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620
REVIEW
What is the origin of ulcerative colitis? Still more questions
than answers
Milan Lukas, Martin Bortlik, Zdenek Maratka
...............................................................................................................................
Postgrad Med J 2006;82:620–625. doi: 10.1136/pmj.2006.047035
Despite more than a century of existence as a clinical entity, AETIOLOGY
Although ulcerative colitis has been known as a
the true origin of ulcerative colitis still remains elusive. clinical entity since 1859, the aetiological mys-
Several factors probably contribute to the development of tery has not yet been completely revealed.3
this condition. Recently discovered technologies have However, the incorporation of new molecular
biology techniques has yielded considerable
clarified the role of bacterial species, which may account progress in the understanding of the aetiology
for intestinal dysbiosis, as a factor triggering ulcerative of ulcerative colitis.4
colitis. Genetic susceptibility together with abnormal innate
immunoreactivity probably comprise the essential What is the role of the intestine’s bacterial
contents in ulcerative colitis?
prerequisites for the initiation and perpetuation of Some of the similarities between ulcerative
ulcerative colitis. Although the genetic background has colitis and infectious colitides have led many
been more clearly recognised in patients with Crohn’s investigators to search for the unidentified
microorganism triggering the chronic inflamma-
disease than in those with ulcerative colitis, some candidate tion in the large bowel. However, until now, no
loci associated with ulcerative colitis have also been single microbial agent has been associated,
intensively studied. Additionally, environmental factors unequivocally, with the development of ulcera-
tive colitis. Many arguments exist against an
may interfere with inherent predispositions to ulcerative infectious aetiology of ulcerative colitis (box 1).5
colitis, and either suppress or reinforce them. Whatever the Over the past few years, we have gained
origin, the search for the aetiology of ulcerative colitis must considerable evidence that it is an abnormal
mucosal immune reactivity, against enteric
have the same goal: the improvement of treatment and the bacteria, that is the key event leading to
quality of life in patients with ulcerative colitis. intestinal injury in patients with IBD.
........................................................................... Molecular biology techniques have shown that
the intestinal space of an adult may contain
.500 different bacterial species; some of them
U
lcerative colitis, together with Crohn’s exert a protective role, whereas others are
disease, is part of the spectrum of inflam- aggressive. The number of bacterial strains along
matory bowel diseases (IBDs). It is a the small bowel progressively increases, with the
chronic inflammatory condition with unknown predominance of Gram-negative aerobes. The
aetiology and only a partially understood patho- bacterial population in the large bowel reaches a
genesis. Starting from the rectum, the disease density of around 1012 microbes per gram of
may affect the mucosa of the large bowel to luminal contents. More than 50% of the bacterial
varying lengths. A typical clinical course of strains cannot be cultured under conditions
ulcerative colitis consists of rectal bleeding and currently available. In adults, the faecal bacterial
diarrhoea; in severe cases, however, a systemic composition is host specific and stable over time,
inflammatory reaction also becomes apparent. with small fluctuations of the strains up to 20%
Moreover, at least 11% of patients with ulcerative (box 2).6
colitis have extraintestinal manifestations that The gut bacteria have an essential role in the
include joint involvement (enteropathic arthri- development of the gut immune system, as they
tis), hepatobiliary disease (primary sclerosing stimulate the lymphocytes to clonal expansion
See end of article for
authors’ affiliations cholangitis), and several types of eye and skin and also prevent lymphocyte apoptosis.7 Selective
....................... lesions.1 bacterial stimulation may occur, with Gram-
Worldwide, the incidence of ulcerative colitis positive bacteria preferentially stimulating inter-
Correspondence to:
M Lukas, Gastroenterology varies greatly from 0.5 to 24.5 per 100 000 leukin (IL)12 production, whereas Gram-nega-
Center, Fourth Medical inhabitants. Both the incidence and prevalence tive organisms induce IL4 production. Gram-
Department, General are related to the economic situation of a negative bacteria and lipopolysacharide are
Faculty Hospital, First country, with the lowest rates in developing
School of Medicine, responsible for inducing oral tolerance.8
Charles University, Karlovo countries and the highest found in North Although standard cultivation techniques are
namesti 32, Prague 2, America, as well as western and central Europe. capable of detecting up to 30% of total micro-
120 00, Czech Republic; At present, the incidence of ulcerative colitis flora, new techniques (including analysis of
lukas.milan@vfn.cz seems to be increasing in central and eastern
Received 22 February 2006 Europe, whereas it has been stable over the past Abbreviations: IBD, inflammatory bowel disease; MDR1,
Accepted 22 April 2006 20 years in western Europe and the multidrug resistance gene 1; NOD, nucleotide-binding
....................... Scandinavian region.2 oligomerisation domain; TLR, toll-like receptor
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Origin of ulcerative colitis 621
Box 1: Arguments against the infectious Box 2: Factors modifying the intestinal bacterial
aetiology of ulcerative colitis profile
N Lack of transmission of ulcerative colitis between N Western type of diet
patients N Use of antibiotics and chemotherapeutics
N High incidence of ulcerative colitis in countries with a N Modern infant nutrition
low incidence of intestinal infections Public health measures
Low levels of sanitation, and consumption of unpro-
N
N N High hygienic standards and sanitation
cessed food as protective factors
N Early and frequent antibiotic treatment in childhood
increases the risk for ulcerative colitis Role of epithelial cells
N Lack of sustained efficacy of antimicrobial agents in the Over the past two decades, many abnormalities have been
treatment of ulcerative colitis described in the epithelial cells of patients with ulcerative
N Inconsistent results of stool cultivation in patients with colitis (box 3). This, conceptually, is based on the anatomical
ulcerative colitis distribution of inflammation, which in the case of ulcerative
colitis is associated predominantly with the rectum. Why
such abnormalities are seen in patients with ulcerative colitis
still remains elusive. The question is whether luminal factors,
autoimmunity or a genetic basis is the major contributor to
bacterial 16S ribosomal RNA, polymerase chain reaction, in the aetiology of ulcerative colitis, or whether some combina-
situ hybridisation, flow cytometry and DNA microarray or tion of any or all of them accounts for the development of the
chip analysis) have markedly increased the detection rate. disease.19 20
The beneficial bacterial strains, such as bifidobacteria and The newer approaches are focused on the interactions
lactobacilli, are generally absent from mucosa-associated among epithelial cells and indigenous bacterial flora.21 22 The
bacterial flora in patients with active ulcerative colitis.9 On cells that comprise the intestinal epithelium have evolved
the other hand, an increased mucosal concentration of Gram- sophisticated mechanisms for the identification of pathogens
negative anaerobes, particularly Escherichia coli, Fusobacterium and counteractions against them, when necessary. These
varium and bacteroides, along with a high frequency of mechanisms include several recognition receptors with
Peptostreptococcus invasion, has been shown. Various authors various locations on and in the cells, including toll-like
have also shown severe bacterial invasions of the mucosa in receptor (TLR) and nucleotide-binding oligomerisation
most colonic specimens from patients with ulcerative colitis, domain (NOD) receptor. Bacterial ligands binding to host
contrary to that in healthy controls.10–13 cell receptors induce cellular signalling events, leading to the
The high bacterial mucosal invasion in patients with IBD production of various molecules, including cytokines, eico-
corresponds well with titres of immunoglobulin G to bacterial sanoids and antimicrobial peptides. It has been hypothesised
antigens. Some of these can now be used for distinguishing that disturbances in the recognition of molecular patterns on
between ulcerative colitis (eg, anti-Peptostreptococcus anaerobius pathogens or commensal microflora might induce chronic
antibody) and Crohn’s disease (eg, anti I2-from Pseudomonas and unrestricted inflammation. Members of the TLR family
fluorescens antibody or antibody to an outer membrane porin are variably expressed throughout the intestine and display
of E coli—anti-OmpC).13 14 Nevertheless, these differences in compartmentalisation. TLRs were found to play a key part in
bacterial mucosal concentrations between ulcerative colitis the defence against infections by Gram-positive bacteria and
and Crohn’s disease were not found by several investigators. fungi. To date, 10 mammalian TLRs have been identified,
The determination of our intestinal flora was previously responsible for recognising conserved bacterial structures.
proposed to be partially under genetic control. Changes in the TLR4,9 encoded by gene polymorphisms is suggested to be
faecal flora were also found among healthy relatives of responsible for the aetiology and pathogenesis of ulcerative
patients with IBD.15 However, the question of whether the colitis23 (fig 1).
dysbiosis in patients with ulcerative colitis is the cause or the Antimicrobial peptides are positively charged polypeptides,
consequence of the disease still lacks a satisfactory answer. ,100 amino acids in length, which are implicated in the
The role of intestinal bacteria in the aetiopathogenesis of microbial activity associated with phagocytes, inflammatory
ulcerative colitis can be summarised as follows: body fluids and epithelial secretions. Two of them, cathe-
licidins and defensins, exert antimicrobial effects and
N Microbial flora in patients with ulcerative colitis differs communicate with the host immune system, including
considerably from that in controls, in both composition neutrophil chemotaxis and recruitment of mastocytes.
and spatial distribution (mucosal invasion).6 7
N Some commensal bacterial strains exert an essential role
in mucosal homeostasis and the maturation of the Box 3: Abnormalities of epithelial cells in
intestinal immune system.16 ulcerative colitis
N Commensal bacterial strains are required to induce
chronic inflammation in genetically susceptible mice or N Deficient b oxidation
rats, and different bacterial species have a variable ability N Abnormal permeability of the cell membrane
to induce chronic intestinal inflammation in these N Abnormal mucus composition
animals.17 Abnormal cellular responses to stress
Evidence from intervention studies with probiotics (E coli
N
N strain Nissle 1917, VSL #3), helminths (Trichuris suis) or
N Inability to use butyrate—starving colonocytes
N Polymorphisms in the toll-like receptor gene
antibiotics (rifaximin) in patients with ulcerative colitis
supports therapeutic gains from manipulation of the N Deficiency of both defensins and cathelicidins
bacterial flora.18
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