Innate immune responses to commensal bacteria in inflammatory bowel disease

Crohn's disease and ulcerative colitis are the two major forms of IBD characterized by acute and chronic inflammation in the absence of a known pathogen. These inflammatory disorders are distinguished by the depth and location of inflammation with ulcerative colitis being limited to the mucosa of the colon and Crohn's disease involving both the small intestine and the colon in a transmural fashion. The patho-genesis of Crohn's disease and ulcerative colitis is multifactorial, resulting from the interplay of genetic predisposition, environmental and immunological factors [21]. Initiation and perpetuation of the intestinal inflammation in this chronic disorder has been thought to result from dysregulated immune response to commensal bacteria in the genetically-susceptible host. For instance, the efficacy of fecal diversion and the recurrence when the fecal stream is restored [22, 23], the existence of subpopulations who can be improved by antibiotics or probiotic treatment [24], and the loss of tolerance observed with commensal bacteria [25, 26] all imply that enteric bacteria have a critical role in the intestinal inflammation in patients with IBD. These clinical observations have been supported by the evidence that commensal bacteria are indispensable for the development of inflammation in most murine models of inflammatory bowel disease [27].

Recent clinical and laboratory investigations appeared to show the answer for why and how IBD patients have dysregulated immune responses to commensal bac teria. Firstly, the disease-susceptibility gene identified in Crohn's disease named NOD2/CARD15 encodes a protein with a leucine-rich repeat domain that has pattern recognition receptor (PRR) function. Thus the genetic predisposition in Crohn's disease is at least partly due to an abnormality of host recognition system for commensal bacteria. Secondly, the intestinal mucosa in patients with IBD may be defective in clearance of luminal bacteria. IBD patients have been found to have a dramatic increase in the number of bacteria adherent to the intestinal mucosa, even in mucosa that is not inflamed [28]. Increased intestinal permeability has been found in patients with Crohn's disease as well as in symptom-free first-degree relatives [29]. These observations suggest that there exists defective barrier function even before the onset of a dysregulated immune response in patients with IBD.

Much work has been done to identify specific bacteria or bacterial components which can serve as a dominant antigen for the aberrant host response seen in IBD. A unique bacterial DNA sequence, termed I2, has been identified in lamina propria mononuclear cells in patients with Crohn's disease [30]. This bacterial sequence derived from Pseudomonas fluorescens can act as a super-antigen in CD4+ T-cell activation [31]. In addition, aberrant T cell responses to the host flora and expression of antimicrobial antibodies have been found in patients with IBD [32-34]. Serologic markers consisting of antibodies against microbial substances such as yeast (anti-Saccharomyces cerevisae), E. coli (anti-OmpC) and anti-flagellin [26, 35] are expressed by patients with IBD, especially Crohn's disease. These unique sero-logical markers associated with abnormal responses to commensal bacteria have begun to contribute to the clinical management of IBD patients.

The next issue to address is whether inappropriate recognition of PAMPs by TLRs plays a role in IBD pathogenesis. Part of the way in which TLRs may be involved in control of local bacterial populations in the gut is through the expression of defensins. Defensins are antimicrobial peptides that may be expressed by Paneth cells (cryptdins) or intestinal epithelial cells. Paneth cells located at the base of small intestinal crypts also express a wide range of TLRs [36]. Stimulation through TLR9 causes degranulation of Paneth cells [37]. We have recently demonstrated that TLR4- and TLR2-dependent pathways can stimulate P-defensin-2 expression by human intestinal epithelial cells [38]. In Nod2-/- mice, cryptdin expression by Paneth cells is decreased suggesting a role for PRRs in Paneth cell function [39]. Therefore, secretion of various antimicrobial peptides by Paneth cells and intestinal epithelial cells can be regulated by TLR-mediated recognition of PAMPs. Defects in the ability to sense microbes through TLRs or nucleotide oligomerization domains (Nods) may result in decreased ability to clear bacteria from the apical surface of the epithelium.

The expression and functional characteristics of TLRs in the IBD mucosa are still under investigation (Fig. 1). Human intestinal epithelial cells normally express TLR3 and TLR5, while TLR2 and TLR4 are only barely detectable [3-5, 40]. However, immunohistochemical examination has revealed that TLR4 is strongly up reg-

Endoscopic views

Clinical presentations

Characteristics in TLR expression

Normal intestine with flat flat and smooth surface, showing fine vascular pattern.



May affect entire digestive tract especially in the terminal ileum.

Crohn's disease (terminal ileum)

Normal intestine with flat flat and smooth surface, showing fine vascular pattern.

Limited repertoire of TLR expression. TLR 2 and TLR 4 have low expression. TLR signaling is normally down-regulated.

Polarized (basolateral) TLR expression.

May affect entire digestive tract especially in the terminal ileum.

Discrete and transmural inflammation; linear ulcer formation. TLR4 is upregulated in IEC. Expression of TLR2 and TLR4 is increased in lamina propria macrophages.

Ulcerative colitis

Rectum involved and may extend to proximal colon; does not affect small intestine. Continuously inflamed mucosa; no involvement beneath submucosa.

TLR4 is upregulated in IEC. TLR3 is downregulated in IEC. Expression of TLR2 and TLR4 is increased in lamina propria macrophages.

Ulcerative colitis

Figure 1

Differences in clinical presentation and characteristics of mucosal TLR expression in normal and IBD intestine

Mucosal bacterial recognition plays a critical role in the pathogenesis of both ulcerative colitis and Crohn's disease. Differences in clinical presentations between these two major forms of IBD may result from alterations in TLR signaling. Characteristic abnormalities of TLR signaling associated with clinical subtypes of IBD are illustrated.

ulated in both Crohn's disease and ulcerative colitis, while the expression of TLR2 and TLR5 remains unchanged [40]. Distribution of TLR4 in the intestinal epithelial cells is different between Crohn's disease and ulcerative colitis. The overexpression in Crohn's disease is in the apical aspect of the cells, whereas in ulcerative colitis it is in the basolateral aspect [40]. Most of these data are based on immunohisto-chemical characterization but the antibodies against TLRs have not been optimal. The expression of TLR3 in the intestinal epithelial cells is down-regulated in active Crohn's disease, but not in ulcerative colitis [40]. In addition, expression of TLR4 and TLR2 is increased in lamina propria macrophages in IBD [8]. A recent study, on the other hand, has demonstrated that colitic animals and patients with Crohn's disease express serum antibody reactivity against flagellin derived from commensal bacteria [35]. The response to flagellin was against a specific peptide sequence derived from a limited array of bacterial species. These data suggest that TLR5-dependent recognition of flagellin may play a role in the dysregulated immune response to commensal bacteria in IBD. Therefore, IBD may be associated with distinctive changes in TLR expression and function in intestinal epithelial cells as well as other types of cells in the gut. However, the numerous possible combinations and crosstalk of TLRs and other signal transduction pathways make the pathogenesis of IBD difficult to elucidate.

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