Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Microbiota: a key orchestrator of cancer therapy

This article has been updated

Key Points

  • The human microbiota is the ensemble of bacteria and other microorganisms that inhabit the epithelial barrier surfaces of the body. The microbiota affects physiological functions, particularly metabolism, neurological and cognitive functions, haematopoiesis, inflammation and immunity.

  • The microbiota and its larger host represent a metaorganism in which the crosstalk between microorganisms and host cells is necessary for health, survival and regulation of physiological functions at the local barrier level and systemically. Mostly because of its effects on metabolism, cellular proliferation, inflammation and immunity, the microbiota regulates cancer at the level of predisposing conditions, initiation, genetic instability, susceptibility to host immune response, progression, comorbidity and response to therapy.

  • The gut microbiota affects aspects of drug metabolism, pharmacokinetics, anticancer effect and toxicity. The rate of absorption and bioavailability of many oral drugs, including cancer therapies, depends on their exposure in the gut to both host and bacterial enzymes before entering the circulation.

  • The microbiota regulates the response to different types of cancer chemotherapy by affecting their mechanism of action and toxicity. The best characterized are oxaliplatin and cyclophosphamide; the anticancer activity of which is affected by the gut microbiota, which primes myeloid cells for production of reactive oxygen species in the case of oxaliplatin and facilitates the induction of an anticancer T cell response in the case of CTX.

  • The role of the microbiota in modulating the response to anticancer radiotherapy remains to be fully characterized. However, germ-free mice have been described as being less susceptible to the toxicity of radiation than conventionally raised mice, and evidence in humans and experimental animals suggests that the composition of the intestinal microbiota may affect the severity of radiation-induced mucosal toxicity.

  • The composition of the gut microbiota modulates both inflammation and adaptive immunity and thereby regulates the effectiveness of cancer immune therapies, such as adoptive T cell transfer preceded by total body irradiation, intratumoural treatment with CpG-oligodeoxynucleotides and immune checkpoint blockade with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 ligand 1 (PDL1).

  • Evidence of the important role of the microbiota in controlling cancer therapy effectiveness and toxicity is derived mainly from data in experimental animals, and translation of these findings to human clinical medicine remains challenging. Additional human data should be obtained and new technologies developed in order to safely target the microbiota to improve anticancer therapies while attenuating the toxic side effects.

Abstract

The microbiota is composed of commensal bacteria and other microorganisms that live on the epithelial barriers of the host. The commensal microbiota is important for the health and survival of the organism. Microbiota influences physiological functions from the maintenance of barrier homeostasis locally to the regulation of metabolism, haematopoiesis, inflammation, immunity and other functions systemically. The microbiota is also involved in the initiation, progression and dissemination of cancer both at epithelial barriers and in sterile tissues. Recently, it has become evident that microbiota, and particularly the gut microbiota, modulates the response to cancer therapy and susceptibility to toxic side effects. In this Review, we discuss the evidence for the ability of the microbiota to modulate chemotherapy, radiotherapy and immunotherapy with a focus on the microbial species involved, their mechanism of action and the possibility of targeting the microbiota to improve anticancer efficacy while preventing toxicity.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Local and systemic effects of the gastrointestinal microbiota.
Figure 2: Major pathways of drug metabolism and the role of microbiota following enteral (for example, oral) or parenteral (for example, intravenous) administration.
Figure 3: The gut microbiota regulates anticancer therapies.
Figure 4: Microbiota-triggered innate immune receptors.

Change history

  • 04 April 2017

    In this article the sentence 'however, in one study, overgrowth of Parabacteroides distasonis in mice treated with broad-spectrum antibiotics was observed to abrogate its antitumour effect' was incorrectly referenced. The correct reference for this sentence is 61.

References

  1. Costello, E. K., Stagaman, K., Dethlefsen, L., Bohannan, B. J. & Relman, D. A. The application of ecological theory toward an understanding of the human microbiome. Science 336, 1255–1262 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Bosch, T. C. & McFall-Ngai, M. J. Metaorganisms as the new frontier. Zoology (Jena) 114, 185–190 (2011).

    Article  Google Scholar 

  3. Dzutsev, A., Goldszmid, R. S., Viaud, S., Zitvogel, L. & Trinchieri, G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur. J. Immunol. 45, 17–31 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Gustafsson, B. E., Daft, F. S., McDaniel, E. G., Smith, J. C. & Fitzgerald, R. J. Effects of vitamin K-active compounds and intestinal microorganisms in vitamin K-deficient germfree rats. J. Nutr. 78, 461–468 (1962).

    Article  CAS  PubMed  Google Scholar 

  6. Gordon, H. A., Bruckner-Kardoss, E. & Wostmann, B. S. Aging in germ-free mice: life tables and lesions observed at natural death. J. Gerontol. 21, 380–387 (1966).

    Article  CAS  PubMed  Google Scholar 

  7. De Santis, S., Cavalcanti, E., Mastronardi, M., Jirillo, E. & Chieppa, M. Nutritional keys for intestinal barrier modulation. Front. Immunol. 6, 612 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host–microbial interface. Proc. Natl Acad. Sci. USA 105, 20858 (2008). This paper identified the role of microbiota signalling in maintaining the host–commensal homeostasis through MYD88-coupled receptors in epithelial cells.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Belkaid, Y. & Naik, S. Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 14, 646–653 (2013). This review discusses the role of the microbiota at different epithelial barriers in regulating immunity both locally and systemically.

    Article  CAS  PubMed  Google Scholar 

  11. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14, e1002533 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chow, J., Tang, H. & Mazmanian, S. K. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr. Opin. Immunol. 23, 473–480 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–381 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Chung, W. S. F. et al. Modulation of the human gut microbiota by dietary fibres occurs at the species level. BMC Biol. 14, 3 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Dinan, T. G. & Cryan, J. F. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 37, 1369–1378 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Sommer, F. & Bäckhed, F. The gut microbiota engages different signaling pathways to induce Duox2 expression in the ileum and colon epithelium. Mucosal Immunol. 8, 372–379 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Wells, J. M., Rossi, O., Meijerink, M. & van Baarlen, P. Epithelial crosstalk at the microbiota–mucosal interface. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4607–4614 (2011).

    Article  PubMed  Google Scholar 

  21. Tulstrup, M. V.-L. et al. Antibiotic treatment affects intestinal permeability and gut microbial composition in Wistar rats dependent on antibiotic class. PLoS ONE 10, e0144854 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Backhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010). References 22 and 23 describe the establishment of the human microbiota during early life.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Faith, J. J. et al. The long-term stability of the human gut microbiota. Science 341, 1237439 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Oh, J., Byrd, A. L., Park, M., Kong, H. H. & Segre, J. A. Temporal stability of the human skin microbiome. Cell 165, 854–866 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. David, L. A. et al. Host lifestyle affects human microbiota on daily timescales. Genome Biol. 15, R89 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Garrett, W. S. et al. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 16, 208–219 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Hu, B. et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl Acad. Sci. USA 110, 9862–9867 (2013). References 31 and 32 demonstrated that the carcinogenic phenotypes associated with dysbiosis of the microbiota in genetically mutated mice can be transmitted to wild-type mice by microbiota transfer.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). This paper presented the first demonstration of the role of the microbiota in modulating responsiveness to anti-CTLA4 therapy.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. DeVita, V. T. Jr & Chu, E. A history of cancer chemotherapy. Cancer Res. 68, 8643–8653 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Sancho-Martinez, S. M., Prieto-Garcia, L., Prieto, M., Lopez-Novoa, J. M. & Lopez-Hernandez, F. J. Subcellular targets of cisplatin cytotoxicity: an integrated view. Pharmacol. Ther. 136, 35–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Mitchell, E. P. Gastrointestinal toxicity of chemotherapeutic agents. Semin. Oncol. 33, 106–120 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Spanogiannopoulos, P., Bess, E. N., Carmody, R. N. & Turnbaugh, P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Li, H. & Jia, W. Cometabolism of microbes and host: implications for drug metabolism and drug-induced toxicity. Clin. Pharmacol. Ther. 94, 574–581 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Feng, R. et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci. Rep. 5, 12155 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Maurice, C. F., Haiser, H. J. & Turnbaugh, P. J. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152, 39–50 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Montassier, E. et al. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment. Pharmacol. Ther. 42, 515–528 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Wilson, I. D. & Nicholson, J. K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 179, 204–222 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Haiser, H. J. & Turnbaugh, P. J. Developing a metagenomic view of xenobiotic metabolism. Pharmacol. Res. 69, 21–31 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Carmody, R. N. & Turnbaugh, P. J. Host–microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics. J. Clin. Invest. 124, 4173–4181 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Bjorkholm, B. et al. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS ONE 4, e6958 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Selwyn, F. P., Cheng, S. L., Klaassen, C. D. & Cui, J. Y. Regulation of hepatic drug-metabolizing enzymes in germ-free mice by conventionalization and probiotics. Drug Metab. Dispos. 44, 262–274 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Selwyn, F. P., Cui, J. Y. & Klaassen, C. D. RNA-Seq quantification of hepatic drug processing genes in germ-free mice. Drug Metab. Dispos. 43, 1572–1580 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Selwyn, F. P. et al. Developmental regulation of drug-processing genes in livers of germ-free mice. Toxicol. Sci. 147, 84–103 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kang, M. J. et al. The effect of gut microbiota on drug metabolism. Expert Opin. Drug Metab. Toxicol. 9, 1295–1308 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Yip, L. Y. & Chan, E. C. Investigation of host-gut microbiota modulation of therapeutic outcome. Drug Metab. Dispos. 43, 1619–1631 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Fujita, K. & Sparreboom, A. Pharmacogenetics of irinotecan disposition and toxicity: a review. Curr. Clin. Pharmacol. 5, 209–217 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Stringer, A. M. et al. Faecal microflora and beta-glucuronidase expression are altered in an irinotecan-induced diarrhea model in rats. Cancer Biol. Ther. 7, 1919–1925 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Lin, X. B. et al. Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats. PLoS ONE 7, e39764 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Dabek, M., McCrae, S. I., Stevens, V. J., Duncan, S. H. & Louis, P. Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol. Ecol. 66, 487–495 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. McIntosh, F. M. et al. Phylogenetic distribution of genes encoding beta-glucuronidase activity in human colonic bacteria and the impact of diet on faecal glycosidase activities. Environ. Microbiol. 14, 1876–1887 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Takasuna, K. et al. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 56, 3752–3757 (1996).

    CAS  PubMed  Google Scholar 

  57. Wallace, B. D. et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Mego, M. et al. Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo controlled pilot study. Complement. Ther. Med. 23, 356–362 (2015).

    Article  PubMed  Google Scholar 

  59. Wallace, B. D. et al. Structure and inhibition of microbiome beta-glucuronidases essential to the alleviation of cancer drug toxicity. Chem. Biol. 22, 1238–1249 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Lehouritis, P. et al. Local bacteria affect the efficacy of chemotherapeutic drugs. Sci. Rep. 5, 14554 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013). This paper describes the role of the microbiota in modulating the anticancer effect of CTX.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013). This paper describes the role of the microbiota in modulating the efficacy of cancer therapy with CpG-ODNs and platinum drugs.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Galluzzi, L. et al. Systems biology of cisplatin resistance: past, present and future. Cell Death Dis. 5, e1257 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Roy, S., Ryals, M. M., Van den Bruele, A. B., Fitzgerald, T. S. & Cunningham, L. L. Sound preconditioning therapy inhibits ototoxic hearing loss in mice. J. Clin. Invest. 123, 4945–4949 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Abuzeid, W. M. et al. Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy. J. Clin. Invest. 119, 1974–1985 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Pabla, N. & Dong, Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 73, 994–1007 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Wagner, J. M. & Karnitz, L. M. Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumor cell survival. Mol. Pharmacol. 76, 208–214 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Zhu, S., Pabla, N., Tang, C., He, L. & Dong, Z. DNA damage response in cisplatin-induced nephrotoxicity. Arch. Toxicol. 89, 2197–2205 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Park, S. B. et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J. Clin. 63, 419–437 (2013).

    Article  PubMed  Google Scholar 

  70. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Sonis, S. T. The pathobiology of mucositis. Nat. Rev. Cancer 4, 277–284 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Kim, S., Lee, T. J., Park, J. W. & Kwon, T. K. Overexpression of cFLIPs inhibits oxaliplatin-mediated apoptosis through enhanced XIAP stability and Akt activation in human renal cancer cells. J. Cell. Biochem. 105, 971–979 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Laurent, A. et al. Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res. 65, 948–956 (2005).

    CAS  PubMed  Google Scholar 

  74. Gui, Q. F., Lu, H. F., Zhang, C. X., Xu, Z. R. & Yang, Y. H. Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model. Genet. Mol. Res. 14, 5642–5651 (2015).

    Article  PubMed  Google Scholar 

  75. Tesniere, A. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Michaud, M. et al. Subversion of the chemotherapy-induced anticancer immune response by the ecto-ATPase CD39. Oncoimmunology 1, 393–395 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Pateras, I. S. et al. The DNA damage response and immune signaling alliance: is it good or bad? Nature decides when and where. Pharmacol. Ther. 154, 36–56 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013). This paper reviewed the mechanisms underlying the phenomenon of immunogenic cell death in cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  81. Zwielehner, J. et al. Changes in human fecal microbiota due to chemotherapy analyzed by TaqMan-PCR, 454 sequencing and PCR-DGGE fingerprinting. PLoS ONE 6, e28654 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Daillere, R. et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45, 931–943 (2016). This paper characterized the role of different bacterial species in regulating antitumour T cell responses induced by CTX.

    Article  CAS  PubMed  Google Scholar 

  83. Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-beta signalling. Nature 467, 967–971 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Chitapanarux, I. et al. Randomized controlled trial of live Lactobacillus acidophilus plus Bifidobacterium bifidum in prophylaxis of diarrhea during radiotherapy in cervical cancer patients. Radiat. Oncol. 5, 31 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wang, Y. et al. Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism. Food Chem. Toxicol. 83, 251–260 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Cario, E. Toll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity. Curr. Opin. Support. Palliat. Care 10, 157–164 (2016).

    Article  PubMed  Google Scholar 

  87. Frank, M. et al. TLR signaling modulates side effects of anticancer therapy in the small intestine. J. Immunol. 194, 1983–1995 (2015).

    Article  PubMed  CAS  Google Scholar 

  88. Mercado-Lubo, R. & McCormick, B. A. The interaction of gut microbes with host ABC transporters. Gut Microbes 1, 301–306 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Napenas, J. J. et al. Molecular methodology to assess the impact of cancer chemotherapy on the oral bacterial flora: a pilot study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 109, 554–560 (2010).

    Article  PubMed  Google Scholar 

  90. Niu, Q. Y., Li, Z. Y., Du, G. H. & Qin, X. M. 1H NMR based metabolomic profiling revealed doxorubicin-induced systematic alterations in a rat model. J. Pharm. Biomed. Anal. 118, 338–348 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Rigby, R. J. et al. Intestinal bacteria are necessary for doxorubicin-induced intestinal damage but not for doxorubicin-induced apoptosis. Gut Microbes 7, 414–423 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Nigro, G., Rossi, R., Commere, P. H., Jay, P. & Sansonetti, P. J. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 15, 792–798 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).

    Article  PubMed  CAS  Google Scholar 

  94. Parseus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 66, 429–437 (2016).

    Article  PubMed  CAS  Google Scholar 

  95. Das, S. K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Ruud, J. et al. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells. FASEB J. 27, 1973–1980 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Suárez-Zamorano, N. et al. Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat. Med. 21, 1497–1501 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. de Matos-Neto, E. M. et al. Systemic inflammation in cachexia — is tumor cytokine expression profile the culprit? Front. Immunol. 6, 629 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Antoun, S., Baracos, V. E., Birdsell, L., Escudier, B. & Sawyer, M. B. Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann. Oncol. 21, 1594–1598 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Toledo, M. et al. A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy. J. Cachexia Sarcopenia Muscle 7, 48–59 (2016).

    Article  PubMed  Google Scholar 

  101. Conte, E. et al. Cisplatin-induced cachexia in rats causes alterations in skeletal muscle calcium homeostasis. Biophys. J. 108 (Suppl. 1), 108a (2015).

    Article  Google Scholar 

  102. Garcia, J. M., Cata, J. P., Dougherty, P. M. & Smith, R. G. Ghrelin prevents cisplatin-induced mechanical hyperalgesia and cachexia. Endocrinology 149, 455–460 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Bruggeman, A. R. et al. Cancer cachexia: beyond weight loss. J. Oncol. Pract. 12, 1163–1171 (2016).

    Article  PubMed  Google Scholar 

  104. Cvan Trobec, K. et al. Influence of cancer cachexia on drug liver metabolism and renal elimination in rats. J. Cachexia Sarcopenia Muscle 6, 45–52 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bindels, L. B. & Delzenne, N. M. Muscle wasting: the gut microbiota as a new therapeutic target? Int. J. Biochem. Cell Biol. 45, 2186–2190 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Klein, G. L., Petschow, B. W., Shaw, A. L. & Weaver, E. Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target. Curr. Opin. Support. Palliat. Care 7, 361–367 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Yeh, K. Y. et al. Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 116, 41–48 (2013).

    Article  PubMed  Google Scholar 

  108. Varian, B. J. et al. Beneficial bacteria inhibit cachexia. Oncotarget 7, 11803–11816 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Schieber, A. M. P. et al. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science 350, 558–563 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Mavragani, I. V. et al. Key mechanisms involved in ionizing radiation-induced systemic effects. A current review. Toxicol. Res. 5, 12–33 (2016).

    Article  Google Scholar 

  111. Azzam, E. I. & Little, J. B. The radiation-induced bystander effect: evidence and significance. Hum. Exp. Toxicol. 23, 61–65 (2004).

    Article  PubMed  Google Scholar 

  112. Vacchelli, E. et al. Trial Watch: anticancer radioimmunotherapy. Oncoimmunology 2, e25595 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Nikitaki, Z. et al. Systemic mechanisms and effects of ionizing radiation: a new 'old' paradigm of how the bystanders and distant can become the players. Semin. Cancer Biol. 37–38, 77–95 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Ermolaeva, M. A. et al. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501, 416–420 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Al-Mayah, A. et al. The non-targeted effects of radiation are perpetuated by exosomes. Mutat. Res. 772, 38–45 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Demaria, S. & Formenti, S. C. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front. Oncol. 2, 153 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  118. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870 (2004).

    Article  PubMed  Google Scholar 

  119. Zitvogel, L., Ayyoub, M., Routy, B. & Kroemer, G. Microbiome and anticancer immunosurveillance. Cell 165, 276–287 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Deng, L. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Baird, J. R. et al. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors. Cancer Res. 76, 50–61 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Barker, H. E., Paget, J. T. E., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Touchefeu, Y. et al. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis — current evidence and potential clinical applications. Aliment. Pharmacol. Ther. 40, 409–421 (2014).

    CAS  PubMed  Google Scholar 

  124. Vanhoecke, B. W. et al. Low-dose irradiation affects the functional behavior of oral microbiota in the context of mucositis. Exp. Biol. Med. (Maywood) 241, 60–70 (2016).

    Article  CAS  Google Scholar 

  125. Broin, P. Ó. et al. Intestinal microbiota-derived metabolomic blood plasma markers for prior radiation injury. Int. J. Radiat. Oncol. Biol. Phys. 91, 360–367 (2015).

    Article  PubMed Central  Google Scholar 

  126. Wang, A. et al. Gut microbial dysbiosis may predict diarrhea and fatigue in patients undergoing pelvic cancer radiotherapy: a pilot study. PLoS ONE 10, e0126312 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Takemura, N. et al. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat. Commun. 5, 3492 (2014).

    Article  PubMed  CAS  Google Scholar 

  128. Vacchelli, E. et al. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2, e25238 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Hu, B. et al. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 354, 765–768 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Ciorba, M. A. et al. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut 61, 829–838 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Jones, R. M. et al. Lactobacilli modulate epithelial cytoprotection through the Nrf2 pathway. Cell Rep. 12, 1217–1225 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Jones, R. M. et al. Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. EMBO J. 32, 3017–3028 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Delia, P. et al. Use of probiotics for prevention of radiation-induced diarrhea. World J. Gastroenterol. 13, 912–915 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Sharma, A. et al. Lactobacillus brevis CD2 lozenges reduce radiation- and chemotherapy-induced mucositis in patients with head and neck cancer: a randomized double-blind placebo-controlled study. Eur. J. Cancer 48, 875–881 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Crawford, P. A. & Gordon, J. I. Microbial regulation of intestinal radiosensitivity. Proc. Natl Acad. Sci. USA 102, 13254–13259 (2005). This paper describes the radioresistance of germ-free mice and characterized the underlying molecular mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Santulli, G. Angiopoietin-like proteins: a comprehensive look. Front. Endocrinol. 5, 4 (2014).

    Article  Google Scholar 

  137. Grootaert, C. et al. Bacterial monocultures, propionate, butyrate and H2O2 modulate the expression, secretion and structure of the fasting-induced adipose factor in gut epithelial cell lines. Environ. Microbiol. 13, 1778–1789 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Jacouton, E. et al. Lactobacillus rhamnosus CNCMI-4317 modulates Fiaf/Angptl4 in intestinal epithelial cells and circulating level in mice. PLoS ONE 10, e0138880 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Korecka, A. et al. ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1025–G1037 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Duncan, A. M., Ronen, A. & Blakey, D. H. Diurnal variation in the response of gamma-ray-induced apoptosis in the mouse intestinal epithelium. Cancer Lett. 21, 163–166 (1983).

    Article  CAS  PubMed  Google Scholar 

  141. Ishihara, H. et al. Circadian transitions in radiation dose-dependent augmentation of mRNA levels for DNA damage-induced genes elicited by accurate real-time RT-PCR quantification. J. Radiat. Res. 51, 265–275 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. Ruifrok, A. C., Weil, M. M., Thames, H. D. & Mason, K. A. Diurnal variations in the expression of radiation-induced apoptosis. Radiat. Res. 149, 360–365 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Leone, V. et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 17, 681–689 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Liang, X., Bushman, F. D. & FitzGerald, G. A. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc. Natl Acad. Sci. USA 112, 10479–10484 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mukherji, A., Kobiita, A., Ye, T. & Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153, 812–827 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Nguyen, K. D. et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6Chi inflammatory monocytes. Science 341, 1483–1488 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).

    Article  CAS  PubMed  Google Scholar 

  148. Maier, I., Berry, D. M. & Schiestl, R. H. Intestinal microbiota reduces genotoxic endpoints induced by high-energy protons. Radiat. Res. 181, 45–53 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714–726 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015). This paper demonstrated that the presence of Bifidobacterium spp. in the gut microbiota promotes antitumour immunity in mice that is amplified by anti-PDL1 therapy.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Paulos, C. M. et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117, 2197–2204 (2007). This paper used a therapy model of adoptive T cell transfer preceded by TBI in mice, to demonstrate for the first time that the microbiota modulates anticancer therapy.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Dudley, M. E. et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26, 5233–5239 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Guiducci, C., Vicari, A. P., Sangaletti, S., Trinchieri, G. & Colombo, M. P. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65, 3437–3446 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Vicari, A. P. et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J. Exp. Med. 196, 541–549 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Stewart, C. A. et al. Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. J. Clin. Invest. 123, 4859–4874 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Eggermont, A. M. Therapeutic vaccines in solid tumours: can they be harmful? Eur. J. Cancer 45, 2087–2090 (2009).

    Article  CAS  PubMed  Google Scholar 

  161. Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P. & Wolchok, J. D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65, 185–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Teply, B. A. & Lipson, E. J. Identification and management of toxicities from immune checkpoint-blocking drugs. Oncology (Williston Park) 28 (Suppl. 3), 30–38 (2014).

    Google Scholar 

  164. Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Hand, T. W. et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337, 1553–1556 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Yang, X. et al. Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell 25, 37–48 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Zitvogel, L., Pitt, J. M., Daillere, R., Smyth, M. J. & Kroemer, G. Mouse models in oncoimmunology. Nat. Rev. Cancer 16, 759–773 (2016).

    Article  CAS  PubMed  Google Scholar 

  168. Ivanov, I. I., Frutos Rde, L., Manel, N., Yoshinaga, K. & Rifkin, D. B. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Wheeler, M. L. et al. Immunological consequences of intestinal fungal dysbiosis. Cell Host Microbe 19, 865–873 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Howitt, M. R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Cadwell, K. The virome in host health and disease. Immunity 42, 805–813 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Ramanan, D. et al. Helminth infection promotes colonization resistance via type 2 immunity. Science 352, 608–612 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Young, G. R. et al. Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491, 774–778 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl Med. 1, 6ra14 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Baxter, N. T., Zackular, J. P., Chen, G. Y. & Schloss, P. D. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome 2, 20 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Plantinga, T. S. et al. Differential Toll-like receptor recognition and induction of cytokine profile by Bifidobacterium breve and Lactobacillus strains of probiotics. Clin. Vaccine Immunol. 18, 621–628 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Kadowaki, N. et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Pamer, E. G. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 352, 535–538 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Goldszmid, R. S. & Trinchieri, G. The price of immunity. Nat. Immunol. 13, 932–938 (2012).

    Article  CAS  PubMed  Google Scholar 

  183. Jobin, C. Colorectal cancer: CRC — all about microbial products and barrier function? Nat. Rev. Gastroenterol. Hepatol. 9, 694–696 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Rao, V. P. et al. Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice. Cancer Res. 66, 7395–7400 (2006).

    Article  CAS  PubMed  Google Scholar 

  185. Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Sears, C. L. & Garrett, W. S. Microbes, microbiota, and colon cancer. Cell Host Microbe 15, 317–328 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Kostic, A. D. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Rubinstein, M. R. et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe 14, 195–206 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Gur, C. et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42, 344–355 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Schistosomes, liver flukes and Helicobacter pylori. Lyon, 7–14 June 1994. IARC Monogr. Eval. Carcinog. Risks Hum. 61, 1–241 (1994).

  192. Poutahidis, T. et al. Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice. PLoS ONE 8, e73933 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Fox, J. G. et al. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut 59, 88–97 (2010).

    Article  PubMed  CAS  Google Scholar 

  194. Yamamoto, M. L. et al. Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity. Cancer Res. 73, 4222–4232 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Farrell, J. J. et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut 61, 582–588 (2012).

    Article  CAS  PubMed  Google Scholar 

  196. Fan, X. et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut http://dx.doi.org/10.1136/gutjnl-2016-312580 (2016).

  197. Westbrook, A. M. et al. The role of tumour necrosis factor-alpha and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity. Mutagenesis 27, 77–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  198. Gyurkocza, B., Rezvani, A. & Storb, R. F. Allogeneic hematopoietic cell transplantation: the state of the art. Expert Rev. Hematol. 3, 285–299 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Taur, Y., Jenq, R. R., Ubeda, C., van den Brink, M. & Pamer, E. G. Role of intestinal microbiota in transplantation outcomes. Best Pract. Res. Clin. Haematol. 28, 155–161 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Taur, Y. et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124, 1174–1182 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Jenq, R. R. et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209, 903–911 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Holler, E. et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol. Blood Marrow Transplant. 20, 640–645 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Taur, Y. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis. 55, 905–914 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Jenq, R. R. et al. Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol. Blood Marrow Transplant. 21, 1373–1383 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Ho, J. T. K., Chan, G. C. F. & Li, J. C. B. Systemic effects of gut microbiota and its relationship with disease and modulation. BMC Immunol. 16, 21 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Boleij, A. et al. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin. Infect. Dis. 60, 208–215 (2015).

    Article  CAS  PubMed  Google Scholar 

  207. Koshiol, J. et al. Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis. Cancer Med. 5, 3310–3235 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Lecuit, M. et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N. Engl. J. Med. 350, 239–248 (2004).

    Article  CAS  PubMed  Google Scholar 

  209. Senff, N. J. et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 112, 1600–1609 (2008).

    Article  CAS  PubMed  Google Scholar 

  210. Ferreri, A. J. et al. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J. Clin. Oncol. 30, 2988–2994 (2012).

    Article  CAS  PubMed  Google Scholar 

  211. Lakritz, J. R. et al. Gut bacteria require neutrophils to promote mammary tumorigenesis. Oncotarget 6, 9387–9396 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Rutkowski, M. R. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40 (2015).

    Article  CAS  PubMed  Google Scholar 

  213. Chu, H. & Mazmanian, S. K. Innate immune recognition of the microbiota promotes host–microbial symbiosis. Nat. Immunol. 14, 668–675 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. McFall-Ngai, M. et al. Animals in a bacterial world, a new imperative for the life sciences. Proc. Natl Acad. Sci. USA 110, 3229–3236 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Kremer, N. et al. Initial symbiont contact orchestrates host-organ-wide transcriptional changes that prime tissue colonization. Cell Host Microbe 14, 183–194 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Hansen, C. H. et al. Patterns of early gut colonization shape future immune responses of the host. PLoS ONE 7, e34043 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Stappenbeck, T. S., Hooper, L. V. & Gordon, J. I. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Le, Y. et al. Biologically active peptides interacting with the G protein-coupled formylpeptide receptor. Protein Pept. Lett. 14, 846–853 (2007).

    Article  CAS  PubMed  Google Scholar 

  219. Chen, K. et al. Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis. J. Clin. Invest. 123, 1694–1704 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giorgio Trinchieri.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Germ-free animals

Animals raised in strict sterile conditions that have no microorganisms living in or on them.

Commensalism

A symbiotic relationship between two species in which one species benefits without causing harm to the other.

Pathobionts

Resident commensal microorganisms that under certain conditions may acquire pathogenic potential.

Mutualism

A symbiotic relationship between two species that is beneficial for both species.

Xenobiotics

Foreign chemical substances, including drugs, that are not naturally produced by the organism.

Biotransformation

The chemical alteration of a xenobiotic, such as a drug, within the body.

Probiotic

Live microorganisms that are consumed by humans and animals as food supplements for their potential health-promoting qualities.

Pathogenic T helper 17 cells

(pTH17 cells). A CD4+ T cell subset that simultaneously expresses markers of TH1 cells (T-bet transcription factor, interferon–γ (IFN–γ) and CXC chemokine receptor 3 (CXCR3)) and of TH17 cells (RORγT transcription factor, interleukin-17 (IL-17) and C-C chemokine receptor 6 (CCR6)).

Cachexia

A wasting syndrome with muscle atrophy and loss of weight and adipose tissue, often associated with cancer and cancer therapy.

Bystander effect

In radiobiology, collateral damage exhibited by unirradiated cells in response to signals received from nearby irradiated cells.

Abscopal effect

In radiotherapy, a phenomenon whereby local radiotherapy induces tumour regression at sites distant from the irradiated site.

Prebiotics

Non-digestible food ingredients, often containing fibre, that promote the growth of beneficial microorganisms in the intestines.

Enterotypes

Classification of individuals based on the composition of their gut bacterial ecosystem, each enterotype having distinct clusters of organisms with characteristic predominant bacterial species.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Roy, S., Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17, 271–285 (2017). https://doi.org/10.1038/nrc.2017.13

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2017.13

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer