Probiotics for the treatment of Clostridium difficile associated disease

Abstract

The purpose of this review paper is to update the current and potential future role of probiotics for Clostridium difficile-associated disease (CDAD). Included in this review, is an update on the testing of newer probiotics (e.g., Bacillus coagulans GBI-30, 6086) in animal models of CDAD. There is a focus on the modulation of signal transduction pathways (i.e., transcription factors like cAMP response element-binding, activator protein 1, and nuclear factor kappa B), as well as the inhibition of certain kinases (e.g., p38 mitogen activated protein kinases) by probiotics. Inhibition of signal transduction by probiotics, such as Saccharomyces boulardii, result in multiple effects on intestinal fluid secretion, neutrophil influx into the colon, inflammation, and colonocyte apoptosis that may positively impact CDAD. Recent clinical approaches with probiotics, for the prevention of primary and recurrent CDAD, are also summarized in this review paper. Future directions for the treatment of CDAD by probiotics are also mentioned in this review. In particular, the use of multi-strain probiotic formulations such as Ecologic(®) AAD and VSL #3(®) may represent a rationale pharmacological approach, particularly as adjunctive therapies for CDAD. Understanding the mechanistic basis of CDAD, and how probiotics interfere at ceratin steps in the pathogenic process, may also present the opportunity to design other multi-strain probiotics that could have a future impact on CDAD.

Keywords: Clostridium difficile; Colitis; Immune modulation; Mechanisms of action; Probiotics; Saccharomyces boulardi; Transcription factors; VSL#3.

Figure 1

Immunomodulation by probiotics for Clostridium difficile-associated disease. Clostridium difficile (C. difficile) associated toxins (red font) engage colonic epithelial cells (colonocytes) leading to nuclear factor-kappa B (NF-κB) activation, interleukin (IL)-8 production, neutrophil influx and inflammation. These toxins also bind to receptors on colonocytes and leukocytes leading to p38 mitogen activated protein kinases (p38 MAPK) and cyclic-AMP response binding protein (CREB) activation. CREB, through cyclooxygenase 2 (COX2), is critical for the production of prostaglandin E2. In turn, this prostaglandin plays an important role in the fluid secretion/diarrhea associated with CDAD. C. difficile associated toxins also lead to the activation of other MAP kinases (ERK 1/2) and activator protein-1 (AP-1), which also plays a role in IL-8 production. There is also cross talk (dotted line) between the various pathways. For example, prostaglandin E2 can stimulate Fas ligand expression and apoptosis in colonic epithelial cells. The green arrows in this figure represent specific points of intervention by certain probiotics, resulting in immunomodulation by these agents. The abbreviations indicate the specific probiotics, which can modulate these signal transduction pathways. These probiotics (green font) include: Saccharomyces boulardii (Sb); Bacillus coagulans GBI-30, 6086 (Bc); Lactobacillus acidophilus (La); Lactobacillus rhamnosus (Lr); and Saccharomyces cerevisiae, strain 905 (Sc).