Oral microbiota reduce wound healing capacity of epithelial monolayers, irrespective of the presence of 5-fluorouracil

Abstract

Oral mucositis is still one of the most painful side effects of chemotherapeutic treatment and a mounting body of evidence suggests a key role for the oral microbiome in mucositis development. However, the underlying mechanisms remain elusive. In this work, we have investigated the interactions between the host, the microbiome, and chemotherapeutic treatments in more detail. The effect of 5-fluorouracil, commonly inducing mucositis, was assessed on a co-culture model that consists of an epithelial cell layer and a biofilm derived from oral microbiota from different types of samples (saliva, buccal swabs and tongue swabs) and donors (healthy individuals and patients suffering from mucositis). After 24 h co-incubation, all oral microbial samples were found to reduce wound healing capacity with 26 ± 15% as compared with untreated condition. Compared with saliva and tongue samples, buccal samples were characterized by lower bacterial cell counts and hence higher wound healing capacity. For samples from healthy individuals, an inverse correlation was observed between bacterial cell counts and wound healing capacity, whereas for patients suffering from mucositis no correlation was observed. Moreover, patient-derived samples had a less diverse microbial community and higher abundances of pathogenic genera. No major impact of 5-fluorouracil on wound healing capacity or the composition of the microbiome was seen at physiologically relevant concentrations in the mouth. In conclusion, bacterial cell count is inversely correlated with wound healing capacity, which emphasizes the importance of oral hygiene during oral wound healing in healthy individuals. However, future research on extra measures besides oral hygiene is needed to assure a good wound healing during mucositis, as for patients the bacterial composition seems also crucial. The direct effect of 5-fluorouracil on both the microbiome and wound healing is minimal, pointing to the importance of the host and its immune system in chemotherapy-induced microbial shifts. Impact statement Chemotherapy-induced oral mucositis has a major impact on the quality of life of patients. The additional costs and treatment time associated with this pathology are significant. Although the pathology of the disease is well understood, the role and importance of oral microbiota currently are less clear. In this study, we focused on the effect of oral microbiota on wound healing, the final phase of oral mucositis, during 5-FU exposure. We show that the bacterial load and composition have a major impact on the healing process in contrast to 5-FU which only marginally slows down healing. This emphasizes the importance of good oral health care during oral mucositis to minimize bacterial load around the oral lesions. However, since we show that also the composition of the oral microbiome plays a role in wound recovery, the identification of specific pathogenic species or their metabolites might be worthwhile to allow proper treatment.

Patterns of salivary microbiota injury and oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation

“…4 Since commensal bacteria facilitate immune responses, 5 the oral microbiome may play a role in OM pathogenesis. [6][7][8][9] Several groups have reported alterations in the oral microbiota following intensive cancer treatment, but cohorts were small and HSCT recipients were underrepresented. [8][9][10][11][12] We aimed to characterize the salivary microbiota among allogeneic HSCT recipients and identify patterns associated with OM.…”

The incidence of severe oral mucositis and its occurrence sites in pediatric oncologic patients

“…An appropriate oral hygiene routine can mitigate the severity of oral mucositis, given that imbalances in biofilm composition due to poor oral hygiene could exacerbate the inflammatory process ( 25 ). Moreover, thriving pathogenic biofilms can significantly disturb the host epithelial wound healing capacity ( 26 ). Therefore, preventive strategies (e.g., educational programs) are recommended and should be implemented ( 27 ).…”

The Effect of Photobiomodulation on Nitrite and Inflammatory Activity in Radiotherapy‐Induced Oral Mucositis: A Randomized Clinical Trial

“…This cytokine is related to the cytotoxic immune response and is secreted by dendritic cells and macrophages, which play a key role in antigen presentation and immune response stimulation [28]. The presence of biofilm is an important factor in the progression of OM [53][54][55]. Furthermore, the expression of toll-like receptors (TLRs) is reportedly associated with lower mucositis rates [56,57].…”