Abstract
The onset of colorectal cancer (CRC) is often attributed to gut bacterial dysbiosis, and thus gut microbiota are highly relevant in devising treatment strategies. Certain gut microbes, like Enterococcus spp., exhibit remarkable anti-neoplastic and probiotic properties, which can aid in silver nanoparticle (AgNPs) induced reactive oxygen species (ROS)-based CRC treatment. However, the effects of AgNPs on gut microbial metabolism have not been reported thus far. In this study, a detailed systems-level understanding of ROS metabolism in Enterococcus durans (E. durans), a representative gut microbe, was gained using constraint-based modeling, wherein, the critical association between ROS and folate metabolism was established. Experimental studies involving low AgNP concentration treatment of E. durans cultures confirmed these modeling predictions (an increased extracellular folate concentration by 52%, at the 9th h of microbial growth, was observed). Besides, the computational studies established various metabolic pathways involving amino acids, energy metabolites, nucleotides, and SCFAs as the key players in elevating folate levels on ROS exposure. The anti-cancer potential of E. durans was also studied through MTT analysis of HCT 116 cells treated with microbial culture (AgNP treated) supernatant. A decrease in cell viability by 19% implicated the role of microbial metabolites (primarily folate) in causing cell death. The genome-scale modeling approach was then extended to extensively model CRC metabolism, as well as CRC–E. durans interactions in the context of CRC treatment, using tissue-specific metabolic models of CRC and healthy colon. These findings on further validation can facilitate the development of robust and effective cancer therapy.
Highlights
The onset of colorectal cancer (CRC) has been associated with various extrinsic factors such as infection, unhealthy diet, and lifestyle[1,2,3], which often result in gut microbiota dysbiosis—a clinical disorder characterized by perturbation in the composition and function of the healthy gut microbiota[4,5]
Effects of AgNPs on the growth and cell viability of E. durans, the bacterial cultures were exposed to different AgNP concentrations (Fig. 2)
Genome-scale metabolic modeling was utilized to substantiate the metabolic interactions between gut microbe and CRC metabolisms, which were identified through experimental analysis
Summary
The onset of colorectal cancer (CRC) has been associated with various extrinsic factors such as infection, unhealthy diet, and lifestyle[1,2,3], which often result in gut microbiota dysbiosis—a clinical disorder characterized by perturbation in the composition and function of the healthy gut microbiota[4,5]. Enterococcus durans was shown to produce butyrate, which is anti-inflammatory in nature and is required to maintain the integrity of intestinal epithelium[10] Such studies have highlighted the relevance of gut microbes in devising effective, novel cancer treatment therapies, as in the case of nanoparticle-based CRC treatment (Fig. 1). Context-specific metabolic models of colon and CRC cell types have been developed to understand the aberrant metabolism in CRC, as well as deciphering drug targets and biomarkers for cancer diagnostics. One such experimental and computational study discovered the FUT9 gene as a crucial promoter of advanced stage colon cancer[15]. It would be interesting to investigate and model the role of gut bacteria secreted metabolites in cancer cell killing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
