At present, the mechanism of OM is not completely illustrated. The incidence of OM is increasing globally, and more and more patients with malignant tumors suffer from oral mucositis when receiving radiotherapy or chemotherapy [1, 28]. Therefore, improving the prevention and treatment of OM caused by tumor radiotherapy and chemotherapy is clinically significant to prolong the survival time of patients, improving the quality of life of patients, reducing the economic burden of patients and improving the connotation of tumor care [29, 30]. As a TCM formula, Shuanghua Baihe Tablet has the functions of regulating the body's immunity, anti-inflammatory and analgesic, which can effectively alleviate the symptoms of mucosal inflammation and oral odor. In recent years, a series of studies have proved that SBT has a good effect in the treatment of chemotherapy-induced OM . It not only reduces the pain of patients, but also significantly promotes the healing of congestive erosions. However, due to the complex active ingredients of TCM compound and the unclear target of action, the mechanism of SBT in the treatment of OM has not been elucidated . With the development of multi-omics technology, it is possible to explore the mechanism of Chinese herbal compound prescriptions .
In this study, we investigated the synergistic effects of the main active components of SBT and explored its potential mechanism. The comprehensive treatment effect of SBT was observed from ulcer score, histopathology, biochemistry and other indexes, which indicated that SBT has a good therapeutic effect on OM caused by chemotherapy. In order to investigate the mechanism of SBT treatment on OM, we compared the transcriptional profiles of NC and MC groups’ tissues with identified dysregulated genes of OM. After the treatment of SBT, several of dysregulated genes were reversed. Gene ontology and pathway enrichment analysis indicated that these reversed genes had notable correlation with immune response, cytokine − cytokine receptor interaction, leukocyte transendothelial migration, IL − 17 signaling pathway, TNF signaling pathway and biological metabolic process. With the treatment of SBT on OM, the immune and inflammation process of cells was also severely affected, thus leading to IL − 17, TNF-α and Treg cells disturbances. The results were verified by Flow Cytometry and Cytokine quantification. Previous studies have shown that IL − 17, TNF-α and Treg cells are closely related to the progression of OM, whose proportion determine the recovery rate and recurrent rate of OM [33–35]. Besides, some disordered metabolic processes contribute to preternatural accumulation of many important metabolites severely affecting cellular behavior.
From the perspective of central dogma, expression genes are upstream products of genetic information while expression metabolites are downstream ones. Therefore, gene expression changes can naturally cause the alteration of metabolites in tumor progression. Transcriptomics analysis verified that many pivotal cellular metabolic pathways are restored in the treatment of SBT on OM. Here, the metabolic profile of linoleic acid metabolism, glycerophospholipid metabolism, valine, leucine and isoleucine biosynthesis and glycine, serine and threonine metabolism pathway were further studied through metabolomics to determine metabolic biomarkers and establish biological model of the treatment of SBT on OM. It’s underscored from our data that the metabolites involving Linoleic acid metabolism, Glycerophospholipid metabolism, Valine, leucine and isoleucine biosynthesis and Glycine, serine and threonine metabolism pathway play indispensable parts in the treatment of SBT on OM. Some essential compounds of these pathways, i.e. LysoPC (18:1(11Z)/0:0), Linoleic acid, 4-Guanidinobutanoic acid, 5-aminolevulinic acid, PE (18:4(6Z,9Z,12Z,15Z)/P-16:0), creatine and L-leucine, were regarded as the significant targets. Linoleic acid is the most highly consumed PUFA found in the human diet, whose content is close to the serum inflammatory factors . Previous study also showed that Glycerophospholipid metabolism, Valine, leucine and isoleucine biosynthesis and Glycine, serine and threonine metabolism pathway can affect the body's immune system and ability to deal with inflammation [37, 38]. These results confirm that metabolomics can explore metabolic profile of metabolic pathway, verifying transcriptional variability, and thus help biologists comprehend the mechanism of the treatment of SBT on OM.
In conclusion, this study is the first to research the therapeutic effect of SBT on OM rat model by combining transcriptomics and metabolomics. The results showed that SBT can improve the inflammatory symptoms of oral mucosa, and the mechanism may be related to its anti-inflammatory function, maintaining immune balance of the body and repairing the metabolic pathways of many disorders. Especially, immune-related pathways like IL-17 signaling pathway, TNF signaling pathway and metabolic-related pathways such as Linoleic acid metabolism play essential roles in the SBT treatment on OM.