Host-Microbiome Cross-talk in Oral Mucositis

Abstract

Oral mucositis (OM) is among the most common, painful, and debilitating toxicities of cancer regimen-related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Novel discoveries in OM have focused on understanding the host-microbial interactions, because current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations, affecting tissue healing. Additional comprehensive and disciplined clinical investigation is needed to carefully characterize the relationship between the clinical trajectory of OM, the local levels of inflammatory changes (both clinical and molecular), and the ebb and flow of the oral microbiota. Answering such questions will increase our knowledge of the mechanisms engaged by the oral immune system in response to mucositis, facilitating their translation into novel therapeutic approaches. In doing so, directed clinical strategies can be developed that specifically target those times and tissues that are most susceptible to intervention.

Keywords: Toll-like receptor; cancer; cancer complications; damage-associated molecular pattern; oral microbiome; pathogen-associated molecular pattern.

Figure 1.

Manifestation of oral mucositis in its severe form presents ulcerative lesions, which penetrate the submucosa. Loss of mucosal layer integrity represents a clinically significant risk factor for bacteremia, fungemia, and sepsis.

Figure 2.

Biological complexities underline the mucosal injury that is initiated by cytotoxic cancer therapy. This figure illustrates the pathogenesis of oral mucositis, which encompasses a series of biological events coupled with the influence of the oral microbiota and overall oral environment. In an oral ecosystem, a host-microbiota homeostasis is maintained under normal health conditions. In patients with cancer undergoing radiation therapy and chemotherapy, a dramatic change in the oral environment occurs, which causes an imbalance of the oral microorganisms and influences the modification of oral mucositis barrier function, innate immunity, and cellular mechanisms. The progression of oral mucositis can be summarized in 5 stages: initiation, messaging and signaling, amplification, ulceration, and healing. Based on this model, inflammation, together with apoptosis, leads to the loss of integrity of the mucosal barrier, thereby promoting bacteria translocation. Adapted from Sonis (2004). IL, interleukin; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; ROS, reactive oxygen species; TNF, tumor necrosis factor.

Figure 3.

This figure describes the molecular pathways involved in microbiota-host interactions and the development of oral mucositis. The detection of microbial components (PAMPs) and endogenous damage-associated molecular patterns (DAMPs and HMGB1) by pattern recognition receptors such as Toll-like receptors triggers a cascade of cellular signals, resulting in activation of NF-κB (among other pathways) that contribute to amplify proinflammatory cytokines and apoptosis. The use of probiotic bacteria has the ability to activate pathways that are involved in the reduction of inflammatory signaling and apoptosis through the downregulation of the innate immune response of the epithelial cells by way of inactivation of the NF-κB pathway. DAMP, damage-associated molecular pattern; HMGB1, high-mobility group box-1; IL, interleukin; NF-κB, nuclear factor-κB; PAMP, pathogen-associated molecular pattern; TNF, tumor necrosis factor.