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.
Gut microbiome plays an important role in determining the effectiveness of cancer therapy. The composition of the microbiome is crucial to maintain good digestive health in the host, and to prevent and treat colorectal cancers. Most cancer therapies employ oxidative stress, which disturbs the redox status of the cell, and consequently affect growth, reductive biosynthesis and cell death. Therefore, oxidative stress can undesirably affect the gut microbiome. Hence, it is important to understand the impact of oxidative stress on gut bacteria to devise effective treatment strategies. The current study induces oxidative stress in the model gut bacterium Enterococcus durans (MTCC 3031) with menadione and H2O2. Oxidative stress considerably decreased the redox ratio (NADPH/NADP), an indicator of the redox status, by 55% (menadione) and 28% (H2O2). In addition, an oxidative stress induced decrease in redox ratio decreased folate synthesis by the bacteria, which is an undesirable consequence for the host, since folate deficiency can induce colorectal cancer. Further, oxidative stress considerably decreased growth and the biomass density by 61% (menadione) and 21% (H2O2). Thus, maintenance of the cellular redox status and management of oxidative stress in the gut microbiome may be crucial to the effectiveness of cancer treatment strategies.
Main conclusion Bioethanol from lignocellulosic biomass is a promising step for the future energy requirements. Grass is a potential lignocellulosic biomass which can be utilised for biorefinery-based bioethanol production. Grass biomass is a suitable feedstock for bioethanol production due to its all the year around production, requirement of less fertile land and noninterference with food system. However, the processes involved, i.e. pretreatment, enzymatic hydrolysis and fermentation for bioethanol production from grass biomass, are both time consuming and costly. Developing the grass biomass in planta for enhanced bioethanol production is a promising step for maximum utilisation of this valuable feedstock and, thus, is the focus of the present review. Modern breeding techniques and transgenic processes are attractive methods which can be utilised for development of the feedstock. However, the outcomes are not always predictable and the time period required for obtaining a robust variety is generation dependent. Sophisticated genome editing technologies such as synthetic genetic circuits (SGC) or clustered regularly interspaced short palindromic repeats (CRISPR) systems are advantageous for induction of desired traits/heritable mutations in a foreseeable genome location in the 1st mutant generation. Although, its application in grass biomass for bioethanol is limited, these sophisticated techniques are anticipated to exhibit more flexibility in engineering the expression pattern for qualitative and qualitative traits. Nevertheless, the fundamentals rendered by the genetics of the transgenic crops will remain the basis of such developments for obtaining biorefinery-based bioethanol concepts from grass biomass.
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 9 th hour 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.
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