Aliment Pharmacol Ther 2004; 20 (Suppl. 4): 18–23.
Review article: gut flora and inflammatory bowel disease
P. MA RTEAU *, P. LEPAGE , I. MA NGINà, A. SUA Uà, J. D ORÉ , P. POCHAR Tà & P. SEK SIK*
*Département d’Hépato-Gastroentérologie, Hôpital Européen Georges Pompidou, Paris, France; INRA, Jouy en Josas, Paris,
France; àLaboratoire de Biologie, Conservatoire National des Arts et Métiers, Paris, France
SUMMARY
The pathogenesis of inflammatory bowel disease involves
interactions between the host susceptibility, mucosal
immunity and intestinal microflora. There is therefore
great interest in the changes in the endogenous flora in
inflammatory bowel disease patients and in the estab-
lishment of potential genetic variations in host responses
to endogenous bacteria. In this review, we summarize the
modifications in the various regional ecosystems in the
gastrointestinal tract during inflammatory bowel disease
INTRODUCTION
The pathogenesis of inflammatory bowel disease
involves interactions between the host susceptibility
(which is partly genetically determined), mucosal
immunity and intestinal milieu. There is a body of
evidence implicating the resident flora in the mucosal
inflammatory response in susceptible individuals
(Table 1).1 The deleterious role of some microorganisms
present within the endogenous flora is well established
in animal models of inflammatory bowel disease.2, 3 In
these models, gut inflammation does not occur when
the animals are kept in Ôgerm-free conditionsÕ (i.e.
sterile).2 Harper et al. reported that the reintroduction of
small-bowel effluent into the colon of patients with
Crohn’s colitis, who had been treated by split ileostomy,
induced inflammation, whilst the reintroduction of a
Correspondence to: Prof. P. Marteau, Service de Gastro-entérologie, Hôpital
Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15,
France.
E-mail: philippe.marteau@egp.ap-hop-paris.fr
18
(luminal bacteria in faeces or inside the gastrointestinal
tract, bacteria in mucus and bacteria directly attached to
the mucosa). Results were obtained following a Ôcandi-
date microorganism strategyÕ and, as is occurring
increasingly frequently, following a Ôfull description
strategyÕ, which has progressed largely due to the
development of culture-independent techniques. The
possibility of modifying the ecosystem using prebiotics
or probiotics offers hope for new treatment developments,
particularly in the prevention of relapse.
sterile ultrafiltrate of small-bowel effluent had no effect.4
Not all bacteria have the same pro-inflammatory
properties, and some may even be protective.5–7 This
depends not only on their capacity to secrete toxins or
their cell wall composition (lipopolysaccharide, pepti-
doglycans), but also on their DNA (especially CpG
DNA).8 Several studies have recently suggested that
probiotic microorganisms, including strains of lactoba-
cilli, bifidobacteria and Saccharomyces, may favourably
influence the course of experimental colitis or even
inflammatory bowel disease in humans.5, 9
Two strategies have been used to search for a role for
microorganisms in inflammatory bowel disease: the
Ôcandidate microorganism strategyÕ and the Ôglobal
description strategyÕ. The Ôcandidate microorganismÕ
has, until now, been directed towards pathogens and
some Escherichia coli. Despite intensive research on the
genera Mycobacterium, Listeria and Mycoplasma, an
Ôinfectious originÕ of inflammatory bowel disease has
not been confirmed.10–13 In this review, we summar-
ize the compelling evidence which suggests that com-
mensal enteric bacteria provide a local environmental

2004 Blackwell Publishing Ltd

REVIEW: GUT FLORA AND INFLAMMATORY BOWEL DISEASE
Table 1. Arguments suggesting a role for the endogenous flora in
inflammatory bowel disease
Physiological effects of the endogenous flora on mucosal
structure, epithelial turnover, motility, immune development
and function
Immunological reactivity to flora in patients with inflammatory
bowel disease (loss of tolerance)
Attenuation of inflammation in animal models of inflammatory
bowel disease when germ-free2
Experimental transfer of colitis with T cells reactive to bacterial
antigens3
Lesions in inflammatory bowel disease occur in areas of highest
bacterial exposure (ileum and colon)
Clinical response to diversion of faecal stream; relapse
on restoration or exposure to faecal material in patients with
Crohn’s disease4
Influence of antibiotics and probiotics in experimental animals
and in pouchitis1, 5
trigger that initiates and perpetuates inflammatory
bowel disease.
REGIONAL ECOSYSTEMS IN THE
GASTROINTESTINAL TRACT AND METHODS OF
STUDY
Diversity in the gastrointestinal tract creates various
niche habitats in which organisms may specialize. The
major determinants are the pH, redox potential (and
oxygen), intestinal transit time, substrate availability
and adhesion sites for microorganisms. It is well
established that the endogenous flora differs between
the stomach, upper small bowel, lower small bowel,
right colon and the rectum. Each ecosystem is complex;
for example, the faecal flora of one subject contains
about 400 bacterial species. These microorganisms can
Figure 1. Faecal flora of patients with
colonic Crohn’s disease vs. healthy volun-
teers. The composition of the flora was
assessed using dot-blot hybridization with
six phylogenetic group probes. The addi-
tivity of the probes was 90% in the healthy
subjects but below 70% in patients with
Crohn’s disease. Reproduced from Seksik
et al. Gut 2003; 52: 237–42 with permis-
sion from the BMJ Publishing Group.

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 4), 18–23
13652036, 2004, s4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.02062.x by Cochrane Philippines, Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
19
be grouped on a genetic basis, and intestinal ecologists
often focus on the dominant flora, i.e. bacterial groups
which represent the majority of the microorganisms.
More than 80% of the bacteria which are present in the
faeces of healthy human adults belong to six dominant
bacterial phylogenetic groups (Figure 1).14 Each of
these groups includes many species. The luminal caecal
flora is significantly different: bacterial concentrations
are 100 times lower and facultative anaerobes (especi-
ally enterobacteria), which represent 1% of faecal
bacteria, represent 25% of caecal bacteria.15 The
composition of regional ecosystems within the gastro-
intestinal tract is often poorly known, owing to
sampling difficulties. The microorganisms present with-
in the mucus layer in the colon differ from those present
in the lumen and from those at the surface of the
intestinal cells.16–19
The intestinal ecologist faces three main obstacles:
sampling (i.e. having access to each of the ecosystems),
typing the microorganisms and analysing significant
differences between microfloras, taking into account the
large physiological interindividual variation. Important
progress has recently been made20, 21 — modern
molecular techniques based on nucleic acid sequence
comparisons are powerful tools for the culture-inde-
pendent characterization of the microbial structure of
complex ecosystems. Several regions of rRNA molecules
and the corresponding genes can serve as probe target
sequences. Highly conserved regions allow the design of
domain probes (such as bacteria or Eukarya probe),
whilst regions with intermediate and high variability
are more appropriate for the design of genus-, species-
and strain-specific hybridization probes. The relative
proportions of the dominant groups of bacteria present
in a sample can be assessed by quantitative dot-blot

20 P. MARTEAU et al.
analysis, and biodiversity can be estimated using
temporal temperature gradient gel electrophoresis.21–23
Computer programs have been designed for the com-
parison of complex ecosystems; results are expressed
using coefficients of similarity.21 This has established
that the faecal flora is very stable over time in a healthy
adult,21, 24 and that the degree of similarity of the faecal
flora is higher between twins than between the
members of a couple or between unrelated individu-
als.24 Finally, it is now also possible to clone, and then
sequence, DNA fragments from a high proportion of the
bacteria present within an ecosystem in order to
establish its Ômolecular inventoryÕ.25
THE FLORA IN INFLAMMATORY BOWEL DISEASE
VS. CONTROLS
Faecal flora
To date, no specific microorganism has been directly
associated with the pathogenesis of inflammatory bowel
disease. However, several studies using different meth-
ods have repeatedly shown that the faecal microflora
differs between subjects with inflammatory bowel
disease and healthy controls.21, 26–34 Some studies
(but not all) using bacterial culture have suggested an
increase in the faecal concentration of Bacteroides
vulgatus in Crohn’s disease, and a decrease in faecal
lactobacilli or bifidobacteria.34 On the other hand, a
significant increase in enterobacteria has repeatedly
been observed using both culture-based and culture-
independent techniques in patients with active Crohn’s
disease.26, 28, 32 It has also been reported that patients
with Crohn’s disease have higher antibody titres against
E. coli than healthy controls.27 Dickinson et al. reported
the presence of E. coli with adhesive and invasive
properties in faecal samples of patients with ulcerative
colitis.29 We compared the faecal microflora between
patients with quiescent colonic Crohn’s disease, active
colonic Crohn’s disease and healthy volunteers using
quantitative dot-blot hybridization and temporal tem-
perature gradient gel electrophoresis.21 Enterobacteria
were indeed significantly increased in active and
quiescent Crohn’s disease. Furthermore, we observed
that more than 30% of the dominant microflora in
patients belonged to undefined phylogenetic groups
(Figure 1).21 The faecal flora in Crohn’s disease
appeared to be unstable as the temporal temperature
gradient gel electrophoresis profiles varied markedly in

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 4), 18–23
13652036, 2004, s4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.02062.x by Cochrane Philippines, Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
the same subject between active and quiescent Crohn’s
disease.21 In a further study, we applied the molecular
inventory method to identify dominant bacterial species
in four patients with Crohn’s disease.25 The two major
results were: (i) numerous clones belonged to species
unusual in dominance (Pectinatus, Sutterella, Fusobacte-
rium, Verrucomicrobium, Clostridium disporicum, C. gly-
colicum, C. ramosum, C. innocuum and C. perfringens);
and (ii) B. vulgatus was the only molecular species
(operational taxonamic unit) shared by all patients.25
B. vulgatus plays a key role in the initiation of
spontaneous colitis in human leucocyte antigen
(HLA)-B27 transgenic rats,35 and so it is a reasonable
assumption that this species may also have a special
role in the pathogenesis of Crohn’s disease.
Mucosal adherent flora
Several studies have repeatedly shown that the mucosa
contains a higher number of bacteria in patients with
inflammatory bowel disease when compared with
controls.16–18 This seems true both in the mucus layer
and at the epithelial surface where bacteria are
physiologically far less abundant. The bacterial com-
position of the mucus layer has been shown to be
constant along the colon in patients with Crohn’s
disease as well as in healthy subjects.36 Schultsz et al.
showed that inflammatory bowel disease rectal speci-
mens contained significantly more bacteria than con-
trol samples, and that these bacteria were localized
within the mucus layer, but did not adhere to the
epithelial cells and were not present within the lamina
propria.16 Kleessen et al. confirmed, using in situ
hybridization, that more bacteria were detected on
the mucosal surface of tissue sections from surgical
Table 2. Flora in inflammatory bowel disease: main conclusions
The subject is as difficult as genetics (interindividual variations)
but as promising
The flora plays a role in every model of inflammatory bowel
disease, including in humans
The flora(s) of patients with inflammatory bowel disease differs
from that of controls and is unstable
Some Escherichia coli and Bacteroides vulgatus may have a special
detrimental role
Potential for therapeutic progress (prevention of recurrence,
probiotics)
We are just at the beginning of the story, and there is a need for
more research
 13652036, 2004, s4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.02062.x by Cochrane Philippines, Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
REVIEW: GUT FLORA AND INFLAMMATORY BOWEL DISEASE 21

Table 3. Randomized controlled trials studying the effects of probiotics in humans with inflammatory bowel disease

Duration Relapses
Situation Probiotic Control n (months) probiotic ⁄ control Reference

Refractory pouchitis VSL #3 Placebo 40 9 15% ⁄ 100%* 41

Refractory pouchitis VSL #3 Placebo 36 12 15% ⁄ 94%* 42
Prophylaxis of pouchitis VSL #3 Placebo 40 12 10% ⁄ 40%* 43
Crohn’s disease postop VSL #3 5-ASA 28 12 20% ⁄ 40%* 44
Crohn’s disease S. boulardii + 5-ASA 5-ASA 28 6 6.3% ⁄ 37.5%* 45
Ulcerative colitis S. boulardii + 5-ASA 5-ASA 31 12 30% ⁄ 35% 46
Ulcerative colitis E. coli Nissle 1917 5-ASA 1.2 g ⁄ day 120 4 16% ⁄ 11.3% 47
Ulcerative colitis E. coli Nissle 1917 5-ASA 1.2 g ⁄ day 120 12 67% ⁄ 73% 48
Ulcerative colitis E. coli Nissle 1917 5-ASA 1.5 g ⁄ day 222 12 36.4% ⁄ 33% 49
Crohn’s disease E. coli Nissle 1917 Placebo 28 12 30% ⁄ 70%* 50
Crohn’s disease postop L. rhamnosus GG Placebo 45 12 60% ⁄ 35% 51
Ulcerative colitis Bifidobacterium Placebo 21 12 27% ⁄ 90%* 52

5-ASA, 5-aminosalicylic acid; postop, prevention of post-operative recurrence; VSL #3, a mixture of eight strains of lactobacillus, bifidobacterium
and streptococcus.
*P < 0.05.

resections of inflammatory bowel disease patients than
on those of non-inflammatory bowel disease controls.17
However, in their series, bacterial invasion of the
mucosa was evident in 83% of colonic specimens from
ulcerative colitis patients, in 56% of ileal and 25% of
colonic specimens from Crohn’s disease patients, but
was not detectable in the tissues of controls. Swidsinski
et al. also found a high concentration of mucosal
bacteria, which increased with the severity of inflam-
matory bowel disease.18 Patients with concentrations
of mucosal bacteria > 50 000 colony-forming units ⁄ lL
had characteristic inclusions of multiple polymorphic
bacteria within solitary enterocytes located next to the
lamina propria.
Darfeuille-Michaud, Neut and the inflammatory bowel
disease research team in Lille have reported that some
invasive E. coli strains with adhesion properties are
more likely to be associated with the ileal mucosa of
patients with Crohn’s disease than others.37–40 Further
studies have demonstrated that the early recurrence of
Crohn’s disease after ileocolonic resection is associated
with high counts of E. coli and Bacteroides in the
mucosal flora, often accompanied by Fusobacterium.39
CONCLUSIONS AND PERSPECTIVES
Our main conclusions concerning this rapidly progress-
ing field of research are summarized in Table 2. Several
studies using various methods have suggested that
E. coli and B. vulgatus may have a special detrimental
role. As they are normal members of the flora,
further research should be performed to establish the
mechanisms for their increase in inflammatory bowel
disease (either primary or secondary to a decrease or
instability in the usual dominant flora or to other
ecological modifications). Some microorganisms, such
as bifidobacteria and lactobacilli (or at least some
members of these bacterial groups), are considered by
some authors to be potentially protective against
inflammatory bowel disease.5, 9 At present, the strong-
est evidence relies on studies using probiotic strains in
animal models and in pouchitis (Table 3).41–52 More
clinical trials in this field should aim to search for a
clinical effect and to understand its ecological mecha-
nisms. Finally, we look forward to the possibility of
genetically manipulating probiotic strains, to secrete or
deliver bioactive compounds at target sites in the
gastrointestinal tract, opening up new and exciting
fields for research and new treatment developments.6, 53
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