The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis

Abstract

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.

Figure 1. The epithelial barrier is comprised of a single layer of epithelial cells intertwined by tight junctions.

The mechanical barrier is increased further by a mucus layer. Binding of bacteria to TLRs present on epithelial cells results in the activation of NFκB, ultimately resulting in the release of pro-inflammatory and anti-inflammatory cytokines. After phagocytosis, bacterial products are internalized and then are recognized by receptors of the NOD family (NLRs), resulting in the modulation of the inflammatory response. Dendritic cells are capable of internalizing bacteria sampled from the lumen, after which bacteria are presented to immune effector cells. HSPs, heat shock proteins; NLR, NOD-like receptor; sIgA, secretory immunoglobulin A; TLR, Toll-like receptor.

Figure 2. The resident microbiota interferes in the process of mucositis.

Depicted are five possible ways in which intestinal bacteria can attenuate or aggrevate mucositis: 1) influencing the inflammatory process, 2) influencing intestinal permeability, 3) influencing the composition of the mucus layer, 4) influencing resistance to harmful stimuli and enhancing epithelial repair, and finally, 5) the activation and release of immune effector molecules.