Previous research has shown that the gut microbiome could influence cancer outcomes through its interaction with host immunity. Indeed, mouse studies have shown the anti-cancer effects of chemotherapeutic drugs such as cyclophosphamide and celecoxib could be mediated by commensal species. However, the mechanisms by which gut microbial communities influence response to chemotherapeutic drugs remains poorly understood.
Two recent studies using a Caenorhabditis elegans host provide new mechanistic insights into the role of the microbiome in the efficacy of cancer drugs. C. elegans is a worm that is used as a simple model for human metabolism due to its evolutionary similarity to humans and its comparable relationship with microbes.
The first study, led by Dr. Marian Walhout from the University of Massachusetts Medical School at Worcester (Massachussetts, USA), has found that bacterial metabolism may play an important role in C. elegans’ ability to respond to chemotherapy drugs.
The researchers used C. elegans to study whether different bacteria have different effects on the host response to chemotherapeutics. C. elegans was exposed to 11 drugs while receiving either Escherichia coli or Comamonas. Four of the 11 drugs tested – camptothecin (CPT), 5-fluorouracil (5-FU), 5-fluoro-2’-deoxyuridine (FUDR) and paclitaxel – led to abnormal phenotypes in C. elegans. The effects of 5-FU, FUDR, and CPT were tested in detail at a range of concentrations and progeny production (no progeny, dead progeny or live progeny) was used as a proxy for drug efficacy. E. coli and Comamonas oppositely affected the C. elegans response to FUDR and CPT: worms on Comamonas produced live progeny when challenged with FUDR, but worsened – they were completely sterile – when supplemented with CPT; whereas worms fed a diet of E. coli were sterile when administered lower doses of both FUDR and CPT as compared to C. elegans. To induce sterility, the worms fed Comamonas had to be exposed to a concentration of FUDR 100 times greater than those fed E. coli. 5-FU had no differential effects between worms fed the two bacterial species.
By performing genetic screens in both bacterial species, the researchers identified that active bacterial nucleotide metabolism was required to modify FUDR and 5-FU efficacy in C. elegans. Several bacterial genes were responsible for increasing or decreasing drug efficacy in C. elegans. Specifically, the bacterial conversion of 5-FU and FUDR into fluorouridine monophosphate (FUMP), an analog of uridine monophosphate (UMP), was critical for the cytotoxic effects of both chemotherapeutic drugs in C. elegans. Mutations in E. coli or Comamonas upp gene reduced the efficacy of 5-FU and FUDR, while mutations in bacterial tdk, tmk, or thyA genes did not. Due to the fact that only uracil supplementation, but not thymine supplementation rescued the effect of 5-FU and FUDR, these results suggest that 5-FU and FUDR predominantly affected C. elegans fecundity via bacterial ribonucleic acid (RNA) rather than via deoxyribonucleic acid (DNA) metabolism. According to the researchers, “although we cannot yet fully explain the mechanisms that cause the bacterial differences in modulation of drug efficacy, our experiments provide insights into the mechanism of action of the different chemotherapeutic drugs”.
In conclusion, this study demonstrates that bacterial metabolism is involved in determining chemotherapy drug efficacy in the nematode C. elegans.
The second study, led by Dr. Filipe Cabreiro from the Institute of Structural and Molecular Biology at University College London and Birkbeck in London (United Kingdom), has found that both microorganisms and dietary cues may affect the efficacy of fluoropyrimidines in the C. elegans host.
The researchers combined two tractable genetic models, the bacterium E. coli and the nematode C. elegans, and high-throughput screening approaches to study the role of microbes in modulating the effect of 5-FU and other fluoropyrimidines on C. elegans.
In worms, large variations were observed in the efficacy of 5-FU and other clinically used fluoropyrimidines; these are a common type of colorectal cancer drug, which include floxuridine (FUdr), flucytosine (5-FC), capecitabine (CAP), and 5-fluoroorotic acid (5-FO). The researchers found that live bacteria are key determinants of fluoropyrimidine efficacy on host metabolism and embryonic survival.
Multiple conditions were screened in C. elegans by varying bacterial genes as well as drug types and doses. Computational analysis was used to map in detail how bacterial genetics, dietary sources and chemical compounds affected the effectiveness of fluoropyrimidines. Host-microbe-drug screens revealed metabolic drug interconversion involving bacterial vitamin B6 and B9, and ribonucleotide metabolism as necessary for microbes to regulate the effects of fluoropyrimidines.
The extensive screening in the study highlighted that bacteria regulate the effects of 5-FU in C. elegans by two distinct mechanisms. Firstly, bacterial ribonucleotide metabolism helps process the prodrug (precursor) into an active drug form. Secondly, the bacteria influence the metabolic environment of the cells making them more prone to drug-induced autophagy and cellular death in a dose- and bacterial-dependent manner. The researchers also found that other cancer co-therapies should be taken into account as a confounding factor as they can affect treatment success.
In conclusion, the beneficial impact of fluoropyrimidine cancer drugs can be explained, at least in part, by effects of drug-dependent alterations in gut microbiome composition rather than by direct action of the cancer drug itself.
References:
García-González AP, Ritter AD, Shrestha S, et al. Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics. Cell. 2017; 169(3):431-441. doi: 10.1016/j.cell.2017.03.046.
Scott TA, Quintaneiro LM, Norvaisas P, et al. Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans. Cell. 2017; 169(3):442-56. doi: 10.1016/j.cell.2017.03.040.
