Netherlands in 2007 [30] (70 patients; followed for 3 months) failed to show any
advantage to use of the probiotic Lactobacillus johnsonii, in terms of clinical or endoscopic recurrence.
An Israeli multi-center group led by Chermesh et al. [31] (30 patients; followed over 24 months)
came to a similar negative conclusion over an aforementioned synbiotic preparation Synbiotic
2000.
Several attempts to combine and re-analyze the data concerning the ability of probiotics to
prevent clinical or endoscopic post-operative recurrence of Crohn's disease were not convincing
[13,32e34].

Prebiotics in Crohn's disease

Prebiotics are functional fibers that may selectively stimulate the growth of beneficial gut micro-
biota, and are fermented to short chain fatty acids. Scant evidence exists regarding their use in Crohn's
disease.
In 2007, Hafer et al. [35] randomized 17 patients with active Crohn's disease to receive lactulose
(10 g daily) or placebo. No significant improvements in clinical activity index, endoscopic score, or
immunohistochemical parameters were observed during the 4 month-long study period; in fact, the
group given placebo responded better.
In a small, open-label trial by Lindsay et al., 2006 [36], 10 patients with active ileocolonic Crohn's
were administered 15 g of fructo-oligosaccharides (inulin) for 3 weeks, with some promising results.
Likewise, Joossens et al., 2011 [37] reported a modest yet statistically significant clinical improvement
in a small subgroup of patients (n ¼ 8) that entered this 4-week long microbiological outcome study
when having mildly to moderately active Crohn's disease. However, when the same prebiotic was
subjected to a well powered (n ¼ 103), placebo-controlled trial by Benjamin et al., 2011 [38], it was
proven to be of no clinical benefit.

Conclusions

A quick search of Pubmed for the MESH terms “probiotic” and “Crohn's disease” reveals 15 original
intervention trials published as full articles, a relative paucity of experimental studies compared to 9
meta-analyses of their data, and over 100 opinion-based reviews. This discrepancy underscores the
great enthusiasm and high expectations of clinicians for therapeutic manipulation of the gut micro-
biota, and an intestinal immune response by means of “beneficial microorganisms.” Unfortunately,
neither the experimental studies themselves, nor the meta-analyses of their findings, are thus far able
to live up to these expectations.
86 L. Lichtenstein et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88

 Probiotics investigated so far confer little benefit in inducing clinical remission in Crohn's patients.
 With the possible exception of Saccharomyces boulardii in certain populations (e.g., non-smokers),
long-term treatment by probiotic microorganisms shows no benefit in maintaining medically
achieved remission in patients with either colonic or ileo-colonic luminal Crohn's disease.
 Data thus far concerning the ability of probiotics to prevent post-operative clinical or endoscopic
recurrence of Crohn's disease are not convincing. However, the trends observed in some experi-
ments with VSL#3, and the observation that Saccharomyces boulardii could be more successful than
other probiotic agents in maintaining medically achieved remission, may serve as a rationale for
carrying out additional studies aimed at exploring the preventive effects of post-operative alter-
ation of the intestinal microflora.

Practice points

 No evidence presently exists that would support the use of probiotics to induce clinical
remission in Crohn's patients.
 With the possible exception of Saccharomyces boulardii in certain populations (e.g., non-
smokers), probiotics show no benefit in maintaining medically achieved remission in pa-
tients with either colonic or ileo-colonic luminal Crohn's disease.
 There is no clear evidence to support the use of probiotics to prevent post-operative recur-
rence of Crohn's disease; however, some related questions remain unanswered, and more
research is required in this field.

Research agenda

 Thus far, attempts to manipulate the gut microbiota in inflammatory bowel disease were
fairly empiric, and failed to explain the striking differences between their observed effects on
ulcerative colitis, pouchitis, and Crohn's disease. As we progress in our understanding of the
mechanisms by which the individual agents influence and reshape the gut immune system,
more precisely designed, mechanism-based experiments are expected in the future.
 Observations that in certain populations, Saccharomyces boulardii could be successful in
maintaining medically achieved remission may warrant additional experimental clarification.
 Trends suggesting that VSL#3 started within 30 days post-surgery may exert a preventive
effect on post-operative recurrence of Crohn's disease, call for additional studies along these
lines.

Conflict of interest statement

The authors declare no conflict of interest.

Authors' contributions

Lev Lichtenstein, Irit Avni-Biron and Ofer Ben Bassat conducted literature searches, and contributed
to the study design, data collection, data analysis, data interpretation, writing and revising the
 L. Lichtenstein et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 81e88 87

manuscript, and table creation. All authors had full access to all of the study data, reviewed it, and take
final responsibility for the decision to submit their findings for publication.

Funding

No specific funding supported this work.

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