The Intestinal Microbiota: Our Best Frenemy in Radiation-Induced Damages?

High-dose ionizing radiation used during cancer radiotherapy is associated with the induction of hematopoietic, gastrointestinal, and cerebrovascular injuries. In a recent Science issue, Guo et al. demonstrated that the gut microbiota—and its associated metabolites—play a central role in protecting against high-dose radiation. High-dose ionizing radiation used during cancer radiotherapy is associated with the induction of hematopoietic, gastrointestinal, and cerebrovascular injuries. In a recent Science issue, Guo et al. demonstrated that the gut microbiota—and its associated metabolites—play a central role in protecting against high-dose radiation. High variability in response to cancer treatment is a significant challenge facing patient care (Yang et al., 2010Yang R. Niepel M. Mitchison T.K. Sorger P.K. Dissecting variability in responses to cancer chemotherapy through systems pharmacology.Clin. Pharmacol. Ther. 2010; 88: 34-38Crossref PubMed Scopus (50) Google Scholar). In terms of therapy efficacy, some subsets of patients obtain full remission, whereas others are non-responsive or resistant to treatments. Moreover, cancer-therapy-induced side effects also differently affect patients and can range from being mild to highly debilitating, even lethal, in some patient subgroups. Hence, understanding why select patients respond to treatments better than others is the main goal of precision medicine, which intends to customize optimal therapeutic approaches for everyone (Krzyszczyk et al., 2018Krzyszczyk P. Acevedo A. Davidoff E.J. Timmins L.M. Marrero-Berrios I. Patel M. White C. Lowe C. Sherba J.J. Hartmanshenn C. et al.The growing role of precision and personalized medicine for cancer treatment.Technology (Singap World Sci). 2018; 6: 79-100PubMed Google Scholar). With the development of genomic research during the preceding decades, one way of stratifying patients is by identifying genetic susceptibilities predisposing patients to therapy response. For example, a subgroup of breast cancers expresses a protein called human epidermal growth factor receptor 2 (HER2), which will importantly dictate treatment approach (Loibl and Gianni, 2017Loibl S. Gianni L. HER2-positive breast cancer.Lancet. 2017; 389: 2415-2429Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). Indeed, anti-HER2 therapies (e.g., Trastuzumab) inhibiting growth signals in HER2 positive cells are highly effective in this subgroup of patients. More recently, with the characterization of the complex community of micro-organisms inhabiting our gastro-intestinal tract, known as the gut microbiota, other approaches have emerged to better understand and characterize inter-individual responses to cancer treatment. Such approaches have gained increasing interest in recent years, as multiple high-end pre-clinical studies have demonstrated that resident gut microbiota can affect patient responses to cancer immunotherapy, suggesting that maintaining a healthy gut flora could help in the anti-cancer fight (Routy et al., 2018Routy B. Le Chatelier E. Derosa L. Duong C.P.M. Alou M.T. Daillère R. Fluckiger A. Messaoudene M. Rauber C. Roberti M.P. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (1864) Google Scholar; Gopalakrishnan et al., 2018Gopalakrishnan V. Spencer C.N. Nezi L. Reuben A. Andrews M.C. Karpinets T.V. Prieto P.A. Vicente D. Hoffman K. Wei S.C. et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (1591) Google Scholar; Matson et al., 2018Matson V. Fessler J. Bao R. Chongsuwat T. Zha Y. Alegre M.-L. Luke J.J. Gajewski T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018; 359: 104-108Crossref PubMed Scopus (998) Google Scholar). Radiation therapy, or radiotherapy, is a cancer treatment based on the use of high-dose radiations to kill cancer cells and shrink tumors (Tubiana, 1992Tubiana M. The role of local treatment in the cure of cancer.Eur. J. Cancer. 1992; 28A: 2061-2069Abstract Full Text PDF PubMed Scopus (51) Google Scholar). It can be used alone or in combination with surgery and/or chemotherapy to treat a wide range of tumors, ranging from solid tumors, such as breast and lung cancer, to leukemia. Among the side effects of high-dose radiotherapy, acute radiation syndrome is observed in select patients, which features very uncomfortable and life-altering symptoms characterized by nausea, vomiting, and inflammation along the gastro-intestinal tract (Macià I Garau et al., 2011Macià I Garau M. Lucas Calduch A. López E.C. Radiobiology of the acute radiation syndrome.Rep. Pract. Oncol. Radiother. 2011; 16: 123-130Crossref PubMed Scopus (64) Google Scholar). Although studies have previously revealed alterations of the intestinal microbiota composition after radiotherapy in mice models (Kim et al., 2015Kim Y.S. Kim J. Park S.-J. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy.Anaerobe. 2015; 33: 1-7Crossref PubMed Scopus (52) Google Scholar), the impact of such alterations on radiotherapy efficacy and associated side effects needed further elucidation. In a recent study published in Science, Guo et al. used a multi-omics approach to compositionally and functionally characterize the intestinal microbiota of mice naturally protected against radiation-induced death (Guo et al., 2020Guo H. Chou W.-C. Lai Y. Liang K. Tam J.W. Brickey W.J. Chen L. Montgomery N.D. Li X. Bohannon L.M. et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.Science. 2020; 370: eaay9097Crossref PubMed Google Scholar). They notably observed that Lachnospiraceae and Enterococcaceae families are associated with protection against radiation-induced intestinal damages and death (Guo et al., 2020Guo H. Chou W.-C. Lai Y. Liang K. Tam J.W. Brickey W.J. Chen L. Montgomery N.D. Li X. Bohannon L.M. et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.Science. 2020; 370: eaay9097Crossref PubMed Google Scholar). Supporting the central role played by these microbiota members, administration of Lachnospiraceae consortia was sufficient to confer a 300% increase in the survival rate after high-dose radiation exposure, highlighting the importance of select members of the intestinal microbiota in protecting against radiotherapy side effects (Guo et al., 2020Guo H. Chou W.-C. Lai Y. Liang K. Tam J.W. Brickey W.J. Chen L. Montgomery N.D. Li X. Bohannon L.M. et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.Science. 2020; 370: eaay9097Crossref PubMed Google Scholar). Interestingly, microbiota composition analysis of 21 leukemic patients undergoing full-body radiation procedure also reported an increase in Lachnospiraceae and Enterococcaceae families in patients with mild side effects (diarrhea <10 days) in comparison with patients with lasting diarrhea (>10 days) (Guo et al., 2020Guo H. Chou W.-C. Lai Y. Liang K. Tam J.W. Brickey W.J. Chen L. Montgomery N.D. Li X. Bohannon L.M. et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.Science. 2020; 370: eaay9097Crossref PubMed Google Scholar). Although the clinical outcomes measured were limited and on a relatively low number of participants, it nonetheless suggests the translational importance of modulating these microbiota members for the benefit of patients undergoing radiotherapy. Species belonging to the Lachnospiraceae families have the potential to ferment dietary polysaccharides to produce short-chain fatty acids (SCFAs), known to play numerous beneficial roles—including dampening intestinal inflammation, promoting intestinal repair, and stimulating hematopoiesis. SCFA quantification revealed a trend toward an increased concentration of acetate, butyrate, and propionate in fecal samples of mice protected against radiation in comparison to that seen in radiation-sensitive mice. Importantly, exogeneous administration of propionate to mice subjected to high-dose radiation was sufficient to confer strong protection against radiation-induced injury, suggesting that propionate is a key factor in Lachnospiraceae-mediated protection against radiation (Guo et al., 2020Guo H. Chou W.-C. Lai Y. Liang K. Tam J.W. Brickey W.J. Chen L. Montgomery N.D. Li X. Bohannon L.M. et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.Science. 2020; 370: eaay9097Crossref PubMed Google Scholar). The authors also observed that fecal levels of select tryptophan metabolites were associated with radioprotection, and exogenous administration of these metabolites was sufficient to induce long-term radioprotection, with decreased hematopoietic and gastrointestinal symptoms (Guo et al., 2020Guo H. Chou W.-C. Lai Y. Liang K. Tam J.W. Brickey W.J. Chen L. Montgomery N.D. Li X. Bohannon L.M. et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites.Science. 2020; 370: eaay9097Crossref PubMed Google Scholar). These observations further suggest the central role played by the microbiota/metabolite axis in protecting against radiation-induced side effects. Although the study tested a mixture of 23 individual strains belonging to the Lachnospiraceae family, further investigation of the effect of individual strains might bring into light mechanistic insights behind Lachnospiraceae-induced protection. It also remains unclear whether the radioprotective metabolites stemming from the tryptophan metabolism are generated by bacterial species belonging to the Lachnospiraceae and Enterococcaceae families that are associated with radioprotection. Another important point is that changes in microbiota composition and function that are associated with an increased host survival to radiation only emerged after radiotherapy. Hence, it remains necessary to test, in larger cohorts, whether microbiota profiling prior to radiotherapy can be used to stratify future high and low survivors, since this will significantly impact the potential clinical application of such an approach. With emerging and promising microbiota-based approaches for disease management, one can easily picture future clinical practices where cancer treatment will be approached in a holistic and personalized manner in order to optimize treatment efficacy and patient outcomes (Figure 1). For instance, cancer patients could benefit from an in-depth microbiota profiling, compositionally and/or functionally, before and during radiotherapy to determine their susceptibility to develop severe side effects. Moreover, interventions such as fecal microbiota transplantation or targeted administration of species belonging to the SCFA-producing Lachnospiraceae and Enterococcaceae families could be envisioned in select patients harboring a microbiota associated with side effects. Targeted dietary recommendations based on microbiota profiling can also be provided to favor microbiota-derived generation of SCFA and tryptophan metabolites. Combining such diet with exogenous administration of Lachnospiraceae and Enterococcaceae species appears to be a promising approach to boost SCFA and tryptophan metabolites synthesis in patients harboring a microbiota that is normally associated with poor outcomes after radiotherapy. To conclude, this study not only offers promising microbiota-based innovative therapeutic approaches for personalized radiotherapy in cancer patients but also constitutes an important methodological framework and reference for future studies investigating the involvement of the microbiota in patient outcomes and treatment stratification. B.C.’s laboratory is supported by a Starting Grant from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. ERC-2018-StG- 804135 ), a Chaire d’Excellence from IdEx Université de Paris ( ANR-18-IDEX-0001 ), and an Innovator Award from the Kenneth Rainin Foundation . The authors thank Hao Q. Tran for his feedback.