Chemotherapeutic Resistant Cholangiocarcinoma Displayed Distinct Intratumoral Microbial Composition and Metabolic Profiles

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. Therefore, 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. The results of 16S rRNA sequencing demonstrated that Gammaproteobacteria were significantly higher in the gemcitabine-resistant group. In addition, intratumoral microbial diversity and abundance were significantly different in gemcitabine-resistant and -sensitive groups. Furthermore, the metabolic phenotype of the gemcitabine-resistant group significantly differed from that of gemcitabine-sensitive group. Increased levels of acetylcholine, adenine, carnitine and inosine were observed in the gemcitabine-resistant group, while the levels of acetylcholine, alpha-D-glucose and carnitine increased in the 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. In summary, our results demonstrated insights into the interruption of the microbiome-metabolome interaction 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.