Crosstalk Between Bacteria And Intestinal Epithelial Cells

As discussed in chapter 5, some ingested probiotic bacteria have shown immunomodulatory properties (44-46). Both commensal and pathogenic bacteria possess recognized structures named pathogen-associated molecular patterns (PAMPS). These recognized structures are essential for the microbe, mostly constitutively expressed and shared by the same group of microorganisms. PAMPS that are characterized to date include N-formylated peptide (47), lipopolysaccharides (LPS) (48), and lipopeptides (49), more recently described PAMPS are flagellin (50) and unmethylated segments of CpG DNA (51). Even though unmethylated segments of CpG DNA are not a cell surface structure, it serves to differentiate the microorganism from the host. Therefore, they epitomize the ideal targets for the innate immune system to identify the presence of infectious agents with a limited numbers of receptors.

The best studied of the PAMPS is the glycolipid LPS, an important component of the outer membrane of Gram-negative bacteria. LPS is recognized by Toll-like receptor (TLR) 4, the first described member of the family of transmembrane TLR molecules that play a central role in the transcription activation of host defense mechanisms, such as chemokine and cytokine secretion, and the expression of costimulatory molecules (52). TLRs are transmembrane receptors defined by the presence of leucine-rich repeats in the extracellular portion of the molecule and a Toll/IL-IR/resistance (TIR) cytoplasmic domain. The extracellular leucine-rich repeats are thought to function in ligand recognition, whereas the TIR domain works in signaling. Leucine-rich repeat domains are common to proteins that are involved in the recognition of foreign proteins. There are currently 10 identified members of the mammalian TLR family (52). From recent publications (53), it has been shown that some types of intestinal epithelial cells express TLR 4.

Upon activation of TLR 4 by LPS, a series of events lead to the activation of ubiquitin ligase TRAF6 by a unique self-polyubiquitination reaction. TRAF6 then activates the TAK1 complex (54). This step leads to the phosphorylation and activation of mitogen-activated protein kinase and the inhibitor kB kinase (IKK) complex (54,55). The IKK complex comprises two kinases, IKKa and IKKb, and one protein, NEMO. When activated, IKKb phosphorylates IkBa, triggering its polyubiquitination and degradation (56,57). In the unstimulated state, the IkBa interacts and traps NFkb in the cytosol. Degradation of IkBa releases the NFkb to translocate into the nucleus and to activate proinflammatory and prosurvival gene expression. Therefore, TLR 4 activates multiple signaling pathways which will eventually lead to the production of cytokines and other factors to protect the host against infection (58). The expression level of TLR 4 in the intestine of patients with inflammatory bowel disease was found to be strongly up-regulated compared to the TLR 4 expression in healthy individuals.

As for the other PAMPS such as N-formylated peptides, the cell surface receptors that recognized them are the heterotrimeric G-protein coupled receptors (59). N-formylated peptides play an important role in recruiting and activating inflammatory cells (60). They will eventually activate the NFkb pathway the same way as the TLR.

On the other hand, enteric pathogens have also evolved mechanisms to evade the immune recognition and defense. Helicobacter pylori, the etiological agent of gastritis and stomach cancer, expresses hypoacylated LPS to avoid recognition by the human TLR4/MD2 module (61). Other pathogens like Yersinia pseudotuberculosis have developed ways to down-regulate TLR 4 signaling by injecting proteins to abolish the signaling leading to NFkP activation (52).

At the beginning of the chapter, we mentioned that the gastrointestinal tract is colonized by huge, complex and dynamic populations of microorganisms. Hence, the molecular pattern recognition of the epithelial cells of the gastrointestinal mucosa needs to be tightly regulated so as to avoid an extreme immune response and uncontrolled inflammatory reaction. The exact mechanism by which they do this still remains to be elucidated. However, recent studies have shed light into this area of interest. The mechanism by which one TLR, TLR 5, achieved this feat is due to the fact that gut epithelial cells express TLR 5 only on their basolateral surfaces. Therefore only those bacteria that breached the epithelial cells or have translocated flagellin across the epithelia will activate the receptor (62).

Using a gnotobiotic mouse model it was shown that Bacteroides thetaiotaomicron is able to induce the production of a-L fucose on intestinal epithelial cells via a regulator, FucR, as a molecular sensor of L-fucose availability (3,68). FucR coordinates expression of an operon encoding enzymes in the L-fucose metabolic pathway in the bacteria with expression of another locus that regulates production of fucosylated glycans in the intestinal enterocytes. By tightly coordinating presentation of host-derived fucose with the rate of fucose utilization, an excess of epithelial fucose is avoided. This may minimize the risk of encroachment by pathogens that use fucosylated glycans as receptors for their adhesins (69).

Certain pathogenic bacteria require intimate contact with the host to cause disease. E. coli (EPEC) is one such pathogen which requires intimate attachment to the host cells for maximum virulence to occur. There are a few factors which facilitate the cross-talk between the microorganism and the host epithelial cells and this involves the EPEC-secreted proteins, the type-three secretion system and the expression of outer membrane protein, intimin (64,65). The release of extracellular protein via the type-three secretion system is necessary for the formation of attaching lesions by EPEC. The attachment of bacteria is by means of intimin binding to a 90 kDa tyrosine phoshorylated protein in the host membrane. This receptor is known as translocated intimin receptor (Tir) and is of bacterial origin; it is translocated on to the host membrane where its tyrosine residues become phosphorylated and binds to intimin. Subsequent signal transduction events that occur within the host cells are the activation of protein kinase C, inositol triphosphate and calcium release. This leads to the formation of an actin-rich pedestal that forms a dome-like anchoring site for the bacteria which is an essential feature of EPEC pathogenesis (63).

There is evidence to suggest that in some strains of Lactobacillus reuteri, mucus-binding adhesion could be induced by the presence of mucin glycoproteins and solid substratum (66).

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