Gut microbes promote chemoradiotherapy resistance via metabolic cross-feeding

Gut microorganisms can modulate response to cancer therapies. In this issue of Cancer Cell, Teng et al. trace the gut bacteria and metabolites in rectal cancer patients over the course of neoadjuvant chemoradiotherapy and identify Bacteroides vulgatus as a driver bacterium of therapeutic resistance by supplying tumors with nucleotides. Gut microorganisms can modulate response to cancer therapies. In this issue of Cancer Cell, Teng et al. trace the gut bacteria and metabolites in rectal cancer patients over the course of neoadjuvant chemoradiotherapy and identify Bacteroides vulgatus as a driver bacterium of therapeutic resistance by supplying tumors with nucleotides. Gut dysbiosis is a causative factor in colorectal tumorigenesis, and emerging evidence indicates that it also plays a role in modulating drug response to chemopreventive and chemotherapeutic agents. Studies in gnotobiotic and germ-free mice demonstrate that gut microbes can have a positive or negative impact on the efficacy of cancer therapy in a cancer-type-specific and context-dependent manner,1Yu T. Guo F. Yu Y. Sun T. Ma D. Han J. Qian Y. Kryczek I. Sun D. Nagarsheth N. et al.Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy.Cell. 2017; 170: 548-563.e16https://doi.org/10.1016/j.cell.2017.07.008Abstract Full Text Full Text PDF PubMed Scopus (1189) Google Scholar,2Geller L.T. Barzily-Rokni M. Danino T. Jonas O.H. Shental N. Nejman D. Gavert N. Zwang Y. Cooper Z.A. Shee K. et al.Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.Science. 2017; 357: 1156-1160https://doi.org/10.1126/science.aah5043Crossref PubMed Scopus (903) Google Scholar underlining a complex host-gut microbiota-drug crosstalk. Yet, the components of gut microbiota that might modulate therapeutic response, and their mechanisms of action in patients, remain elusive. In this issue of Cancer Cell, Teng et al.3Teng H. Wang Y. Sui X. Fan J. Li S. Lei X. Shi C. Sun W. Song M. Wang H. et al.Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer.Cancer Cell. 2022; 41: 124-138https://doi.org/10.1016/j.ccell.2022.11.017Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar report the microbial and metabolic features associated with non-response to preoperative neoadjuvant chemoradiotherapy (nCRT), a standard treatment in locally advanced rectal cancer (LARC). They enrolled a cohort of 126 LARC patients in a prospective study with longitudinal follow-up and performed integrated analyses of the metagenome, metatranscriptome, and metabolome (Figure 1). Given the considerable interindividual variations in the gut microbiome, a longitudinal sampling strategy enables more reliable identification of predictive markers that differentiate responders and non-responders to nCRT. Moreover, the authors used metatranscriptomic and metabolomic datasets to correlate the microbial changes to functional consequences that contribute to nCRT responsiveness. The authors observed marked reduction of microbial diversity post-nCRT, with enriched Firmicutes but depleted Bacteroidetes, in accordance with their differing sensitivity to chemotherapy treatment.4Spanogiannopoulos P. Kyaw T.S. Guthrie B.G.H. Bradley P.H. Lee J.V. Melamed J. Malig Y.N.A. Lam K.N. Gempis D. Sandy M. et al.Host and gut bacteria share metabolic pathways for anti-cancer drug metabolism.Nat. Microbiol. 2022; 7: 1605-1620https://doi.org/10.1038/s41564-022-01226-5Crossref PubMed Scopus (16) Google Scholar nCRT also promoted the emergence of a network of butyrate producers that could potentially confer antitumor effects. Further stratification of the patient cohort into responders and non-responders revealed that several species in the Bacteroides genus, most notably Bacteroides vulgatus, become selectively enriched in non-responders after nCRT regimens. On the other hand, anti-CRC probiotic species, such as Streptococcus thermophilus, are enriched in responders. B. vulgatus is a commensal bacterium highly abundant in human gut, and the notion that this bacterium mediates chemoradiotherapy resistance is surprising. B. vulgatus is suggested to be pathogenic in inflammatory bowel diseases but nonetheless has no known role in colon tumorigenesis. In contrast, recent evidence shows that selected B. vulgatus strains are probiotics that alleviate experimental models of colitis and intestinal injury.5Li S. Wang C. Zhang C. Luo Y. Cheng Q. Yu L. Sun Z. Evaluation of the effects of different Bacteroides vulgatus strains against DSS-induced colitis.J. Immunol. Res. 2021; 2021: 1-15https://doi.org/10.1155/2021/9117805Crossref Scopus (14) Google Scholar,6Wang C. Xiao Y. Yu L. Tian F. Zhao J. Zhang H. Chen W. Zhai Q. Protective effects of different Bacteroides vulgatus strains against lipopolysaccharide-induced acute intestinal injury, and their underlying functional genes.J. Adv. Res. 2022; 36: 27-37https://doi.org/10.1016/j.jare.2021.06.012Crossref PubMed Scopus (45) Google Scholar Further strain-level elucidation of B. vulgatus will enable the identification of driver strains that function as pathobionts leading to nCRT resistance in LARC. While metagenomics could offer a glimpse of the altered microbial signatures, it is the functional profiles that modulate therapeutic outcomes. The authors used a combination of metatranscriptomics and metabolomics to identify that microbial de novo nucleotide biosynthesis pathways predominate in non-responders of nCRT, together with elevated levels of nucleotide metabolites in stool, plasma, and tumor tissues. Increased de novo nucleotide biosynthesis has been reported to promote chemotherapy resistance by preventing excessive accumulation of DNA damage.7Pranzini E. Pardella E. Muccillo L. Leo A. Nesi I. Santi A. Parri M. Zhang T. Uribe A.H. Lottini T. et al.SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis.Cell Rep. 2022; 40111233https://doi.org/10.1016/j.celrep.2022.111233Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar B. vulgatus is the main contributor to microbial gene counts in nucleotide biosynthesis and releases abundant nucleotides into its surrounding milieu. It is unclear why B. vulgatus actively secretes nucleotides. Beyond their intracellular functions in energy and DNA/RNA metabolism, extracellular nucleotides are emerging signaling molecules involved in immunity and inflammation. It will be of interest to understand the physiological roles of B. vulgatus-secreted nucleotides in microbe-host cell interactions, which are exploited by LARC to mediate drug resistance. The authors next sought to answer the question of whether B. vulgatus-derived nucleotide metabolites play a causal role in resistance to nCRT, rather than being a consequence of it. Experiments with exogenous nucleoside supplementation showed that they protect against 5-FU and radiotherapy-induced DNA damage, provoking therapeutic resistance in CRC cell lines and in CRC xenograft models. Oral gavage of B. vulgatus similarly protected orthotopic CRC tumors against 5-FU therapy, an effect that was reversed by pharmacological blockade of the nucleoside uptake transporter. Taken together, these data support the idea that cross-feeding of B. vulgatus-derived nucleotides to LARC enables survival against chemoradiotherapy. It is proposed that an increased supply of nucleotides from B. vulgatus averts cell death by facilitating DNA repair, although this notion is not formally proven. To corroborate this proposition, analysis of TCGA rectal cancer cohorts demonstrates that non-response to radiotherapy correlates with increased DNA repair and nucleotide transport activities. Nevertheless, it is possible that increased circulating nucleotides could have additional effects beyond DNA damage. Gut-microbe-derived inosine, which is also present in B. vulgatus supernatant, has been shown to activate antitumor T cells,8Mager L.F. Burkhard R. Pett N. Cooke N.C.A. Brown K. Ramay H. Paik S. Stagg J. Groves R.A. Gallo M. et al.Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.Science. 2020; 369: 1481-1489https://doi.org/10.1126/science.abc3421Crossref PubMed Google Scholar whereas extracellular adenosine can suppress the cytotoxic activity of T cells and NK cells.9Cekic C. Linden J. Purinergic regulation of the immune system.Nat. Rev. Immunol. 2016; 16: 177-192https://doi.org/10.1038/nri.2016.4Crossref PubMed Scopus (560) Google Scholar Elucidation of the tumor immune microenvironment in mice models undergoing chemoradiotherapy will provide insights on the molecular mechanism of B. vulgatus or its derived nucleotides in promoting therapy resistance. Finally, the authors identified that serum uric acid, a marker of purine metabolism, can predict a poor prognosis in LARC patients treated with nCRT. This result is somewhat expected, given the numerous reports showing the negative prognostic value of uric acid in cancers, but it is unclear the extent to which the gut microbiome, and specifically B. vulgatus, contributes to this observation in LARC. Levels of circulating and intratumoral nucleotides could be affected by a number of factors, including dietary intake, the host's endogenous nucleotide biosynthesis/salvage activities, and gut microbes, that are in no way mutually exclusive. A more comprehensive assessment of nucleotides in vivo, with a metabolic labeling strategy, will provide a better picture of contribution of the gut microbe-derived nucleotides in LARC patients undergoing nCRT. Gut microbes modulate cancer therapy by a variety of mechanisms, including microbial drug biotransformation, modulation of chemotherapy resistance pathways, and therapy-elicited immunity. The findings of this study add to an ever-increasing list of gut microbe-host interactions in modulating anticancer drug efficacy and suggests potential approaches for improving nCRT efficacy in LARC, such as the targeting of nucleotide transporters or elimination of B. vulgatus. Indeed, targeting of purine or pyrimidine metabolism has been shown to potentiate the effects of chemotherapy and radiotherapy. However, a number of important questions need to be addressed for clinical translation. For instance, the pharmacological inhibition of nucleotide transporters, which also mediate uptake of antimetabolite nucleoside drugs, can reduce bioavailability to tumor cells. Moreover, it is unclear if other members of the Bacteroides genus could release nucleotides to elicit similar effects on nCRT resistance, and suppressing B. vulgatus alone might be insufficient. Selective manipulation of the gut microbiome remains a key challenge, as antibiotics have broad-spectrum effects on gut microbes. In this regard, bacteriophages are species or even strain specific and are potentially safe and effective for targeted depletion of gut microbes.10Federici S. Kredo-Russo S. Valdes-Mas R. Kviatcovsky D. Weinstock E. Matiuhin Y. Silberberg Y. Atarashi K. Furuichi M. Oka A. et al.Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation.Cell. 2022; 185: 2879-2898.e24https://doi.org/10.1016/j.cell.2022.07.003Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Ultimately, targeting gut microbiota is a promising strategy for potentiating the efficacy of radiotherapy and chemotherapy to improve patient outcomes, and bacterial biomarkers can be used for predicting disease prognosis. The authors declare no competing interests. Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancerTeng et al.Cancer CellDecember 22, 2022In BriefTeng et al. report that Bacteroides vulgatus-mediated nucleotide biosynthesis attenuates the response of rectal cancer patients to chemoradiotherapy; uric acid is a potential prognosis marker for rectal cancer patients receiving chemoradiotherapy. The findings give insights into the cross-talk between cancer cells and gut microbiota during cancer therapies. Full-Text PDF Open Access