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The inflammatory response is the beginning of an immunological process and is necessary to protect the body against invading pathogens. When pathogens cross the intestinal epithelial barrier, a non-specific inflammatory response is mediated by the

Figure 1.3 Structure of tight junctions and adherens junctions (together known as apical junctional complex) between epithelial cells of the intestine and actin cytoskeleton (adapted from Steed et al. [47] and

cytokines (e.g. interleukins, chemokines and interferons), recruiting more immune cells to the site of inflammation.

The activation of the adaptive immune system is mediated by T lymphocytes and B cells (Figure 1.4), but IBD is mostly attributed to a dysregulation of T cell-mediated immunity [50-55]. T cells recognise antigens that are bound to specific receptors, the major histocompatibility complexes (MHC) class I and class II. MHC class I molecules are expressed and presented by all nucleated cells, while MHC class II molecules are primarily expressed by specialised antigen-presenting cells, including dendritic cells,

macrophages and B cells [as reviewed in 56]. Cytotoxic T cells (also known as CD8+ _T

cell) actively kill other cells by inducing apoptosis, while T helper (Th) cells (also known

as CD4+ _{T cell) regulate the innate and adaptive immune response by recruiting other}

immune cells to the site and assisting in maturation of other white blood cells (e.g. B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and

macrophages). Upon encountering antigens, naïve CD4+ _{T cells and naïve CD8}+ _{T cells}

become activated and differentiate into a variety of T cell subsets. Naïve CD4+ _{T cells}

differentiate into one of several subtypes, including effector T cells (Th1, Th2, Th3, Th9, Th17, or follicular Th cells), memory Th cells, regulatory Th cells (Treg), or natural killer

T (NKT) cells. This differentiation depends on the antigen presented to the naïve CD4+ _T

cells, and is coupled to the release of various cytokines that affect cells in the local environment, resulting in recruitment of different types of immune cells that ultimately drive the immune response. As illustrated in Figure 1.4, the cytokine pattern and immune cell responses are characteristic to the disease phenotypes. CD is linked to an excessive activation of Th1 and Th17 cells [53, 55, 57], while UC is suggested to be connected to Th2, Th17 and specialised NKT cells [50, 55]. The activation/production of these molecules must be ordered and controlled to avoid excessive damage to host tissue and chronic inflammatory disorders. A defect in resolving the inflammation and returning the

99% of microorganisms in the intestine are of bacterial origin, with the remainder being archaic, and to a lesser extent eukaryotic and viral [60]. The intestinal microbiota can be viewed as its own organ, “composed of different cell lineages with a capacity to communicate with one another and the host; it consumes, stores, and redistributes energy; it mediates physiologically important chemical transformations; and it can maintain and repair itself through self-replication” [61]. It is therefore not surprising that the microbiota has a profound impact on the host metabolism. Complex interactions between the host’s innate and adaptive immune systems protects against microbial invasion, while maintaining tolerance towards the commensal microbiota. In a chronic inflammatory state, such as IBD, the protection of the host’s immunity to the commensal microbiota is defective [15], and when coupled with a loss of mucosal tolerance, it leads to an uncontrolled mucosal immune response and ultimately, a severe disruption of intestinal tissue [62].

Considering the size of the microbial pool, the bacterial diversity in the adult GIT is fairly low, with the phyla Bacteroidetes and Firmicutes dominating the large intestine [60]. In IBD, the community profile of the microbiota is altered (Table 1.2),

commonly referred to as “dysbiosis”. Despite large interpersonal variation, common

themes of dysbiosis have been observed in IBD [as reviewed in 63]: (i) decreased

bacterial species diversity, (ii) increased taxa of Enterobacteriaceae, Escherichia coli,

Ruminococcus gnavus, Clostridium difficile, and Bacteroides (but decreased species

diversity within the genus), and (iii) decreased taxa of Faecalibacterium prausnitzii,

Lachnospiraceae and Akkermansia. It is yet to be confirmed whether the changes in the microbial community profile are causative to the inflammatory process (due to a disturbed balance of detrimental/beneficial bacterial species), or are a consequence of the inflammatory process. Frank et al. [64] reported that shifts in the intestinal community profile correlated with susceptibility loci/genes of CD patients (e.g. NOD2), postulating that bacterial dysbiosis cannot be a consequence of inflammatory processes alone. Others suggest that the alterations in the community profile may be explained by the inflammatory state in the GIT that is characteristic of IBD [65, 66]. For example, increasing bile acid influx might disturb the fragile environment [65], or the introduction of oxygen into the intestine that favours the growth of facultative anaerobe bacterial

strains (e.g. Enterobacteriaceae including E. coli), while depleting obligate anaerobes,

Figure 1.4 Overview of regulatory pathways involved in the cell-mediated immune response and the characteristic defects in the disease phenotypes Crohn’s disease (CD) and ulcerative colitis (UC). Upon encounter with antigens presented by dendritic cells and macrophages, naïve T cells (Th0) differentiate into Th1, Th2, Th17 or natural killer T cells that further produce cytokines (interleukins, interferon γ, tumor necrosis factor) and drive the immune response. Atypical responses of Th1 and Th17 cells are linked to CD, while atypical responses of Th2, Th17, and natural killer T cells are linked to UC. Adapted from

Table 1.2 Characteristic changes in microbial community composition in inflammatory bowel diseases (IBD) compared to healthy individuals, obtained from human intestinal biopsies (“B”) and/or faecal samples (“F”) and identified by 16S rRNA gene sequencing. Reprinted from Berry et al. [63] with

permission from Elsevier.

Observation Sample origin

Increased taxa Enterobacteriaceae B, F Escherichiacoli Adherent-invasive E. coli B, F B Mycobacterium avium subspecies paratuberculosis B

Bacteroides (decreased species richness within the genus) B, F

Desulfovibrio spp. B, F

Members of the Epsilonproteobacteria (Campylobacter and Helicobacter) B

Ruminococcusgnavus B, F Clostridiumdifficile F Decreased taxa Faecalibacterium prausnitzii B, F Lachnospiraceae B, F Akkermansia B, F

hypothesis” is suggested to be linked to blood entering the GIT during chronic inflammation and the release of haemoglobin carrying oxygen into the mucosa [66].