The Function And Mechanism Of Short Chain Fatty Acids (SCFAs) Produced By Gut Microbiota After Probiotic VSL#3 Supplementation Inhibit Tumor Metastasis

Diet has been recognized as an effective method in cancer prevention and treatment.Studies have shown that changes of diet can effectively reduce the incidence of cancer and prolong the survival time of cancer patients.The role of gut microbiota is an important link of diet affecting the progress of cancer.Probiotics are living microorganisms that are beneficial to the health of the host when administered in an appropriate amount,and have the functions of regulating gut microbiota composition,promoting the recovery of gut microbiota,the production of metabolites and host immune response.Short-chain fatty acids(SCFAs),one of the metabolites,mainly including acetic acid,propionic acid and butyric acid,can act as histone deacetylase inhibitors to influence gene expression and participate in the occurrence and development of intestinal tumors.In addition,SCFAs can also affect leukocyte migration and T cell differentiation in inflammatory diseases.Previous studies have focused on the effects of probiotics and their metabolites on intestinal health and tumors,but gut microbiota and its metabolites can systematically influence the immune system and participate in the process of extra-intestinal tumors.In this study,we explored the effect of probiotics on lung metastasis of melanoma cell in mice by commercial probiotics VSL#3.First,we established a mouse model of melanoma cell lung metastasis,the number of lung metastasis in mice was significantly reduced and their survival period was significantly prolonged after VSL#3 gavage.16s r RNA analysis results showed that the number of short-chain fatty acid(SCFAs)related bacteria in VSL#3 feeding mice was increased.Gas chromatography mass spectrometry(GC/MS)also verified that SCFAs levels in the intestine and serum of mice were significantly increased after VSL#3 treatment.The increased SCFAs were mainly acetate,propionate and butyrate,and propionate and butyrate were the main effective SCFAs.Flow cytometry and magnetic bead sorting experiments confirmed that propionate and butyrate promoted the expression of CCL20 in pulmonary endothelial cells,and the recruitment of Th17 cells to lung via CCL20/CCR6 axis.Th17 cells recruited to lungs play an important role in lung metastasis of melanoma cell in mice.Th17 cells were adoptively transferred into mice,and results showed a significant reduction in the number of lung metastases in mice.The mechanism may be that Th17 cells promote the secretion of granzyme B by CD8~+cytotoxic T cells.Thus,we have identified the main mechanism of probiotics VSL#3 inhibits lung metastasis of melanoma cell in mice.The role of Th17 cells in different types of tumors has always been controversial in previous studies.Our study discussed the role of Th17cells in lung metastasis of mouse melanoma,and further improved the existing studies.The comprehensive role of probiotics VSL#3 in tumor metastasis provides a new information for the follow-up intervention of tumor treatment by regulating gut microbiota.