1 Center for Microbial Ecology and Technology (CMET), Ghent University, Ghent 9000, Belgium.
2 Cell Systems and Cellular Imaging Group, Department of Molecular Biotechnology, Ghent University, Ghent 9000, Belgium.
Exp Biol Med (Maywood). 2018 Feb;243(4):350-360. doi: 10.1177/1535370217753842. Epub 2018 Jan 16.
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.
口腔黏膜炎仍是化疗治疗中最常见的一种痛苦副作用，越来越多的证据表明口腔微生物组在黏膜炎发展中起着关键作用。然而，其潜在机制仍难以捉摸。在这项工作中，我们更详细地研究了宿主、微生物组和化疗治疗之间的相互作用。我们评估了常用的诱导黏膜炎的氟尿嘧啶对来自不同类型样本（唾液、口腔拭子和舌拭子）和供体（健康个体和患有黏膜炎的患者）的口腔微生物群衍生的生物膜的上皮细胞层的共培养模型的影响。共孵育 24 小时后，所有口腔微生物样本均被发现与未经处理的条件相比，伤口愈合能力降低了 26%±15%。与唾液和舌样本相比，颊样本的细菌细胞计数较低，因此伤口愈合能力较高。对于来自健康个体的样本，观察到细菌细胞计数与伤口愈合能力呈负相关，而对于患有黏膜炎的患者则未观察到这种相关性。此外，患者来源的样本具有较少的微生物群落多样性和较高的致病性属丰度。在口腔中生理相关浓度下，5-氟尿嘧啶对伤口愈合能力或微生物组的组成没有明显影响。总之，细菌细胞计数与伤口愈合能力呈负相关，这强调了在健康个体口腔伤口愈合期间进行口腔卫生的重要性。然而，需要进一步研究除口腔卫生以外的额外措施，以确保在黏膜炎期间伤口愈合良好，因为对于患者来说，细菌组成似乎也很重要。5-氟尿嘧啶对微生物组和伤口愈合的直接影响很小，这表明宿主及其免疫系统在化疗引起的微生物变化中起着重要作用。
