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Novel cancer therapy targeting microbiome

Authors Nagano T , Otoshi T, Hazama D, Kiriu T , Umezawa K, Katsurada N , Nishimura Y

Received 4 March 2019

Accepted for publication 10 April 2019

Published 13 May 2019 Volume 2019:12 Pages 3619—3624


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Leo Jen-Liang Su

Tatsuya Nagano, Takehiro Otoshi, Daisuke Hazama, Tatsunori Kiriu, Kanoko Umezawa, Naoko Katsurada, Yoshihiro Nishimura

Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Abstract: In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.

Keywords: dysbiosis, prebiotics, probiotics, antibiotics


Gut microbiota

The human microbiota is a complex ecosystem of bacteria, viruses and fungi resident on or in the skin, oral cavity, lungs, intestines and vagina.1 The human gastrointestinal tract is colonized by a complex and abundant microbial community of 1013 to 1014 microorganisms in the colon.2,3 Firmicutes, Proteobacteria, Bacteroidetes and Acinetobacteria are major residents in normal bowels.

The commensal microbiota is a major regulator of the host immune system. Indeed, early innate immunity to Klebsiella pneumoniae in the lungs is regulated systemically by the commensal gut microbiota via Nod-like receptor (NLR) ligands.3 Segmented filamentous bacteria (SFB) not only induce cells that produce immunoglobulin A (IgA) and intraepithelial lymphocytes (IELs), but also promote host defense reactions and the accumulation of T helper type 17 (Th17) cells, which produce interleukin (IL)-17.4,5 Moreover, Clostridium enhances the differentiation and proliferation of regulatory T (Treg) cells.6,7

In addition to these functions, the microbiota has a role in the synthesis of vitamins and short-chain fatty acids from dietary fiber such as acetic acid, propionic acid and butyric acid. Although acetic acid and amino acids do not have a role in the differentiation and induction of Treg cells, butyric acid has a crucial role.8 Additionally, short-chain fatty acids bind to G protein-coupled receptors and regulate obesity.9 Numerous clinical studies have revealed that disruption of host–commensal interactions (dysbiosis) can lead to a variety of diseases and conditions,1022 including cancer,16 chronic intestinal inflammation,20,23 autoimmunity22 and impairment of the self-protection mechanisms against bacteria, viruses and parasites.10,12,2432

Lofgren et al demonstrated that germ-free INS-GAS mice were slower to develop atrophic gastritis and gastric cancer than specific pathogen free (SPF) INS-GAS mice.33 This result suggest that the gastric microbiota contributes to gastric cancer.

Microbiota and cancer

Several studies have shown that the colonic microbiota is associated with the development of colorectal cancer. In a chemically induced mouse model of colorectal cancer, transplantation of the fecal microbiota from colorectal cancer patients to germ-free mice increased susceptibility to colonic tumorigenesis.34

The hypotheses regarding the microbiota-related mechanisms of carcinogenesis in colorectal cancer include the following: the alpha-bug hypothesis, driver-passenger hypothesis, biofilm hypothesis and bystander effect hypothesis.35 The alpha-bug hypothesis posits that specific pathogenic bacteria induce colorectal cancer. For example, enterotoxigenic Bacteroides fragilis (ETBF) secretes Bacteroides fragilis toxin (BFT), which decreases E-cadherin levels. This loosens the attachments between intestinal epithelial cells and results in exposure to many antigens.36 Moreover, decreased E-cadherin promotes intracellular migration of β-catenin and accelerates carcinogenic-related signaling such as Wnt signaling. The driver-passenger hypothesis postulates that other bacteria, that is, passenger bacteria that adapt to the tumor environment produced by the driver bacteria, proliferate, leading to carcinogenesis. Fusobacterium nucleatum has an antagonistic effect against probiotics and has a role as a tumor-associated bacterium or oncobacterium.37,38 The biofilm hypothesis suggests that biofilm, produced by the gut microbiota, is associated with colorectal cancer carcinogenesis, which involves lack of E-cadherin or activation of signal transducers and activator of transcription (STAT)-3. Lastly, the bystander effect hypothesis involves gut microbiota-produced metabolites that induce colorectal cancer carcinogenesis.

Deoxycholic acid and lithocholic acid, secondary bile acids produced from bile acids by intestinal bacteria, induce DNA damage and contribute to carcinogenesis.39 In mice that are prone to developing cancer, mice with diet-induced and hereditary obesity develop significantly more liver cancer than mice on a normal diet.40 Moreover, deoxycholic acid-induced DNA damage in hepatic stellate cells in the liver interstitium become senescent and secrete many inflammatory cytokines and proteases (senescence-associated secretory phenotype, SASP). These promote carcinogenesis and form a microenvironment that further promotes carcinogenesis. IL-1β promotes liver cancer carcinogenesis. Intriguingly, in obese mice administered oligosaccharides that inhibit deoxycholic acid and ursodeoxycholic acid production (which promotes external release of bile acids), the incidence of liver cancer and hepatic stellate cell senescence are remarkably decreased. Moreover, lipoteichoic acid, which is a component of Gram-positive bacterial walls and a ligand of Toll-like receptor 2 (Tlr2), increases in liver cancer and upregulates cyclooxygenase-2 (Cox-2) expression.41 Increased Cox-2 expression induces the overproduction of prostaglandins. An antagonist of prostaglandin E2 receptor 4 (EP4) has been shown to decrease liver tumors in obese mice.42 In addition, the EP4 antagonist also decreases programmed death-1 (PD-1)-positive CD8-positive T and Treg cells.

Several studies showed that bladder microbiome was related to urothelial cell carcinoma pathogenesis or progression.43 Bladder microbiome act as a noninvasive biomarker and can be a target of immunotherapy agents such as intravesical bacillus Calmette-Guerin.

Oral microbiota and pancreatic cancer

The human oral cavity is colonized by many bacteria, including about 600 prevalent taxa at the species level.44 Indeed, the Human Oral Microbiome Database (HOMD) includes 619 taxa in the following 13 phyla: Actinobacteria, Bacteroidetes, Chlamydiae, Chloroflexi, Euryarchaeota, Firmicutes, Fusobacteria, Proteobacteria, Spirochaetes, SR1, Synergistetes, Tenericutes and TM7. The association between the salivary microbiota and pancreatic cancer has been analyzed using the Human Oral Microbe Identification Microarray,45 and two out of six bacterial candidates (Neisseria elongate and Streptococcus mitis) had significantly lower levels in pancreatic cancer patients than in the control group (P<0.05). Another prospective cohort study analyzed 361 patients with incident pancreatic cancer and 371 matched controls and revealed that Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were associated with a higher risk of pancreatic cancer (odds ratio: 2.20, 95% confidence interval: 1.16 to 4.18). In contrast, the genus Leptotrichia and its phylum Fusobacteria were associated with a lower risk of pancreatic cancer (odds ratio: 0.87, 95% confidence interval: 0.79 to 0.95).46

Gut–lung axis and lung microbiota

Lung cancer is a disease with poor prognosis, and the development of further preventive strategies is important. The concept of the “gut–lung axis” involves immune cells (such as T and B cells) that are activated by the gut microbiota, carried to the lungs by lymphatic or hematogenous spread, activate lung immune cells, and induce respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and respiratory infection.4750

It has been reported that the lung microbiota and oral microbiota are involved in lung carcinogenesis.5153 Salivary Capnocytophaga, Selenomonas, Veillonella and Neisseria were significantly altered in patients with squamous cell carcinoma (n=10) and adenocarcinoma (n=10) compared with control subjects (n=10).52 In another study, although the sample size was small (n=8/group), the bacterial diversity in sputum samples was significantly different between lung cancer patients and control subjects (P=0.038).54 Lung cancer cases had more Granulicatella (6.1% vs 2.0%; P=0.0016), Abiotrophia (1.5% vs 0.085%; P=0.0036) and Streptococcus (40.1 vs 19.8%; P=0.0142) than the control subjects.54 Another study revealed that Granulicatella adiacens had a higher abundance in sputum samples of four patients with lung cancer compared to six control subjects.55 Analysis of bronchoalveolar lavage fluid (BALF) from 20 patients with lung cancer and eight control subjects revealed that the levels of two phyla (Firmicutes and TM7) were significantly increased in the patients with lung cancer (P=0.037 and 0.035, respectively).56 Moreover, a study analyzed bronchoscopic specimens from 24 patients with lung cancer and 18 healthy controls and revealed that the genus Streptococcus was significantly more abundant in the lung cancer patients and, for predicting lung cancer, the area under the curve (AUC) of Streptococcus was 0.693 (sensitivity =87.5%, specificity =55.6%).51

Cancer prevention

The following treatment methods are being studied for controlling intestinal bacteria: improvement of gut microbiota dysbiosis, administration of prebiotics, which regulate the gut microbiota, administration of probiotics, which activate T cells, and administration of antibiotics.57 When high-fat diets were administered to K-rasG12Dint mice, tumors were formed in the small intestine, which was due to dysbiosis rather than obesity.58 B. fragilis-specific CD4-positive Th1 cells enhanced the anti-tumor effect of cytotoxic T-lymphocyte antigen (CTLA)-4 antibody.59 In addition, Bifidobacterium spp. increased the expression of immune-associated genes on spleen or lymph node dendritic cells and induced anti-tumor CD8-positive cells.60 Bifidobacterium lactis decreased the incidence of colorectal tumor in a mouse model61 and rat model62 of azoxymethane (AOM)-induced colorectal cancer, by inducing apoptosis or suppressing NF-κB signaling. Probiotics consisting of a mixture of Lactobacillus rhamnosus GG and Lactobacillus casei Shirota suppress the development of aflatoxin-induced liver cancer in rats.63 The probiotic product VSL#3, which is composed of L. casei, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis and Streptococcus salivarius subsp. thermophilus, suppressed trinitrobenzene sulfonic acid (TNBS)-induced colitis-related colorectal cancer in rats.64 VSL#3 also suppressed the development of diethylnitrosamine (DEN)-induced liver cancer by improving the gut microbiota and suppressing the release of endotoxin from the intestines to the blood.65 Probiotics consisting of a mixture of VSL#3, L. rhamnosus GG and Escherichia coli Nissle 1917 suppressed the growth of a xenograft of the liver cancer cell line Hepa1-6 by decreasing Th17 cells and suppressing cytokine production.66 When antibiotics were administered to ApcMin/+Msh2−/- mice, the development of colorectal cancer was significantly suppressed.67

Clinical trials of probiotics

A prospective cohort study that followed 45,241 participants for 12 years revealed that participants who ingested yoghurt produced by Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus had a lower risk of developing colorectal cancer than participants who did not ingest the yoghurt (hazard ratio: 0.62, 95% confidence interval: 0.46 to 0.83).68 A case-control study comparing 304 female breast cancer patients aged 40–55 years old with 662 subjects matched for age and residential area revealed that those who drank beverages containing L. casei Shirota >4 times/week were less likely to experience breast cancer relapse than those who did not (odds ratio: 0.65).69 Moreover, a randomized controlled trial of postoperative bladder cancer patients showed a significantly higher 3-year relapse-free survival rate in the epirubicin plus L. casei Shirota group than the epirubicin-only group (74.6% vs 59.9%, P=0.0234).70 Patients with colon cancer that received probiotics, Bifidobacterium lactis Bl-04 and Lactobacillus acidophilus NCFM had an increased abundance of butyrate-producing bacteria, especially Faecalibacterium and Clostridiales spp in the tumour, non-tumour mucosa and faecal microbiota, resulting in the reduction of colorectal cancer-associated genera such as Fusobacterium and Peptostreptococcus.71 Recent study showed that a probiotic combination containing Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis and Bacillus cereus reduced the physiological disorders induced by gastrectomy.72 Another randomized, double-blind, placebo-controlled trial showed that probiotics reduced the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma.73 However, in cancer patients and immunosuppressed patients, caution is required because probiotic administration may lead to bacteremia directly caused by the probiotic bacteria.74

Observations and conclusions

Based on the results of animal experiments, probiotics seem to be effective for the prevention of carcinogenesis to some extent. However, there are few randomized controlled trials in humans, and further studies are necessary.


We thank members of Division of Respiratory Medicine at the Kobe University Graduate School of Medicine for their support.


Dr Yoshihiro Nishimura reports grants from Eli Lilly Japan K.K. and personal fees from AstraZeneca K.K. outside the submitted work. The authors report no other conflicts of interest in this work.


1. Chen J, Domingue JC, Sears CL. Microbiota dysbiosis in select human cancers: evidence of association and causality. Semin Immunol. 2017;32:25–34. doi:10.1016/j.smim.2017.08.001

2. Zhu Q, Gao R, Wu W, Qin H. The role of gut microbiota in the pathogenesis of colorectal cancer. Tumour Biol. 2013;34(3):1285–1300. doi:10.1007/s13277-013-0684-4

3. Clarke TB. Early innate immunity to bacterial infection in the lung is regulated systemically by the commensal microbiota via nod-like receptor ligands. Infect Immun. 2014;82(11):4596–4606. doi:10.1128/IAI.02212-14

4. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–498. doi:10.1016/j.cell.2009.09.033

5. Atarashi K, Tanoue T, Ando M, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell. 2015;163(2):367–380. doi:10.1016/j.cell.2015.08.058

6. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331(6015):337–341. doi:10.1126/science.1198469

7. Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500(7461):232–236. doi:10.1038/nature12331

8. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446–450. doi:10.1038/nature12721

9. Kimura I, Inoue D, Maeda T, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A. 2011;108(19):8030–8035. doi:10.1073/pnas.1016088108

10. Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–795. doi:10.1146/annurev-immunol-020711-074937

11. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–1273. doi:10.1126/science.1223490

12. Abt MC, Artis D. The dynamic influence of commensal bacteria on the immune response to pathogens. Curr Opin Microbiol. 2013;16(1):4–9. doi:10.1016/j.mib.2012.12.002

13. Berer K, Krishnamoorthy G. Microbial view of central nervous system autoimmunity. FEBS Lett. 2014;588(22):4207–4213. doi:10.1016/j.febslet.2014.04.007

14. Chu H, Mazmanian SK. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol. 2013;14(7):668–675. doi:10.1038/ni.2635

15. Erturk-Hasdemir D, Kasper DL. Resident commensals shaping immunity. Curr Opin Immunol. 2013;25(4):450–455. doi:10.1016/j.coi.2013.06.001

16. Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–970. doi:10.1126/science.1240527

17. Khosravi A, Mazmanian SK. Disruption of the gut microbiome as a risk factor for microbial infections. Curr Opin Microbiol. 2013;16(2):221–227. doi:10.1016/j.mib.2013.03.009

18. Molloy MJ, Bouladoux N, Belkaid Y. Intestinal microbiota: shaping local and systemic immune responses. Semin Immunol. 2012;24(1):58–66. doi:10.1016/j.smim.2011.11.008

19. Naik S, Bouladoux N, Wilhelm C, et al. Compartmentalized control of skin immunity by resident commensals. Science. 2012;337(6098):1115–1119. doi:10.1126/science.1225152

20. Rakoff-Nahoum S, Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science. 2007;317(5834):124–127. doi:10.1126/science.1140488

21. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9(5):313–323. doi:10.1038/nri2515

22. Wu HJ, Ivanov II, Darce J, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010;32(6):815–827. doi:10.1016/j.immuni.2010.06.001

23. Rakoff-Nahoum S, Hao L, Medzhitov R. Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity. 2006;25(2):319–329. doi:10.1016/j.immuni.2006.06.010

24. Abt MC, Osborne LC, Monticelli LA, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37(1):158–170. doi:10.1016/j.immuni.2012.04.011

25. Brandl K, Plitas G, Mihu CN, et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature. 2008;455(7214):804–807. doi:10.1038/nature07250

26. Deshmukh HS, Liu Y, Menkiti OR, et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med. 2014;20(5):524–530. doi:10.1038/nm.3542

27. Didierlaurent A, Goulding J, Patel S, et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J Exp Med. 2008;205(2):323–329. doi:10.1084/jem.20070891

28. Duarte R, Silva AM, Vieira LQ, Afonso LC, Nicoli JR. Influence of normal microbiota on some aspects of the immune response during experimental infection with Trypanosoma cruzi in mice. J Med Microbiol. 2004;53(Pt 8):741–748. doi:10.1099/jmm.0.45657-0

29. Fagundes CT, Amaral FA, Vieira AT, et al. Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J Immunol. 2012;188(3):1411–1420. doi:10.4049/jimmunol.1101682

30. Ganal SC, Sanos SL, Kallfass C, et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity. 2012;37(1):171–186. doi:10.1016/j.immuni.2012.05.020

31. Inagaki H, Suzuki T, Nomoto K, Yoshikai Y. Increased susceptibility to primary infection with Listeria monocytogenes in germfree mice may be due to lack of accumulation of L-selectin+ CD44+ T cells in sites of inflammation. Infect Immun. 1996;64(8):3280–3287.

32. Khosravi A, Yáñez A, Price JG, et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe. 2014;15(3):374–381. doi:10.1016/j.chom.2014.02.006

33. Lofgren JL, Whary MT, Ge Z, et al. Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology. 2011;140(1):210–220. doi:10.1053/j.gastro.2010.09.048

34. Baxter NT, Zackular JP, Chen GY, Schloss PD. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome. 2014;2:20. doi:10.1186/2049-2618-2-20

35. Van Raay T, Allen-Vercoe E. Microbial Interactions and Interventions in Colorectal Cancer. Microbiol Spectr. 2017;5(3).

36. Sears CL, Islam S, Saha A, et al. Association of enterotoxigenic Bacteroides fragilis infection with inflammatory diarrhea. Clin Infect Dis. 2008;47(6):797–803. doi:10.1086/591130

37. Guo S, Li L, Xu B, et al. A simple and novel fecal biomarker for colorectal cancer: ratio of. Clin Chem. 2018;64(9):1327–1337. doi:10.1373/clinchem.2018.289728

38. Brennan CA, Garrett WS. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17(3):156–166. doi:10.1038/s41579-018-0129-6

39. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12(10):661–672. doi:10.1038/nrmicro3344

40. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101. doi:10.1038/nature12347

41. Loo TM, Kamachi F, Watanabe Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE. Cancer Discov. 2017;7(5):522–538. doi:10.1158/2159-8290.CD-16-0932

42. Okumura Y, Yamagishi T, Nukui S, Nakao K. Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist. Bioorg Med Chem Lett. 2017;27(5):1186–1192. doi:10.1016/j.bmcl.2017.01.067

43. Bajic P, Wolfe AJ, Gupta GN. The Urinary Microbiome: implications in Bladder Cancer Pathogenesis and Therapeutics. Urology. 2019.

44. Dewhirst FE, Chen T, Izard J, et al. The human oral microbiome. J Bacteriol. 2010;192(19):5002–5017. doi:10.1128/JB.00542-10

45. Farrell JJ, Zhang L, Zhou H, et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut. 2012;61(4):582–588. doi:10.1136/gutjnl-2011-300784

46. Fan X, Alekseyenko AV, Wu J, et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut. 2018;67(1):120–127. doi:10.1136/gutjnl-2016-312580

47. Bingula R, Filaire M, Radosevic-Robin N, et al. Desired turbulence? Gut-lung axis, immunity, and lung cancer. J Oncol. 2017;2017:5035371. doi:10.1155/2017/5035371

48. Budden KF, Gellatly SL, Wood DL, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol. 2017;15(1):55–63. doi:10.1038/nrmicro.2016.142

49. Marsland BJ, Trompette A, Gollwitzer ES. The gut-lung axis in respiratory disease. Ann Am Thorac Soc. 2015;12(Suppl 2):S150–S156. doi:10.1513/AnnalsATS.201503-133AW

50. Shukla SD, Budden KF, Neal R, Hansbro PM. Microbiome effects on immunity, health and disease in the lung. Clin Transl Immunol. 2017;6(3):e133. doi:10.1038/cti.2017.6

51. Liu HX, Tao LL, Zhang J, et al. Difference of lower airway microbiome in bilateral protected specimen brush between lung cancer patients with unilateral lobar masses and control subjects. Int J Cancer. 2018;142(4):769–778. doi:10.1002/ijc.31098

52. Yan X, Yang M, Liu J, et al. Discovery and validation of potential bacterial biomarkers for lung cancer. Am J Cancer Res. 2015;5(10):3111–3122.

53. Mao Q, Jiang F, Yin R, et al. Interplay between the lung microbiome and lung cancer. Cancer Lett. 2018;415:40–48. doi:10.1016/j.canlet.2017.11.036

54. Hosgood HD, Sapkota AR, Rothman N, et al. The potential role of lung microbiota in lung cancer attributed to household coal burning exposures. Environ Mol Mutagen. 2014;55(8):643–651. doi:10.1002/em.21878

55. Cameron SJS, Lewis KE, Huws SA, et al. A pilot study using metagenomic sequencing of the sputum microbiome suggests potential bacterial biomarkers for lung cancer. PLoS One. 2017;12(5):e0177062. doi:10.1371/journal.pone.0177062

56. Lee SH, Sung JY, Yong D, et al. Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions. Lung Cancer. 2016;102:89–95. doi:10.1016/j.lungcan.2016.10.016

57. Pitt JM, Vétizou M, Daillère R, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity. 2016;44(6):1255–1269. doi:10.1016/j.immuni.2016.06.001

58. Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature. 2014;514(7523):508–512. doi:10.1038/nature13398

59. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–1084. doi:10.1126/science.aad1329

60. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–1089. doi:10.1126/science.aac4255

61. Kim SW, Kim HM, Yang KM, et al. Bifidobacterium lactis inhibits NF-kappaB in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice. Inflamm Bowel Dis. 2010;16(9):1514–1525. doi:10.1002/ibd.21262

62. Le Leu RK, Brown IL, Hu Y, et al. A synbiotic combination of resistant starch and Bifidobacterium lactis facilitates apoptotic deletion of carcinogen-damaged cells in rat colon. J Nutr. 2005;135(5):996–1001. doi:10.1093/jn/135.5.996

63. Kumar M, Verma V, Nagpal R, et al. Effect of probiotic fermented milk and chlorophyllin on gene expressions and genotoxicity during AFB₁-induced hepatocellular carcinoma. Gene. 2011;490(1–2):54–59. doi:10.1016/j.gene.2011.09.003

64. Appleyard CB, Cruz ML, Isidro AA, Arthur JC, Jobin C, De Simone C. Pretreatment with the probiotic VSL#3 delays transition from inflammation to dysplasia in a rat model of colitis-associated cancer. Am J Physiol Gastrointest Liver Physiol. 2011;301(6):G1004–G1013. doi:10.1152/ajpgi.00167.2011

65. Zhang HL, Yu LX, Yang W, et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol. 2012;57(4):803–812. doi:10.1016/j.jhep.2012.06.011

66. Li J, Sung CY, Lee N, et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci U S A. 2016;113(9):E1306–E1315. doi:10.1073/pnas.1518189113

67. Belcheva A, Irrazabal T, Robertson SJ, et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell. 2014;158(2):288–299. doi:10.1016/j.cell.2014.04.051

68. Pala V, Sieri S, Berrino F, et al. Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. Int J Cancer. 2011;129(11):2712–2719. doi:10.1002/ijc.26193

69. Toi M, Hirota S, Tomotaki A, et al. Probiotic beverage with soy isoflavone consumption for breast cancer prevention: a case-control study. Curr Nutr Food Sci. 2013;9(3):194–200. doi:10.2174/15734013113099990001

70. Naito S, Koga H, Yamaguchi A, et al. Prevention of recurrence with epirubicin and lactobacillus casei after transurethral resection of bladder cancer. J Urol. 2008;179(2):485–490. doi:10.1016/j.juro.2007.09.031

71. Hibberd AA, Lyra A, Ouwehand AC, et al. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol. 2017;4(1):e000145. doi:10.1136/bmjgast-2017-000145

72. Zheng C, Chen T, Wang Y, et al. A randomised trial of probiotics to reduce severity of physiological and microbial disorders induced by partial gastrectomy for patients with gastric cancer. J Cancer. 2019;10(3):568–576. doi:10.7150/jca.29072

73. Jiang C, Wang H, Xia C, et al. A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma. Cancer. 2019;125(7):1081–1090. doi:10.1002/cncr.31907

74. Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014;25(10):1919–1929. doi:10.1093/annonc/mdu106

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