Oral mucositis, characterized by both inflammation and cell loss in the epithelial barrier lining the oral cavity, is one of the most debilitating side effects of chemotherapy. It is associated with pain, malnutrition, and systemic infections. Moreover, the presence of oral mucositis leads to prolonged hospital stays, interruption of antineoplastic treatments and even higher mortality in cancer patients. Sonis has proposed a five-phase model to describe the development of oral mucositis during chemotherapy, in which oral microbiota plays little role in the phathophysiology of mucositis. However, the outcome of treatment based on Sonis' theory is not that much satisfactory. A recent study has demonstrated the potential role of commensal intestinal microbiota in chemotherapy-induced intestinal mucositis. It's reasonable to suspect that the disruption of microbial ecology within oral cavity by antineoplastic treatments may also have potential influence on the pathogenesis of oral mucositis. Therefore, we hypothesize that the oral microbiota may play an essential role in the pathobiology of chemotherapy-induced oral mucositis by influencing the activation of NFÎºB through TLRs and NLRs.
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Oral mucositis, characterized by both inflammation and cell loss in the epithelial barrier lining the oral cavity, is one of the most debilitating side effects of chemotherapy. In patients undergoing high-dose myeloablative therapies, the incidence rate of oral mucositis is almost 100%, and in cancer patients undergoing standard-dose chemotherapy is generally 40-60% . The mild form of mucositis presents erythema of oral mucosa, and patients have sensitivity similar to food burn. In severe forms, oral mucosa develops ulcerations which cause severe pain and then necessitates narcotic analgesia and parenteral nutrition. Pain, odynophagia, dysguesia, and subsequent malnutrition reduce the quality of life of affected patients. Mucositis has become a frequent reason for reducing the dosages of antineoplastic agents, necessitating deference or cessation of antineoplastic treatments, preventing patients from optimal chemotherapy regimens, ultimately leading to higher mortality in cancer patients. In addition, the presence of mucositis results in extra medical care expenses. Moreover, it adversely affects the general health of patients. A vast variety of microorganisms including bacteria, fungi and virus in oral cavity may enter the bloodstream due to loss of mucosal integrity, and lead to systemic infections that interrupt antineoplastic treatments, or even jeopardize patients' life in neutropenic cancer patients .
Recent advances in understanding the pathobiology of oral mucositis suggest a complex, multistep process, characterized by interaction of the epithelia and submucosa in response to chemotherapy administration. Sonis has proposed a model to describe the major steps in the development and resolution of mucositis, which include five phases: (1) the initiation phase, characterized by the formation of reactive oxygen species (ROS) which leads to the activation of nuclear factor kappa B (NFÎºB), (2) the induction of messenger molecules such as tumor necrosis factor alpha (TNFa) during the primary damage response phase, resulting in treatment-related tissue inflammation and apoptosis, (3) the amplification of messenger molecules, leading to more inflammation and apoptosis in the signal amplification phase, (4) discontinuity of the epithelial barrier resulting from apoptosis during the ulcerative phase, thereby promoting bacterial translocation, and (5) a spontaneous healing phase, characterized by cell proliferation [3, 4]. According to this model, both inflammation and apoptosis of the mucosal barrier result in its discontinuity thereby promoting bacterial translocation, and the oral microbiota is thought to play little role in the initiation of oral mucositis.
However, therapy options based on this mechanism is not satisfactory. For example, keratinocyte growth factor 1, known as Palifermin, is biologically pleotropic . It stimulates epithelial proliferation, and its therapeutic effects are likely because of its action on the nrf2 pathway, its ability to attenuate proinflammatory cytokine levels and stimulate anti-inflammatory cytokines, and its cytoprotective effects. Although potential beneï¬t for keratinocyte growth factor has been demonstrated by a body of evidence comprising six trials of 550 participants in a recent Cochrane review, all trials were assessed as being at either high or unclear risk of bias . In addition, Palifermin is only approved as a mucositis intervention in patients receiving conditioning regimens before stem cell transplantation for the treatment of hematological malignancies, and it is not effective in patients with solid tumors [4, 7]. Hence, chemotherapy-induced oral mucositis is a therapeutic challenge frequently encountered by physicians, and it still lacks well-defined and effective measures to prevent this adverse event occurred during the chemotherapy of cancer patients due to its unclear pathogenesis.
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Recent studies have implicated a role of oral microbiota in several local and systemic inflammatory diseases, such as periodontitis, cardiovascular diseases, rheumatoid arthritis, obesity and diabetes mellitus [8-11]. Moreover, van Vliet has proposed that bacteria may play a dynamic role in the development of chemotherapy-induced mucosal injury within small intestine, by influencing (1) the inflammatory process and oxidative stress, (2) intestinal permeability, (3) the composition of the mucus layer, (4) the resistance towards harmful stimuli and epithelial repair mechanisms, and (5) the activation and release of immune effector molecules . The correlation of the ecological shift of gut microbiota composition and biological function with the initiation and progression of intestinal mucositis among cancer patients undergoing chemotherapy has become a hot topic in the cancer rehabilitation field these days. Promising results have been obtained from the therapeutic use of probiotics to alleviate chemotherapy-induced diarrhea, i.e. mucositis in intestine, both in animal model  and clinical trial .
Several studies have shown that the antineoplastic agents have effect on oral microbiota both in vitro and in vivo [15-18]. Methotrexate (MTX) and doxorubicin have been found to inhibit the growth of Streptococcus mutans and Streptococcus sanguinis in vitro, and saliva collected from those cancer patients is able to inhibit S. mutans accordingly . Studies have also qualitatively and quantitatively investigated the ecological shift of oral microbiota among cancer patients undergoing chemotherapy [16-18]. However, the relationship between ecological shift of oral microbiota and chemotherapy-induced oral mucositis is still to be elucidated.
We hypothesize that the commensal bacteria within oral cavity may offer protection against oral mucositis, and the ecological shift of oral microbiota during chemotherapy may initiate a cascade of inflammatory process involving in the development of chemotherapy-induced oral mucositis.
Evaluation of the hypothesis
Oral epithelium-microbiota interactions
The human oral cavity is a complex ecosystem characterized by the simultaneous presence of a large number of bacterial colonizers, coexisting with each other and thriving in a dynamic environment . As health is the most frequent state in host, the resident microbiota has coevolved with its host to interact in a dynamic balanced state that is mutually beneficial . Although such physiological benefits are not well-defined in the oral cavity, in an analogous situation, indigenous bacteria of the gastrointestinal tract provide an appreciable number of documented benefits to the host [21-23], such as the synthesis of vitamins and amino acids; the resistance toÂ colonization of allochthonous or pathogenic microorganisms through direct competition for niches or by immune cross-reactivity; and the contribution to the normal development of immune system. Study on the effect of oral commensal microorganisms on epithelium is less advanced, however, emerging evidences suggest that oral microbiota plays an important role in stimulating mucosal epithelial cells in maintaining the barrier that contributes to homeostasis and host defense. A recent review by Handfield et al.  has systematically analyzed the cellular response of an oral epithelial cell line to challenge by four distinct oral microbes: Streptococcus gordonii, Fusobacterium nucleatum, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Overall, P. gingivalis and A. actinomycetemcomitans are able to perturb the epithelial cell transcriptome to a greater extent than F. nucleatum and S. gordonii, correlating with the concept that the less pathogenic species present a greater degree of host adaptation compared with the more overt pathogens. Considering the degree of perturbation in pathways comprising apoptosis and MAPK signaling, the recognized pathogenic species such as P. gingivalis and A. actinomycetemcomitans are more likely to induce proinflammatory response. Thus, it is conceivable that the commensal oral microbiota is capable of suppressing severe inflammatory response, and their disturbance during chemotherapy may result in incremental inflammation. Another study showed that human Î²-defensin 2 (hBD-2), an antimicrobial peptide stimulating antigen-presenting dendritic cells that signal the adaptive immune system, was induced by cell wall extract of F. nucleatum, but not by that of P. gingivalis . Therefore, we believe that the inflammatory response may arise at the mucosal surface of a susceptible host due to the ecological shift of oral microbiota toward a community predominated with more pathogenic bacteria. Meanwhile, the stress imposed by cytotoxic antineoplatic agents makes the immunocompromised host more susceptible to the microbial invasion, and thus oral mucositis occurs during chemotherapy.
Pathways of oral microbiota involving in mucositis
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In molecular level, the oral microbiota could be involved in the inflammatory process of chemotherapy-induced mucositis through two groups of receptors: Toll-like receptors (TLRs) and Nucleotide oligomerization domain (NOD)-like receptors (NLRs). TLRs, present at the outer membrane of the epithelial cells, function as pattern recognition receptors that recognize a wide range of microbial pathogens. Activation of TLRs by recognition of microbial components, such as peptidoglycan, lipopolysaccharide, bacterial DNA and protein flagellin, triggers a cascade of cellular signals resulting in the activation of NFÎºB which leads to inflammatory gene expression and development of inflammatory response of mucosa . Moreover, after binding to TLRs, bacteria are processed and bacterial parts are transported intracellularly, and then bind to NLRs which are a newfound group of intracellular cytosolic sensors playing a critical role in the regulation of the host inflammatory response. NLRs act as scaffolding proteins assembling signaling platforms that trigger NFÎºB and mitogen-activated protein kinase signaling pathways, and control the activation of inflammatory caspases . Mutations in several members of the NLR family have been linked to a variety of inflammatory diseases, such as Crohn's disease  , Blau syndrome  and early-onset sarcoidosis , further suggesting the essential role of these molecules in host-microbial interactions and inflammatory response. Therefore, NLRs and its downstream pathways may also be the potential target of oral microbes to initiate mucosa inflammation among cancer patient undergoing chemotherapy.
In short, ecological shift of oral microbiota induced by chemotherapy may influence the activation of NFÎºB through TLRs and NLRs involved in inflammatory response of the host cell, thus initiating the onset of oral mucositis among cancer patients.
Implication of the hypothesis
Treatment for malignancies with cytotoxic chemotherapy is becoming increasingly effective despite its short and long term adverse effects, among which chemotherapy-induced oral mucositis is one of the most difficult and debilitating complications usually underappreciated by some healthcare professionals. Till now, it still lacks effective measures to control this complication mainly due to its unclear pathogenesis. The development of clinical practice guidelines of antineoplastic treatments highlights the fact that preventing and managing oral mucositis in cancer patients is imperative worldwide. Further research is warranted to clarify the pattern of ecological shift of oral microbiota during chemotherapy and its relationship with inflammatory response of oral mucosa using high-throughput metagenomic sequencing and global transcriptomic profiling. If our hypothesis is validated, it may have important implications for the prevention and treatment of chemotherapy-induced oral mucostitis by reversing dysbiosis within oral cavity. This would not only improve the quality of life but also influence the treatment options, thereby decrease the mortality of cancer patients.
Conï¬‚ict of interest statement
The authors disclose no conï¬‚icts of interest. This work is supported by the Scientific Research Foundation for Young Investigators, Sichuan University, China (Grant Number:2011scu11999-2), and the National Basic Research Program of China ("973 Pilot Research Program" (Grant Number: 2011CB512108) .