The pathogenesis of IBD

Both Crohn's disease and ulcerative colitis represent the clinical outcome of a complex interaction of immune, genetic, and environmental factors. The normal physiological response to indigenous micro-organisms is one of immunological quiescence. Deviations from this, and in particular, genetically-influenced aberrant immune responses to luminal antigens are now recognised to underlie IBD. The intestinal barrier can be impaired in IBD. Defects in epithelial barrier function may precede the onset of inflammation and lead to persistent immune activation (Irvine and Marshall, 2000). Leukocyte recruitment from the gut vasculature contributes to the initiation and perpetuation of mucosal inflammatory responses. Upregulation of various transcription factors including nuclear factor (NF)-kB, the master coordinator of immune responses to danger signals, drives the subsequent excessive local release of a diverse array of immune mediators. These include cytokines, growth factors, reactive oxygen metabolites, nitric oxide, and leukotrienes. Characteristically, the activated immune response of IBD is dominated by mucosal CD4+ T lymphocytes. Crohn's disease bears the immunological signature of an exaggerated Th1 response, with excess interleukin (IL)-12, IL-18, interferon-7, and tumour necrosis factor-a (Cobrin and Abreu, 2005).

Conversely, but less clearly, ulcerative colitis is associated with a dominant atypical Th2 cytokine response that is probably driven by the production of

IL-13 (Targan and Karp, 2005).

5.3.1 Genetic influences on microbial perception in IBD

Family studies and gene searches have established an important role of genetic predisposition in the pathogenesis of IBD (Peeters et al., 2000). At least ten genomic regions that harbour genes that can contribute to IBD have been identified (Korzenik and Podolsky, 2006). Of these, mutations of CARD15, which encodes NOD2, and certain TLR polymorphisms have been strongly associated with Crohn's disease. This implicates PRR dysfunction and impaired innate immune responses in the pathogenesis of IBD. Moreover, expression of some TLRs, including TLR4 which recognises bacterial lipopolysaccharide, is differentially altered in Crohn's disease and ulcerative colitis (Cario and Podolsky, 2000). It may be that increased TLR4 expression in patients with IBD confers hyperresponsiveness to lipopolysaccharide. Alternatively, it may reflect a loss of response.

NOD2 is involved in the recognition of muramyl dipeptide, a bacterial cell wall component, and intracellular triggering of NOD2 activates NF-kB. Three major polymorphisms in the CARD15 gene have been specifically associated with ~15% of Crohn's disease patients (Gaya et al., 2006). The risk of developing Crohn's disease is 20-40-fold higher in individuals who carry two copies of the risk alleles (Bairead et al., 2003; Macdonald and

Monteleone, 2005). Nevertheless, this risk factor is neither sufficient nor necessary for development of the disease (Inoue et al., 2002), and the functional phenotypic consequences of the genetic defect are controversial and remain to be elucidated (Mueller and Macpherson, 2006). In selective populations, promoter polymorphisms in the TLR9 gene that encodes the receptor for bacterial DNA, and a polymorphism in the TLR4 gene that encodes a lipopolysaccharide receptor have been associated with IBD (Cario, 2005; Franchimont et al., 2004; Torok et al., 2004). Together with the reported hyperreactivity to flagellins in sera from Crohn's disease patients (Lodes et al. , 2004), these findings indicate that PRR polymorphisms could lead to impaired bacterial clearance and, thus, an increased load of bacterial antigens in the lumen. This is supported by evidence for defective handling of bacteria and increased bacterial numbers in the mucosa of patients with Crohn's disease (Sitaraman et al., 2005).

5.3.2 The enteric microbiota as a disease liability - the environmental component?

An environmental contribution to the pathogenesis of IBD is underpinned by the lack of complete accordance of IBD among monozygotic twins and the absence of a family history in the majority of cases (Tysk et al., 1988). Numerous environmental factors have been reported to be associated with either form of IBD. These include smoking, diet, appendectomy, non-steroidal anti-inflammatory drugs, socio-economic conditions and more sanitary conditions during childhood in developed countries (Bernstein et al., 2006; Shanahan, 2004). These factors are undoubtedly complex. For example, smoking which enhances the risk of Crohn's disease, unexpectedly appears to protect against ulcerative colitis (Rubin and Hanauer, 2000).

After the lesson of Helicobacter pylori and peptic ulcer disease, an infectious contribution to the pathogenesis of IBD is plausible. Despite intensive pursuit of a specific infectious cause for IBD, this subject remains controversial. However, an aetiological role for a single pathogenic micro-organism in the pathogenesis of IBD has not been established (Shanahan, 2004). On the other hand, compelling data from murine models of colitis as well as circumstantial evidence in patient-related studies, implicate the enteric microbiota in the pathogenesis of both Crohn's disease and ulcerative colitis (Table 5.1). The level at which the dysregulated immunity to commensal organisms occurs has not been identified. It remains unclear whether the associated inflammatory responses, both within the gut and at extra-intestinal sites, are elicited in response to a specific subset of intestinal microbes. Alternatively, sensing of commensal bacteria in general may be affected. Nevertheless, what is clear is that exposure to the microbiota is a pre-requisite for expression of the disease (Shanahan, 2002). Together the evidence implicating the microbiota in IBD underpins the rationale for using pharmabiotics as a therapeutic strategy. Pharmabiotics could beneficially modulate mucosal and systemic immunity, as well as improve nutritional and microbial balance. Of the various pharmabiotic options available, probiotics and prebiotics have been most extensively studied.

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