The intestinal microbiota dysbiosis and Clostridium difficile infection: is there a relationship with inflammatory bowel disease?

Abstract

Gut microbiota is a compilation of microorganisms dwelling in the entire mammalian gastrointestinal tract. They display a symbiotic relationship with the host contributing to its intestinal health and disease. Even a slight fluctuation in this equipoise may be deleterious to the host, leading to many pathological conditions like Clostridium difficile infection or inflammatory bowel disease (IBD). In this review, we focus on the role of microbial dysbiosis in initiation of C. difficile infection and IBD, and we also touch upon the role of specific pathogens, particularly C. difficile, as causative agents of IBD. We also discuss the molecular mechanisms activated by C. difficile that contribute to the development and exacerbation of gastrointestinal disorders.

Keywords: Clostridium difficile; inflammatory bowel disease; microbial dysbiosis.

Figure 1.

(a) Mechanism of Clostridium difficile toxin A-mediated inflammation. After receptor binding, toxin A is internalized into target cells (Rho-dependent signaling) and induced interleukin (IL)-8 expression at the level of gene transcription; this effect occurred through a mechanism requiring intracellular Ca2+, calmodulin, calcium/calmodulin-dependent kinase (CaMK), protein tyrosine kinase (PTK), and nuclear factor κB (NFκB), and activator protein 1 (AP-1) activation. The Rho-independent signaling pathway induced by toxin A in human monocytic cells occurred through a mechanism requiring interaction with surface receptor, p38 mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinase (ERK) activation. Kinase activation leads to NFκB translocation and IL-8 gene expression in target cells. (b). Mechanism of C. difficile toxin B-mediated inflammation. Toxin B through an unidentified membrane receptor activates the ERK-MAP kinase pathway via signaling dependent on epidermal growth factor receptor (EGFR). Metalloproteinase (MMP)-mediated transforming growth factor α (TGFα) is needed for phosphorylation of EGFR. Toxin B-mediated EGFR and ERK-MAP kinase activation and IL-8 gene expression are independent of Rho glucosylation. NFκB activation is not linked to toxin B-mediated IL-8 expression gene, but other unidentified signaling pathways may be involved in this process. EGFR activation of the MAP kinase-associated pathway has also been associated with cell proliferation and tissue repair. This process recruits the RAS-RAF-MAP kinase pathway, resulting in increased cellular proliferation. EFGR signaling also activates the phosphatidylinositol 3 kinase (PI3K)-serine threonine kinase Akt (AKT)-mammalian target of rapamycin (mTOR) pathway, which activates the major cellular survival and antiapoptosis signals via activating NFκB. Color legend: bacterial cell (gray); epithelial cell (green/violet); immune cells (red).