The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies

Science

Volumn 359, Issue 6382, 2018, Pages 1366-1370

  Zitvogel, Laurence ^a,b,c,d   Ma, Yuting ^e,f   Raoult, Didier ^g   Kroemer, Guido ^h,i   Gajewski, Thomas F ^j  

^a INSTITUT GUSTAVE ROUSSY   (France)

^b INSERM   (France)

^c UNIVERSITÉ PARIS SACLAY   (France)

^d Center of Clinical Investigations in Biotherapies of Cancer (CICBT)   (France)

^e INSTITUTE OF BASIC MEDICAL SCIENCES   (China)

^f SUZHOU INSTITUTE OF SYSTEMS MEDICINE   (China)

^g AIX MARSEILLE UNIVERSITÉ   (France)

^h CENTRE DE RECHERCHE DES CORDELIERS   (France)

ⁱ GRCC   (France)

^j UNIVERSITY OF CHICAGO   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; CYCLOPHOSPHAMIDE; FLUOROURACIL; IPILIMUMAB; LIPOPOLYSACCHARIDE; NIVOLUMAB; OXALIPLATIN; PEMBROLIZUMAB;

BIOME; CANCER; DETECTION METHOD; DISEASE; IMMUNE SYSTEM; IMMUNIZATION; MEDICINE;

AKKERMANSIA MUCINIPHILA; ALISTIPES; ALISTIPES SHAHII; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; BACTERIAL STRAIN; BACTEROIDES FRAGILIS; BARNESIELLA INTESTINIHOMINIS; BIFIDOBACTERIUM; BLAUTIA; BURKHOLDERIALES; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER PATIENT; CANCER RISK; CARCINOGENESIS; CLOSTRIDIALES; CLOSTRIDIUM; CLOSTRIDIUM DIFFICILE INFECTION; CLOSTRIDIUM ORBISCINDENS; COLITIS; COLLINSELLA; DISEASE SEVERITY; ENTEROCOCCUS; ENTEROCOCCUS FAECIUM; ENTEROCOCCUS HIRAE; EUBACTERIUM LIMOSUM; FAECALIBACTERIUM; FECAL MICROBIOTA TRANSPLANTATION; FUSOBACTERIUM NUCLEATUM; GAMMAPROTEOBACTERIA; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNOGENICITY; IMMUNOSUPPRESSIVE TREATMENT; INFECTION; INTESTINE FLORA; INTESTINE MUCOSA PERMEABILITY; LUNG CANCER; METASTATIC MELANOMA; NONHUMAN; PERSONALIZED MEDICINE; PORPHYROMONADACEAE; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROSPECTIVE STUDY; REVIEW; RISK FACTOR; RUMINOCOCCACEAE; SYMBIOSIS; TUMOR MICROENVIRONMENT; GENETICS; IMMUNE SYSTEM; IMMUNOTHERAPY; METAGENOME; MICROBIOLOGY; NEOPLASM; PROCEDURES; TREATMENT OUTCOME;

GASTROINTESTINAL MICROBIOME; HUMANS; IMMUNE SYSTEM; IMMUNOTHERAPY; METAGENOME; NEOPLASMS; TREATMENT OUTCOME;

EID: 85046048647     PISSN: 00368075     EISSN: 10959203     Source Type: Journal    
DOI: 10.1126/science.aar6918     Document Type: Review

References (74)

1. P. Sharma, S. Hu-Lieskovan, J. A. Wargo, A. Ribas, Primary, Adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017). doi:10.1016/j.cell.2017.01.017
2. D. S. Chen, I. Mellman, Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017). doi:10.1038/nature21349
3. T. S. Stappenbeck, H. W. Virgin, Accounting for reciprocal host-microbiome interactions in experimental science. Nature 534, 191–199 (2016). doi:10.1038/nature18285
4. W. M. de Vos, E. A. de Vos, Role of the intestinal microbiome in health and disease: From correlation to causation. Nutr. Rev. 70 (suppl. 1), S45–S56 (2012). doi:10.1111/j.17534887.2012.00505.x
5. R. Sender, S. Fuchs, R. Milo, Revised estimates for the number of human and bacteria cells in the body. PLOS Biol. 14, e1002533 (2016). doi:10.1371/journal.pbio.1002533
6. Y. Belkaid, S. Naik, Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 14, 646–653 (2013). doi:10.1038/ni.2604
7. S. P. Rosshart, B. G. Vassallo, D. Angeletti, D. S. Hutchinson, A. P. Morgan, K. Takeda, H. D. Hickman, J. A. McCulloch, J. H. Badger, N. J. Ajami, G. Trinchieri, F. Pardo-Manuel de Villena, J. W. Yewdell, B. Rehermann, Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 171, 1015.e13–1028.e13 (2017). doi:10.1016/j.cell.2017.09.016
8. A. Dzutsev, J. H. Badger, E. Perez-Chanona, S. Roy, R. Salcedo, C. K. Smith, G. Trinchieri, Microbes and cancer. Annu. Rev. Immunol. 35, 199–228 (2017). doi:10.1146/annurevimmunol-051116-052133
9. L. Zitvogel, R. Daillère, M. P. Roberti, B. Routy, G. Kroemer, Anticancer effects of the microbiome and its products. Nat. Rev. Microbiol. 15, 465–478 (2017). doi:10.1038/nrmicro.2017.44
10. + T cells via TLR4 signaling. J. Clin. Invest. 117, 2197–2204 (2007). doi:10.1172/JCI32205
11. N. Iida, A. Dzutsev, C. A. Stewart, L. Smith, N. Bouladoux, R. A. Weingarten, D. A. Molina, R. Salcedo, T. Back, S. Cramer, R.-M. Dai, H. Kiu, M. Cardone, S. Naik, A. K. Patri, E. Wang, F. M. Marincola, K. M. Frank, Y. Belkaid, G. Trinchieri, R. S. Goldszmid, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013). doi:10.1126/science.1240527
12. S. Viaud, F. Saccheri, G. Mignot, T. Yamazaki, R. Daillère, D. Hannani, D. P. Enot, C. Pfirschke, C. Engblom, M. J. Pittet, A. Schlitzer, F. Ginhoux, L. Apetoh, E. Chachaty, P.-L. Woerther, G. Eberl, M. Bérard, C. Ecobichon, D. Clermont, C. Bizet, V. Gaboriau-Routhiau, N. Cerf-Bensussan, P. Opolon, N. Yessaad, E. Vivier, B. Ryffel, C. O. Elson, J. Doré, G. Kroemer, P. Lepage, I. G. Boneca, F. Ghiringhelli, L. Zitvogel, The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013). doi:10.1126/science.1240537
13. M. Vétizou, J. M. Pitt, R. Daillère, P. Lepage, N. Waldschmitt, C. Flament, S. Rusakiewicz, B. Routy, M. P. Roberti, C. P. M. Duong, V. Poirier-Colame, A. Roux, S. Becharef, S. Formenti, E. Golden, S. Cording, G. Eberl, A. Schlitzer, F. Ginhoux, S. Mani, T. Yamazaki, N. Jacquelot, D. P. Enot, M. Bérard, J. Nigou, P. Opolon, A. Eggermont, P.-L. Woerther, E. Chachaty, N. Chaput, C. Robert, C. Mateus, G. Kroemer, D. Raoult, I. G. Boneca, F. Carbonnel, M. Chamaillard, L. Zitvogel, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). doi:10.1126/science.aad1329
14. B. Routy, E. Le Chatelier, L. Derosa, C. P. M. Duong, M. T. Alou, R. Daillère, A. Fluckiger, M. Messaoudene, C. Rauber, M. P. Roberti, M. Fidelle, C. Flament, V. Poirier-Colame, P. Opolon, C. Klein, K. Iribarren, L. Mondragón, N. Jacquelot, B. Qu, G. Ferrere, C. Clémenson, L. Mezquita, J. R. Masip, C. Naltet, S. Brosseau, C. Kaderbhai, C. Richard, H. Rizvi, F. Levenez, N. Galleron, B. Quinquis, N. Pons, B. Ryffel, V. Minard-Colin, P. Gonin, J.-C. Soria, E. Deutsch, Y. Loriot, F. Ghiringhelli, G. Zalcman, F. Goldwasser, B. Escudier, M. D. Hellmann, A. Eggermont, D. Raoult, L. Albiges, G. Kroemer, L. Zitvogel, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). doi:10.1126/science.aan3706
15. A. Sivan, L. Corrales, N. Hubert, J. B. Williams, K. Aquino-Michaels, Z. M. Earley, F. W. Benyamin, Y. M. Lei, B. Jabri, M.-L. Alegre, E. B. Chang, T. F. Gajewski, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015). doi:10.1126/science.aac4255
16. R. Daillère, M. Vétizou, N. Waldschmitt, T. Yamazaki, C. Isnard, V. Poirier-Colame, C. P. M. Duong, C. Flament, P. Lepage, M. P. Roberti, B. Routy, N. Jacquelot, L. Apetoh, S. Becharef, S. Rusakiewicz, P. Langella, H. Sokol, G. Kroemer, D. Enot, A. Roux, A. Eggermont, E. Tartour, L. Johannes, P.-L. Woerther, E. Chachaty, J.-C. Soria, E. Golden, S. Formenti, M. Plebanski, M. Madondo, P. Rosenstiel, D. Raoult, V. Cattoir, I. G. Boneca, M. Chamaillard, L. Zitvogel, Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45, 931–943 (2016). doi:10.1016/j.immuni.2016.09.009
17. R. R. Jenq, Y. Taur, S. M. Devlin, D. M. Ponce, J. D. Goldberg, K. F. Ahr, E. R. Littmann, L. Ling, A. C. Gobourne, L. C. Miller, M. D. Docampo, J. U. Peled, N. Arpaia, J. R. Cross, T. K. Peets, M. A. Lumish, Y. Shono, J. A. Dudakov, H. Poeck, A. M. Hanash, J. N. Barker, M.-A. Perales, S. A. Giralt, E. G. Pamer, M. R. M. van den Brink, Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol. Blood Marrow Transplant. 21, 1373–1383 (2015). doi:10.1016/j.bbmt.2015.04.016
18. N. Chaput, P. Lepage, C. Coutzac, E. Soularue, K. Le Roux, C. Monot, L. Boselli, E. Routier, L. Cassard, M. Collins, T. Vaysse, L. Marthey, A. Eggermont, V. Asvatourian, E. Lanoy, C. Mateus, C. Robert, F. Carbonnel, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28, 1368–1379 (2017). doi:10.1093/annonc/mdx108
19. V. Gopalakrishnan et al., Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 358, eaan4236 (2017).
20. V. Matson, J. Fessler, R. Bao, T. Chongsuwat, Y. Zha, M.-L. Alegre, J. J. Luke, T. F. Gajewski, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018). doi:10.1126/science.aao3290
21. J. U. Peled, S. M. Devlin, A. Staffas, M. Lumish, R. Khanin, E. R. Littmann, L. Ling, S. Kosuri, M. Maloy, J. B. Slingerland, K. F. Ahr, K. A. Porosnicu Rodriguez, Y. Shono, A. E. Slingerland, M. D. Docampo, A. D. Sung, D. Weber, A. M. Alousi, B. Gyurkocza, D. M. Ponce, J. N. Barker, M.-A. Perales, S. A. Giralt, Y. Taur, E. G. Pamer, R. R. Jenq, M. R. M. van den Brink, Intestinal microbiota and relapse after hematopoietic-cell transplantation. J. Clin. Oncol. 35, 1650–1659 (2017). doi:10.1200/JCO.2016.70.3348
22. K. Dubin, M. K. Callahan, B. Ren, R. Khanin, A. Viale, L. Ling, D. No, A. Gobourne, E. Littmann, C. Huttenhower, E. G. Pamer, J. D. Wolchok, Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016). doi:10.1038/ncomms10391
23. R. Hebbandi Nanjundappa, F. Ronchi, J. Wang, X. Clemente-Casares, J. Yamanouchi, C. Sokke Umeshappa, Y. Yang, J. Blanco, H. Bassolas-Molina, A. Salas, H. Khan, R. M. Slattery, M. Wyss, C. Mooser, A. J. Macpherson, L. K. Sycuro, P. Serra, D. M. McKay, K. D. McCoy, P. Santamaria, A gut microbial mimic that hijacks diabetogenic autoreactivity to suppress colitis. Cell 171, 655–667.e17 (2017). doi:10.1016/j.cell.2017.09.022
24. V. P. Balachandran, M. Luksza, J. N. Zhao, V. Makarov, J. A. Moral, R. Remark, B. Herbst, G. Askan, U. Bhanot, Y. Senbabaoglu, D. K. Wells, C. I. O. Cary, O. Grbovic-Huezo, M. Attiyeh, B. Medina, J. Zhang, J. Loo, J. Saglimbeni, M. Abu-Akeel, R. Zappasodi, N. Riaz, M. Smoragiewicz, Z. L. Kelley, O. Basturk, M. Gönen, A. J. Levine, P. J. Allen, D. T. Fearon, M. Merad, S. Gnjatic, C. A. Iacobuzio-Donahue, J. D. Wolchok, R. P. DeMatteo, T. A. Chan, B. D. Greenbaum, T. Merghoub, S. D. Leach, Australian Pancreatic Cancer Genome Initiative, Garvan Institute of Medical Research, Prince of Wales Hospital, Royal North Shore Hospital, University of Glasgow, St Vincent’s Hospital, QIMR Berghofer Medical Research Institute, University of Melbourne, Centre for Cancer Research, University of Queensland, Institute for Molecular Bioscience, Bankstown Hospital, Liverpool Hospital, Royal Prince Alfred Hospital, Chris O’Brien Lifehouse, Westmead Hospital, Fremantle Hospital, St John of God Healthcare, Royal Adelaide Hospital, Flinders Medical Centre, Envoi Pathology, Princess Alexandria Hospital, Austin Hospital, Johns Hopkins Medical Institutes, ARC-Net Centre for Applied Research on Cancer, Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).
25. H. Takada et al., Molecular and structural requirements of a lipoteichoic acid from Enterococcus hirae ATCC 9790 for cytokine-inducing, antitumor, and antigenic activities. Infect. Immun. 63, 57–65 (1995).
26. N. Yissachar, Y. Zhou, L. Ung, N. Y. Lai, J. F. Mohan, A. Ehrlicher, D. A. Weitz, D. L. Kasper, I. M. Chiu, D. Mathis, C. Benoist, An intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk. Cell 168, 1135–1148.e12 (2017). doi:10.1016/j.cell.2017.02.009
27. F. Pietrocola, J. Pol, E. Vacchelli, S. Rao, D. P. Enot, E. E. Baracco, S. Levesque, F. Castoldi, N. Jacquelot, T. Yamazaki, L. Senovilla, G. Marino, F. Aranda, S. Durand, V. Sica, A. Chery, S. Lachkar, V. Sigl, N. Bloy, A. Buque, S. Falzoni, B. Ryffel, L. Apetoh, F. Di Virgilio, F. Madeo, M. C. Maiuri, L. Zitvogel, B. Levine, J. M. Penninger, G. Kroemer, Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016). doi:10.1016/j.ccell.2016.05.016
28. P. Joglekar, J. A. Segre, Building a translational microbiome toolbox. Cell 169, 378–380 (2017). doi:10.1016/j.cell.2017.04.009
29. E. van Nood, A. Vrieze, M. Nieuwdorp, S. Fuentes, E. G. Zoetendal, W. M. de Vos, C. E. Visser, E. J. Kuijper, J. F. W. M. Bartelsman, J. G. P. Tijssen, P. Speelman, M. G. W. Dijkgraaf, J. J. Keller, Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). doi:10.1056/NEJMoa1205037
30. N. Alang, C. R. Kelly, Weight gain after fecal microbiota transplantation. Open Forum Infect. Dis. 2, ofv004 (2015). doi:10.1093/ofid/ofv004
31. S. H. Wong, L. Zhao, X. Zhang, G. Nakatsu, J. Han, W. Xu, X. Xiao, T. N. Y. Kwong, H. Tsoi, W. K. K. Wu, B. Zeng, F. K. L. Chan, J. J. Y. Sung, H. Wei, J. Yu, Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germfree and conventional mice. Gastroenterology 153, 1621–1633.e6 (2017). doi:10.1053/j.gastro.2017.08.022
32. P. Moayyedi, Y. Yuan, H. Baharith, A. C. Ford, Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: A systematic review of randomised controlled trials. Med. J. Aust. 207, 166–172 (2017). doi:10.5694/mja17.00295
33. S. Caballero, S. Kim, R. A. Carter, I. M. Leiner, B. Sušac, L. Miller, G. J. Kim, L. Ling, E. G. Pamer, Cooperating commensals restore colonization resistance to vancomycinresistant Enterococcus faecium. Cell Host Microbe 21, 592–602.e4 (2017). doi:10.1016/j.chom.2017.04.002
34. T. Odamaki, A. Horigome, H. Sugahara, N. Hashikura, J. Minami, J. Z. Xiao, F. Abe, Comparative genomics revealed genetic diversity and species/strain-level differences in carbohydrate metabolism of three probiotic Bifidobacterial species. Int. J. Genomics 2015, 567809 (2015). doi:10.1155/2015/567809
35. J. Zhang, Y. Hong, N. J. Harman, A. Das, P. D. Ebner, Genome sequence of a salmonella phage used to control salmonella transmission in Swine. Genome Announc. 2, e00521-14 (2014). doi:10.1128/genomeA.00521-14
36. S. J. Bultman, The microbiome and its potential as a cancer preventive intervention. Semin. Oncol. 43, 97–106 (2016). doi:10.1053/j.seminoncol.2015.09.001
37. C. A. Thaiss, M. Levy, T. Korem, L. Dohnalová, H. Shapiro, D. A. Jaitin, E. David, D. R. Winter, M. Gury-BenAri, E. Tatirovsky, T. Tuganbaev, S. Federici, N. Zmora, D. Zeevi, M. Dori-Bachash, M. Pevsner-Fischer, E. Kartvelishvily, A. Brandis, A. Harmelin, O. Shibolet, Z. Halpern, K. Honda, I. Amit, E. Segal, E. Elinav, Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510.e12 (2016). doi:10.1016/j.cell.2016.11.003
38. V. Venugopalan, K. A. Shriner, A. Wong-Beringer, Regulatory oversight and safety of probiotic use. Emerg. Infect. Dis. 16, 1661–1665 (2010). doi:10.3201/eid1611.100574
39. A. Enache-Angoulvant, C. Hennequin, Invasive Saccharomyces infection: A comprehensive review. Clin. Infect. Dis. 41, 1559–1568 (2005).
40. J. C. Lagier, S. Khelaifia, M. T. Alou, S. Ndongo, N. Dione, P. Hugon, A. Caputo, F. Cadoret, S. I. Traore, E. H. Seck, G. Dubourg, G. Durand, G. Mourembou, E. Guilhot, A. Togo, S. Bellali, D. Bachar, N. Cassir, F. Bittar, J. Delerce, M. Mailhe, D. Ricaboni, M. Bilen, N. P. M. Dangui Nieko, N. M. Dia Badiane, C. Valles, D. Mouelhi, K. Diop, M. Million, D. Musso, J. Abrahão, E. I. Azhar, F. Bibi, M. Yasir, A. Diallo, C. Sokhna, F. Djossou, V. Vitton, C. Robert, J. M. Rolain, B. La Scola, P.-E. Fournier, A. Levasseur, D. Raoult, Culture of previously uncultured members of the human gut microbiota by culturomics. Nat. Microbiol. 1, 16203 (2016). doi:10.1038/nmicrobiol.2016.203
41. N. Ottman, M. Davids, M. Suarez-Diez, S. Boeren, P. J. Schaap, V. A. P. Martins Dos Santos, H. Smidt, C. Belzer, W. M. de Vos, Genome-scale model and omics analysis of metabolic capacities of Akkermansia muciniphila reveal a preferential mucin-degrading lifestyle. Appl. Environ. Microbiol. 83, e01014-17 (2017). doi:10.1128/AEM.01014-17
42. H. Plovier, A. Everard, C. Druart, C. Depommier, M. Van Hul, L. Geurts, J. Chilloux, N. Ottman, T. Duparc, L. Lichtenstein, A. Myridakis, N. M. Delzenne, J. Klievink, A. Bhattacharjee, K. C. H. van der Ark, S. Aalvink, L. O. Martinez, M.-E. Dumas, D. Maiter, A. Loumaye, M. P. Hermans, J.-P. Thissen, C. Belzer, W. M. de Vos, P. D. Cani, A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017). doi:10.1038/nm.4236
43. C. S. Kang, M. Ban, E.-J. Choi, H.-G. Moon, J.-S. Jeon, D.-K. Kim, S.-K. Park, S. G. Jeon, T.-Y. Roh, S.-J. Myung, Y. S. Gho, J. G. Kim, Y.-K. Kim, Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLOS ONE 8, e76520 (2013). doi:10.1371/journal.pone.0076520
44. A. Hänninen, R. Toivonen, S. Pöysti, C. Belzer, H. Plovier, J. P. Ouwerkerk, R. Emani, P. D. Cani, W. M. De Vos, Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut 10.1136/gutjnl-2017-314508 (2017).
45. N. Geva-Zatorsky, E. Sefik, L. Kua, L. Pasman, T. G. Tan, A. Ortiz-Lopez, T. B. Yanortsang, L. Yang, R. Jupp, D. Mathis, C. Benoist, D. L. Kasper, Mining the human gut microbiota for immunomodulatory organisms. Cell 168, 928–943.e11 (2017). doi:10.1016/j.cell.2017.01.022
46. J. L. Round, S. M. Lee, J. Li, G. Tran, B. Jabri, T. A. Chatila, S. K. Mazmanian, The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011). doi:10.1126/science.1206095
47. J. L. Round, S. K. Mazmanian, The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009). doi:10.1038/nri2515
48. Y. Shen, M. L. Giardino Torchia, G. W. Lawson, C. L. Karp, J. D. Ashwell, S. K. Mazmanian, Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509–520 (2012). doi:10.1016/j.chom.2012.08.004
49. S. M. Lee, G. P. Donaldson, Z. Mikulski, S. Boyajian, K. Ley, S. K. Mazmanian, Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013). doi:10.1038/nature12447
50. + CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes 5, 552–561 (2014). doi:10.4161/gmic.29797
51. X. Liang, H. Li, G. Tian, S. Li, Dynamic microbe and molecule networks in a mouse model of colitis-associated colorectal cancer. Sci. Rep. 4, 4985 (2014). doi:10.1038/srep04985
52. L. B. Bindels, A. M. Neyrinck, N. Salazar, B. Taminiau, C. Druart, G. G. Muccioli, E. François, C. Blecker, A. Richel, G. Daube, J. Mahillon, C. G. de los Reyes-Gavilán, P. D. Cani, N. M. Delzenne, Non digestible Oligosaccharides modulate the gut microbiota to control the development of leukemia and associated cachexia in mice. PLOS ONE 10, e0131009 (2015). doi:10.1371/journal.pone.0131009
53. H. C. Huang, W.-Y. Huang, S.-H. Chiu, H.-J. Ke, S. W. Chiu, S.-Y. Wu, F.-S. Kuo, T.-M. Chang, Antimelanogenic and antioxidative properties of Bifidobacterium bifidum. Arch. Dermatol. Res. 303, 527–531 (2011). doi:10.1007/s00403-011-1135-y
54. A. L. Steed, G. P. Christophi, G. E. Kaiko, L. Sun, V. M. Goodwin, U. Jain, E. Esaulova, M. N. Artyomov, D. J. Morales, M. J. Holtzman, A. C. M. Boon, D. J. Lenschow, T. S. Stappenbeck, The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357, 498–502 (2017). doi:10.1126/science.aam5336
55. N. J. Roberts, L. Zhang, F. Janku, A. Collins, R.-Y. Bai, V. Staedtke, A. W. Rusk, D. Tung, M. Miller, J. Roix, K. V. Khanna, R. Murthy, R. S. Benjamin, T. Helgason, A. D. Szvalb, J. E. Bird, S. Roy-Chowdhuri, H. H. Zhang, Y. Qiao, B. Karim, J. McDaniel, A. Elpiner, A. Sahora, J. Lachowicz, B. Phillips, A. Turner, M. K. Klein, G. Post, L. A. Diaz Jr., G. J. Riggins, N. Papadopoulos, K. W. Kinzler, B. Vogelstein, C. Bettegowda, D. L. Huso, M. Varterasian, S. Saha, S. Zhou, Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci. Transl. Med. 6, 249ra111 (2014). doi:10.1126/scitranslmed.3008982
56. J. Pahle, L. Menzel, N. Niesler, D. Kobelt, J. Aumann, M. Rivera, W. Walther, Rapid eradication of colon carcinoma by Clostridium perfringens Enterotoxin suicidal gene therapy. BMC Cancer 17, 129 (2017). doi:10.1186/s12885-017-3123-x
57. C. Gur, Y. Ibrahim, B. Isaacson, R. Yamin, J. Abed, M. Gamliel, J. Enk, Y. Bar-On, N. Stanietsky-Kaynan, S. Coppenhagen-Glazer, N. Shussman, G. Almogy, A. Cuapio, E. Hofer, D. Mevorach, A. Tabib, R. Ortenberg, G. Markel, K. Miklic, S. Jonjic, C. A. Brennan, W. S. Garrett, G. Bachrach, O. Mandelboim, Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42, 344–355 (2015). doi:10.1016/j.immuni.2015.01.010
58. Y. Yang, W. Weng, J. Peng, L. Hong, L. Yang, Y. Toiyama, R. Gao, M. Liu, M. Yin, C. Pan, H. Li, B. Guo, Q. Zhu, Q. Wei, M.-P. Moyer, P. Wang, S. Cai, A. Goel, H. Qin, Y. Ma, Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating Toll-like receptor 4 signaling to nuclear factor-?b, and up-regulating expression of microRNA-21. Gastroenterology 152, 851–866.e24 (2017). doi:10.1053/j.gastro.2016.11.018
59. L. T. Geller, M. Barzily-Rokni, T. Danino, O. H. Jonas, N. Shental, D. Nejman, N. Gavert, Y. Zwang, Z. A. Cooper, K. Shee, C. A. Thaiss, A. Reuben, J. Livny, R. Avraham, D. T. Frederick, M. Ligorio, K. Chatman, S. E. Johnston, C. M. Mosher, A. Brandis, G. Fuks, C. Gurbatri, V. Gopalakrishnan, M. Kim, M. W. Hurd, M. Katz, J. Fleming, A. Maitra, D. A. Smith, M. Skalak, J. Bu, M. Michaud, S. A. Trauger, I. Barshack, T. Golan, J. Sandbank, K. T. Flaherty, A. Mandinova, W. S. Garrett, S. P. Thayer, C. R. Ferrone, C. Huttenhower, S. N. Bhatia, D. Gevers, J. A. Wargo, T. R. Golub, R. Straussman, Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017). doi:10.1126/science.aah5043
60. T. Yu, F. Guo, Y. Yu, T. Sun, D. Ma, J. Han, Y. Qian, I. Kryczek, D. Sun, N. Nagarsheth, Y. Chen, H. Chen, J. Hong, W. Zou, J.-Y. Fang, Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170, 548–563.e16 (2017). doi:10.1016/j.cell.2017.07.008
61. S. Bullman, C. S. Pedamallu, E. Sicinska, T. E. Clancy, X. Zhang, D. Cai, D. Neuberg, K. Huang, F. Guevara, T. Nelson, O. Chipashvili, T. Hagan, M. Walker, A. Ramachandran, B. Diosdado, G. Serna, N. Mulet, S. Landolfi, S. Ramon Y Cajal, R. Fasani, A. J. Aguirre, K. Ng, E. Élez, S. Ogino, J. Tabernero, C. S. Fuchs, W. C. Hahn, P. Nuciforo, M. Meyerson, Analysis of Fusobacteriumpersistence and antibiotic response in colorectal cancer. Science 358, 1443–1448 (2017). doi:10.1126/science.aal5240
62. T. Takahashi, A. Kushiro, K. Nomoto, K. Uchida, M. Morotomi, T. Yokokura, H. Akaza, Antitumor effects of the intravesical instillation of heat killed cells of the Lactobacillus casei strain Shirota on the murine orthotopic bladder tumor MBT-2. J. Urol. 166, 2506– 2511 (2001). doi:10.1016/S0022-5347(05)65625-X
63. A. Takagi, T. Matsuzaki, M. Sato, K. Nomoto, M. Morotomi, T. Yokokura, Enhancement of natural killer cytotoxicity delayed murine carcinogenesis by a probiotic microorganism. Carcinogenesis 22, 599–605 (2001). doi:10.1093/carcin/22.4.599
64. J. Sato, A. Kanazawa, K. Azuma, F. Ikeda, H. Goto, K. Komiya, R. Kanno, Y. Tamura, T. Asahara, T. Takahashi, K. Nomoto, Y. Yamashiro, H. Watada, Probiotic reduces bacterial translocation in type 2 diabetes mellitus: A randomised controlled study. Sci. Rep. 7, 12115 (2017). doi:10.1038/s41598-017-12535-9
65. G. L. Banna, F. Torino, F. Marletta, M. Santagati, R. Salemi, E. Cannarozzo, L. Falzone, F. Ferraù, M. Libra, Lactobacillus rhamnosus GG: An overview to explore the rationale of its use in cancer. Front. Pharmacol. 8, 603 (2017). doi:10.3389/fphar.2017.00603
66. K. Roszkowski, B. Nozdryn-Plotnicki, W. Roszkowski, H. L. Ko, J. Jeljaszewicz, G. Pulverer, Small-cell lung cancer and immunochemotherapy with Propionibacterium granulosum KP 45. J. Cancer Res. Clin. Oncol. 109, 72–77 (1985). doi:10.1007/BF01884258
67. A. Pluzanska, J. Stempczynska, S. Szmigielski, J. Jeljaszewicz, [Effect of intratumor administration of Propionibacterium granulosum in patients with advanced breast carcinoma on the clinical course of the disease and the behavior of certain indices of immune resistance]. Pol. Arch. Med. Wewn. 73, 351–360 (1985).
68. L. V. Blanton, M. R. Charbonneau, T. Salih, M. J. Barratt, S. Venkatesh, O. Ilkaveya, S. Subramanian, M. J. Manary, I. Trehan, J. M. Jorgensen, Y. M. Fan, B. Henrissat, S. A. Leyn, D. A. Rodionov, A. L. Osterman, K. M. Maleta, C. B. Newgard, P. Ashorn, K. G. Dewey, J. I. Gordon, Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science 351, aad3311 (2016). doi:10.1126/science.aad3311
69. V. Gaboriau-Routhiau, S. Rakotobe, E. Lécuyer, I. Mulder, A. Lan, C. Bridonneau, V. Rochet, A. Pisi, M. De Paepe, G. Brandi, G. Eberl, J. Snel, D. Kelly, N. Cerf-Bensussan, The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009). doi:10.1016/j.immuni.2009.08.020
70. I. I. Ivanov, K. Atarashi, N. Manel, E. L. Brodie, T. Shima, U. Karaoz, D. Wei, K. C. Goldfarb, C. A. Santee, S. V. Lynch, T. Tanoue, A. Imaoka, K. Itoh, K. Takeda, Y. Umesaki, K. Honda, D. R. Littman, Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009). doi:10.1016/j.cell.2009.09.033
71. C. Pustelny, U. Komor, V. Pawar, A. Lorenz, A. Bielecka, A. Moter, B. Gocht, D. Eckweiler, M. Müsken, C. Grothe, H. Lünsdorf, S. Weiss, S. Häussler, Contribution of Veillonella parvula to Pseudomonas aeruginosa-mediated pathogenicity in a murine tumor model system. Infect. Immun. 83, 417–429 (2015). doi:10.1128/IAI.02234-14
72. S. Thiemann, N. Smit, U. Roy, T. R. Lesker, E. J. C. Gálvez, J. Helmecke, M. Basic, A. Bleich, A. L. Goodman, U. Kalinke, R. A. Flavell, M. Erhardt, T. Strowig, Enhancement of IFN? production by distinct commensals ameliorates Salmonella-induced disease. Cell Host Microbe 21, 682–694.e5 (2017). doi:10.1016/j.chom.2017.05.005
73. J. Li, C. Y. J. Sung, N. Lee, Y. Ni, J. Pihlajamäki, G. Panagiotou, H. El-Nezami, Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc. Natl. Acad. Sci. U.S.A. 113, E1306–E1315 (2016). doi:10.1073/pnas.1518189113
74. J. C. Arthur, R. Z. Gharaibeh, J. M. Uronis, E. Perez-Chanona, W. Sha, S. Tomkovich, M. Mühlbauer, A. A. Fodor, C. Jobin, VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer. Sci. Rep. 3, 2868 (2013). doi:10.1038/srep02868