Alimentary Pharmacology & Therapeutics

Meta-analysis: targeting the intestinal microbiota in prophylaxis

for post-operative Crohns disease
G. A. DOHERTY, G. C. BENNETT, A. S. CHEIFETZ & A. C. MOSS

Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical

Center and Harvard Medical School,
Boston, MA, USA
Correspondence to:
Dr A. C. Moss, Beth Israel Deaconess
Medical Center Harvard Medical
School, 330 Brookline Avenue,
Boston, MA 02215, USA.
E-mail: amoss@bidmc.harvard.edu

Publication data
Submitted 2 November 2009
First decision 10 December 2009
Resubmitted 30 December 2009
Accepted 30 December 2009
Epub Accepted Article 4 January 2010

SUMMARY
Background
Enteric bacteria play an important early role in the pathogenesis of
Crohns disease.
Aim
To perform a meta-analysis of trials testing antibiotics or probiotics for
prevention of post-operative recurrence of Crohns disease.
Methods
Review of all randomized controlled trials comparing antibiotics or probiotics with placebo in prevention of endoscopic or clinical recurrence
of Crohns disease after surgical resection. Fixed-effect meta-analysis
was performed with dichotomous data summarized using relative risk
with 95% confidence intervals, where appropriate.
Results
Seven studies were identified as suitable for inclusion (two comparing
antibiotics with placebo, five comparing probiotics with placebo). The
use of nitroimidazole antibiotics (metronidazole, ornidazole) reduced the
risk of clinical (RR 0.23; 95% CI 0.090.57, NNT = 4) and endoscopic
(RR 0.44; 95% CI 0.260.74, NNT = 4) recurrence relative to placebo.
However, these agents were associated with higher risk of adverse
events (RR 2.39, 95% CI 1.53.7) and patient withdrawal. Probiotic
administration was not associated with any significant difference in risk
of recurrence compared with placebo.
Conclusions
Nitroimidazole antibiotics are effective in the prevention of post-operative Crohns disease recurrence, but their side-effects limit acceptability.
Probiotics have failed to show efficacy for post-operative prophylaxis,
but may merit further study.
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doi:10.1111/j.1365-2036.2010.04231.x

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INTRODUCTION
Crohns disease (CD) is a disorder characterized by
chronic intestinal inflammation leading to resection in
many patients with rates of surgery as high as 70% at
10 years reported in some series.1 Following surgical
resection, endoscopic evidence of CD recurrence can
be seen at the anastamosis in a majority of patients
within a year.2 The severity of endoscopic recurrence
is predictive of subsequent clinical recurrence3, 4 and
without further treatment, a quarter or more of CD
patients will require a further surgical resection within
5 years.5 There is no current consensus on the optimal
approach for the prevention of recurrent Crohns disease following surgery.6
Endoscopic recurrence of mucosal inflammation can
develop after only a few days and is dependent on the
return of faecal stream and re-establishment of faecal
flora.7 Following ileocolectomy, the neoterminal ileum
shows increased bacterial colonization and the predominance of certain bacterial strains such as Escherichia
coli, bacteroides and fusobacteria is associated with
early recurrence of Crohns disease.8 Conversely, probiotic species appear to improve intestinal barrier function9 and the absence of certain anti-inflammatory
commensal strains has also been associated with
increased risk of disease recurrence.10 It is not surprising therefore that there has been interest in the role of
both antibiotics and probiotic supplements to alter the
intestinal flora with the goal of limiting mucosal
inflammation. The published trials of manipulation of
enteric flora by antibiotics or probiotics have, to date,
produced mixed results, leaving no consensus to guide
clinical practice in this area. To provide clarity on this
topic, we performed a systematic review of randomized
controlled trials of the use of antibiotics or probiotics
for prevention of post-operative recurrence of CD.

METHODS
This paper is based on a Cochrane Review published
in The Cochrane Library 2009, Issue 4 (see www.
thecochranelibrary.com for information).11 Cochrane
Reviews are regularly updated as new evidence
emerges and in response to feedback, and The
Cochrane Library should be consulted for the most
recent version of the review.
A systematic analysis of the published literature
relating to the prevention of post-operative recurrence
of Crohns disease was undertaken as part of a broader
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review of strategies for prevention of post-operative

recurrence for the Cochrane Collaboration.11

Search methods
A search was performed to identify randomized
controlled trials comparing the effect of antibiotics or
probiotics with placebo, when used to prevent either
clinical or endoscopic post-operative recurrence of
Crohns disease. Articles published in any language
were considered for inclusion. The following electronic
databases were searched: The Cochrane Central Register
of Controlled Trials CENTRAL on The Cochrane
Library (2008) MEDLINE (1966 to February 2009) and
EMBASE (1980 to February 2009). The following search
strategy was constructed by using a combination of
MeSH subject headings and text-words relating to the
use of medical therapy for the prevention of recurrence
of Crohns disease; Crohns disease, recurrence, postoperative, surgery, prevention, antibiotic, probiotic.
Reference lists from trials selected by electronic searching were hand-searched to identify further relevant trials. Published abstracts from conference proceedings
from Digestive Disease Week (published in Gastroenterology) for the last 5 years were hand-searched.

Selection criteria
Two authors independently scanned the abstract of
each trial identified by the search to determine eligibility. Blinding to source was not performed. Full articles were selected for further assessment if the abstract
suggested that the study included patients with postoperative Crohns disease and compared prophylactic
treatment with an antibiotic or probiotic with placebo.
If these criteria were unclear from the abstract, the full
article was retrieved for clarification. Papers not meeting the inclusion criteria were excluded. Any disagreement was resolved by discussion, and if required, by
consultation with the senior author (AM). Two authors
then extracted data and independently assessed methodological quality; an assessment was made of the
method of allocation generation, allocation concealment, blinding, incomplete outcome data and selective
outcome reporting in each trial in accordance with the
Cochrane risk of bias tool.12 A risk of bias assessment
was performed for all included studies based on the
Cochrane risk bias tool12 and Jadad quality scores.13
Disagreements were resolved by discussion, and if
required, by consultation with the senior author (AM).

3
Unclear

3
Unclear

5
Low

5
Low

5
Low

2
Unclear

Risk of bias
assessment

The primary outcome measure was clinical recurrence.

Secondary outcome measures assessed were any
endoscopic recurrence, severe endoscopic recurrence
(generally defined as a Rutgeerts score of i3 4), patient
withdrawal and rates of serious adverse events (as
defined in each individual study).

Unclear

Jadad quality
score

Outcomes

804 G . A . D O H E R T Y et al.

12 months
n = 80

3 months

3 months
n = 70

n = 60

52 weeks
n = 45

Clinical and endoscopic recurrence at

6 months
Clinical and endoscopic recurrence at
52 weeks
Clinical, endoscopic and histological
recurrence at 3 months
Clinical, endoscopic and histological
recurrence at 3 years
Clinical, endoscopic and histological
recurrence at 3 and 12 months
6 months
n = 98

2002

2007

1995

2005

Van Gossum

Rutgeerts

Rutgeerts

2006
Marteau

Prantera

2008
Madsen

VSL#3 (900 billion bacteria) or

placebo twice daily
Lactobacillus johnsonii (LA1)
2 109 cfu twice daily or placebo
Lactobacillus GG, 12 billion cfu day
or placebo
Lactobacillus johnsonii (LA1)
1010cfu day or placebo
Metronidazole 20 mg kg day or
placebo
Ornidazole 1 g day or placebo

n = 120

3 months

Cumulative clinical and endoscopic

recurrence to 24 months
Endoscopic recurrence at 3 months
24 months
n = 30
Synbiotic 2000 daily or placebo

Follow-up
Number
Intervention

2007

Five studies were identified as suitable for incorporation into a meta-analysis of the effect of probiotics.
None of the studies had individually demonstrated
a benefit to probiotic therapy; therefore, despite

Chermesh

Probiotics vs. placebo

Years

Using the search criteria as outlined, 69 studies were

identified for potential inclusion. Of these studies, 62
were excluded because they were not randomized controlled trials, evaluated treatment rather than prevention of post-operative recurrence or were duplicate
reports of results of the same study from different
sources. Seven randomized controlled trials fulfilled
all inclusion criteria for the systematic review. These
are summarized in Table 1 which incorporates a risk
of bias assessment for each of the included studies.

Author

RESULTS

Table 1. Summary of studies suitable for inclusion in meta-analysis

Data were analysed using Review Manager (RevMan

4.2.10) software. Meta-analysis was performed if at
least two studies evaluating the same agent were suitable for combination. All data were analysed on an
intention-to-treat basis. Heterogeneity was assessed
using the chi-square test with a value of P < 0.10 considered statistically significant. Publication bias was
assessed by visual inspection of funnel plots for comparisons with four or more studies (sample shown as
Figure S1). Data were pooled for meta-analysis if the
outcomes were sufficiently similar and a fixed effects
model employed if there was no significant statistical
heterogeneity, otherwise a random effects model was
applied (Der Simonian-Laird method).14 Dichotomous
data were then summarized using the relative risk and
95% confidence intervals and the number needed to
treat was calculated, where informative. Sensitivity
analyses were performed for each comparison to test
the strength of observed differences.

Outcomes

Statistical analysis

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Figure 1. Forest plots of fixed effects comparison of probiotics vs. placebo for clinical recurrence (a), any endoscopic
recurrence (b), severe endoscopic recurrence (i3 or i4) (c). For each comparison, the results of tests for heterogeneity (Mantel
Haenszel with Chi-squared statistic with associated P value) are shown in addition to Z statistic and associated P value for
the strength of the observed effect.

significant heterogeneity in the probiotic species

used, it seemed justified to combine the results in a
single meta-analysis to evaluate if a more significant
effect was obvious when the effects were pooled.
Two studies evaluated the efficacy of Lactobacillus
johnsonii (LA1).15, 16 A single study examined the
effect of Lactobacillus rhamnosus strain GG (LGG).17
Two additional studies evaluated the use of probiotic
cocktails containing several bacterial strains. Synbiotic 2000 is a cocktail of four probiotics and four
prebiotics studied by Chermesh et al.18 The final
study looking at VSL#3, a cocktail of four strains of
lactobacilli, three strains of bifidobacteria and streptococcus thermophilus was only reported in abstract
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form and has not been published as a full manuscript.19 None of the individual studies reported a
significant effect of probiotic use on clinical or
endoscopic recurrence. Meta-analysis of the effects of
probiotics as a class also suggested that their effect
was no different from that of placebo. The relative
risk of clinical recurrence with any probiotic relative
to placebo (n = 213) was 1.41 (95% CI 0.593.36;
Figure 1a) and the relative risks of any endoscopic
recurrence (n = 333) and severe endoscopic recurrence (n = 213) were 0.98 (95% CI 0.741.29, Figure 1b) and 0.96 (95% CI 0.581.58, Figure 1c)
respectively. The risk of withdrawal and serious
adverse events were similar to those of placebo.

806 G . A . D O H E R T Y et al.

Figure 2. Forest plots of fixed effects comparison of nitroimidazoles with placebo for clinical recurrence (a), severe endoscopic recurrence (b) and patient withdrawal (c). For each comparison, the results of tests for heterogeneity (Mantel Haenszel with Chi-squared statistic with associated P value) are shown in addition to Z statistic and associated P value for the
strength of the observed effect.

Sensitivity analysis performed by comparing interventions (single vs. multiple strains), analysis methods (fixed vs. random effects, odds ratio vs. relative
risk) and study risk of bias (high vs. low) did not
impact the results of the meta-analysis.

Antibiotics vs. placebo

Two studies evaluated the efficacy of nitroimidazole
antibiotics for prevention of post-operative recurrence. The initial trial randomized 60 patients to
receive metronidazole 20 mg kg or placebo for
3 months with 3 years of follow-up.20 For reasons of
high rates of side-effects in the metronidazole treatment arm, an alternative nitroimidazole was
employed in a subsequent study, which randomized
80 patients to receive ornidazole (1 g day) or placebo

for 12 months.21 While recognizing differences in

duration of treatment and outcomes, some comparisons were possible. The risk of clinical recurrence at
1 year was significantly reduced in the nitroimidazole
treatment groups relative to placebo (RR 0.23, 95%
CI 0.090.57, Figure 2a). The number needed to treat
was four (NTT = 4). Relative risk of severe endoscopic
recurrence (Rutgeerts score i3 or i4 in the metronidazole study, defined as i2 or greater in the ornidazole
study) at 3 months was also significantly reduced in
the treatment groups relative to placebo (RR 0.44,
95% CI 0.260.74; n = 140; Figure 2b). Sensitivity
analysis performed by comparing interventions (metronidazole vs. ornidazole), analysis methods (fixed vs.
random effects, odds ratio vs. relative risk) and study
risk of bias (high vs. low) suggested that the relative
risk of clinical recurrence was no longer statistically
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significant if only metronidazole was used (RR 0.3,

95% CI 0.11.2). Patient withdrawal (RR 3.00; 95%
CI 1.376.58) and significant adverse events (RR
2.39; 95% CI 1.543.70) were both significantly
increased with nitroimidazole therapy relative to placebo. The principal adverse events in both trials were
metallic taste, gastro-intestinal intolerance and paresthesia neuropathy.

DISCUSSION
The majority of patients with Crohns disease require
surgical resection at some point in the course of
their illness.22 Recurrent inflammation at the anastomosis can occur within days and by 1 year, up to
20% of patients have clinical signs of recurrence.2, 3
While a range of disease phenotypes associated with
increased risk of early post-operative recurrence have
been identified,5, 2326 there is often significant
uncertainty in any individual case about how best to
approach post-surgical prophylaxis.27 5-aminosalicylates are safe and well tolerated, but have limited
efficacy with NNT of 12 to prevent a single clinical
recurrence at one year with mesalazine (mesalamine).28
While immunomodulators and infliximab can reduce
the risk of post-operative recurrence,29, 30 both agents
have significant toxicity which may be difficult to
justify in the prevention of active disease in all
situations. The decision on how best to proceed
requires a careful risk-benefit analysis for the
individual patient.
The intestinal microflora is increasingly recognized
as playing a key role in conditioning of mucosal
immune responses in the gastro-intestinal tract31 and
may play an important role in shaping the aberrant
responses observed in IBD. The predominance of certain bacterial strains appears important in the recurrence of mucosal inflammation following surgical
resection for Crohns disease.8, 10 This systematic
review of the use of either antibiotics or probiotics to
alter the intestinal flora and limit CD recurrence
offers confirmation that antibiotic therapy aimed at
altering the intestinal microflora is a valid approach.
There is evidence that post-operative administration
of nitroimidazole antibiotics has a significant effect
on the early rate of endoscopic and clinical recurrence. The tolerability and toxicity of these agents
appear, however, to limit their continuous use to
short-term administration. Whether a similar effect
could be achieved with use of pulsed or alternating
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antibiotic therapy employed over a longer timeframe

is an issue that has not been explored. In addition,
the combination of early antibiotic use with longterm immunomodulator use has early evidence of
efficacy.32 Overall, use of antibiotics remains an
attractive and biologically reasonable strategy, but
has been limited by the side-effects of the nitromidazole class. Recent promising data on the activity of
the non-absorbable antibiotic rifaximin (which is
generally well tolerated) in CD suggest that assessment of this agent in reducing post-operative recurrence is warranted.33
This review also demonstrates that studies to date
have failed to identify any benefit to the administration of probiotic supplements in the prevention of
post-operative CD recurrence. While recognizing
potential concerns about the validity of combining
the results of studies which evaluate the use of distinct single or combination probiotic strains, there is
remarkable homogeneity in the absence of any beneficial effect. The findings are indeed disappointing
given that certain probiotic preparations (notably
VSL#3) have anti-inflammatory effects in prevention
of pouchitis34 and with recent data showing efficacy
for VSL#3 in active UC.35, 36 Continued efforts may
well therefore be justified in studying probiotics in
this situation as timing of therapy, dosing and species may all be important variables. Studies in pouchitis have shown that once probiotic agents are
stopped, the beneficial mix of bacteria can no longer
be cultured in stool samples. It is therefore possible
that combination strategies, with early post-operative
use of antibiotics to prevent pathogenic re-colonization followed by maintenance use of probiotics to
establish a durable anti-inflammatory post-operative
microflora, may be what ultimately yield the greatest
benefit with the least long-term risk of toxicity to CD
patients.

ACKNOWLEDGEMENTS
Declaration of personal interests: None. Declaration of
funding interests: Funding for the Cochrane IBD FBD
Review Group (October 1, 2005September 30, 2010)
has been provided by the Canadian Institutes of
Health Research (CIHR) Knowledge Translation
Branch; the Canadian Agency for Drugs and Technologies in Health (CADTH); and the CIHR Institutes of
Health Services and Policy Research; Musculoskeletal
Health and Arthritis; Gender and Health; Human

808 G . A . D O H E R T Y et al.

Development, Child and Youth Health; Nutrition,

Metabolism and Diabetes; and Infection and Immunity. Miss Ila Stewart has provided support for the
IBD FBD Review Group through the Olive Stewart
Fund.

SUPPORTING INFORMATION
Additional Supporting Information may be found in
the online version of this article:

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