Silver nanoparticle induced oxidative stress augments anticancer gut bacterial metabolites production

Abstract

Colorectal cancer (CRC) is the fourth leading cause of mortality, world-wide. Gut bacterial dysbiosis being one of the major causes of CRC onset. Gut microbiota produced metabolites, e.g. folate and butyrate play crucial roles in cancer progression and treatment, and thus, need to be considered for effective CRC management. A potential cancer therapy, i.e., use of silver nanoparticles (AgNPs), imparts cytotoxic effects by inducing high intracellular reactive oxygen species (ROS) levels. However, the simultaneous interactions of AgNPs with gut microbiota to aid CRC treatment has not been reported thus far. Therefore, in this study, variation of intracellular ROS concentrations, in Enterococcus durans (E. durans), a representative gut microbe, was studied in the presence of low AgNP concentrations (25 ppm). Increases were observed in intracellular hydroxyl radical and extracellular folic acid concentrations by 48% and 52%, respectively, at the 9thhour of microbial growth. To gain a systems level understanding of ROS metabolism in E. durans, genome scale metabolic network reconstruction and modeling was adopted. In silico modeling reconfirmed the critical association between ROS and folate metabolism. Further, amino acids, energy metabolites, nucleotides, and butyrate were found to be important key players. Consequently, the anticancer effect of folic acid was experimentally studied on HCT116 (i.e., colon cancer cell line), wherein, its viability was reduced to 79% via folate present in the supernatants from AgNP treated E. durans cultures. Thus, we suggest that the inter-relationship between gut bacteria and AgNP-based cancer treatment can be used to design robust and effective cancer therapies.