Chemotherapeutic resistant cholangiocarcinoma displayed distinct intratumoral microbial composition and metabolic profiles

BACKGROUND: Cholangiocarcinoma (CCA) is a malignancy of the cholangiocytes. One of the major issues regarding treatment for CCA patients is the development of chemotherapeutic resistance. Recently, the association of intratumoral bacteria with chemotherapeutic response has been reported in many cancer types. METHOD: In the present study, we aimed to investigate the association between the intratumoral microbiome and its function on gemcitabine and cisplatin response in CCA tissues using 16S rRNA sequencing and 1H NMR spectroscopic analysis. RESULT: The results of 16S rRNA sequencing demonstrated that Gammaproteobacteria were significantly higher in both gemcitabine- and cisplatin-resistance groups compared to sensitive groups. In addition, intratumoral microbial diversity and abundance were significantly different compared between gemcitabine-resistant and sensitive groups. Furthermore, the metabolic phenotype of the low dose gemcitabine-resistant group significantly differed from that of low dose gemcitabine-sensitive group. Increased levels of acetylcholine, adenine, carnitine and inosine were observed in the low dose gemcitabine-resistant group, while the levels of acetylcholine, alpha-D-glucose and carnitine increased in the low dose cisplatin-resistant group. We further performed the intergrative microbiome-metabolome analysis and revealed a correlation between the intratumoral bacterial and metabolic profiles which reflect the chemotherapeutics resistance pattern in CCA patients. CONCLUSION: Our results demonstrated insights into the disruption of the microbiome and metabolome in the progression of chemotherapeutic resistance. The altered microbiome-metabolome fingerprints could be used as predictive markers for drug responses potentially resulting in the development of an appropriate chemotherapeutic drug treatment plan for individual CCA patients.