Human microbiome and prostate cancer development: current insights into the prevention and treatment

doi:10.1007/s11684-019-0731-7

Front. Med.

2021, Vol. 15

Issue (1) : 11-32 https://doi.org/10.1007/s11684-019-0731-7

REVIEW

Human microbiome and prostate cancer development: current insights into the prevention and treatment

Solmaz Ohadian Moghadam(

), Seyed Ali Momeni

Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran

Download: PDF(790 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

The huge communities of microorganisms that symbiotically colonize humans are recognized as significant players in health and disease. The human microbiome may influence prostate cancer development. To date, several studies have focused on the effect of prostate infections as well as the composition of the human microbiome in relation to prostate cancer risk. Current studies suggest that the microbiota of men with prostate cancer significantly differs from that of healthy men, demonstrating that certain bacteria could be associated with cancer development as well as altered responses to treatment. In healthy individuals, the microbiome plays a crucial role in the maintenance of homeostasis of body metabolism. Dysbiosis may contribute to the emergence of health problems, including malignancy through affecting systemic immune responses and creating systemic inflammation, and changing serum hormone levels. In this review, we discuss recent data about how the microbes colonizing different parts of the human body including urinary tract, gastrointestinal tract, oral cavity, and skin might affect the risk of developing prostate cancer. Furthermore, we discuss strategies to target the microbiome for risk assessment, prevention, and treatment of prostate cancer.

Keywords microbiome prostate cancer prevention treatment molecular pathological epidemiology (MPE) biomarker

Corresponding Author(s): Solmaz Ohadian Moghadam

Just Accepted Date: 21 January 2020 Online First Date: 30 June 2020 Issue Date: 11 February 2021

Cite this article:

Solmaz Ohadian Moghadam,Seyed Ali Momeni. Human microbiome and prostate cancer development: current insights into the prevention and treatment[J]. Front. Med., 2021, 15(1): 11-32.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0731-7
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I1/11

Fig.1 Schematic representation of the effect of microbiome dysbiosis on prostate cancer development.

Samples	Method	Findings
Pre-biopsy urine samples (before cancer diagnosis)	16S rDNA sequencing	A higher prevalence of proinflammatory bacteria associated with urogenital infections (prostatitis, bacterial vaginosis, and urinary tract infections) in biopsy proven prostate cancer men (Streptococcus anginosus, Anaerococcus lactolyticus, Anaerococcus obesiensis, Actinobaculum schaalii, Varibaculum cambriense, Propionimicrobium lymphophilum) [²⁹]
Voided urine, EPS¹, seminal fluid of patients with prostate cancer and BPH²	16S rRNA gene sequencing with PCR-DGGE analysis	Significant microbial difference in EPS of patients with prostate cancer compared to BPH ones, suggesting the role of dysbiosis in the pathobiology of prostate cancer The prostate cancer group had a considerably increased number of Bacteroidetes bacteria, Alphaproteobacteria, Firmicutes bacteria, Lachnospiraceae, Propionicimonas, Sphingomonas, and Ochrobactrum, and a decrease in Eubacterium and Defluviicoccus compared to the BPH group [¹⁵⁵]
Rectal swab of patients prior to undergoing transrectal biopsy of prostate (before cancer diagnosis)	16S rRNA gene sequencing	Abundance of the proinflammatory species (Bacteroides and Streptococcus) in prostate cancer patients Bacteria associated with carbohydrate metabolism pathways in prostate cancer group were significantly higher than non-cancer groups, whereas bacteria associated with folate, biotin, and riboflavin were less abundant [⁹⁸]
Tumoral, peritumoral, and non-tumoral prostate tissue after RP³	UDPS⁴ of 16S rRNA	Microbial composition varies according to the nature of the tissue In all types of samples, the major phylum was Actinobacteria (dominant genera: Propionibacterium), followed by Firmicutes and Proteobacteria Staphylococcus spp. were more represented in the tumor/peri-tumor tissues [⁹⁷]
Fecal samples of healthy male and men with localized, biochemically recurrent and metastatic prostate cancer	16S rDNA sequencing	Significant difference in alpha diversity in gut microbiome of prostate cancer patients compared to non-cancer individuals Significant difference in gut microbiome composition of patients receiving oral ATT⁵ [²⁴⁶]
Fecal swab, voided urine (after prostatic massage) before performing the biopsy	16S rRNA NGS⁶	The urinary microbiome composition of prostate cancer patients differs from non-cancer patients An increased abundance of the Veillonella, Streptococcus, and Bacteroides, and a decreased abundance of Faecalibacterium, Lactobaccili, and Actinetobacter in cancer patients An increased abundance of Bacteroides in fecal samples of prostate cancer patients [¹⁹⁵]
Prostate tumor tissue of prostate biopsy and post-RP tissue samples after RP	Host-derived whole-genome sequencing	Presence of a core, bacteria-rich, prostate microbiome (Enrichment of the Proteobacteria) [¹⁹⁶]
RP tissue samples	Shotgun metagenomic sequencing	Non-sterile prostatic tissue in prostate cancer patients Escherichia, Propionibacterium, Acinetobacter, and Pseudomonas constituting the core of the prostate microbiome No significant difference between the microbiome and local progression of prostate tumor Correlated expression of Pseudomonas genes and human small RNA genes providing primary evidence that Pseudomonas infection may inhibit metastasis [¹⁹⁷]
The Swedish Twin Registry	Data retrieving from national registries, between 1963 and 2004	Significant association of periodontal disease due to proinflammatory Gram-negative bacteria with an increased risk of prostate cancer [²⁶⁰]
Prostatic fluid samples of prostate cancer patients and non-prostate cancer people	16S rRNA gene sequencing	Beneficial role of microbiome in maintaining the microenvironment stability of the prostate Significant difference of several species (genera Alkaliphilus, Enterobacter, Lactococcus, Cronobacter, Carnobacterium, and Streptococcus) between the cancer group and non-cancer group [¹⁹⁸]
TURP⁷ and/or RP specimens from prostate cancer patients and TURP specimen from BPH patients	PCR screening primer	Significant increase of Mycoplasma genitalium infection in prostate cancer patients in comparison with the BPH patients [²⁶¹]
Prostate tissue from patients with prostate cancer or BPH	Immunohistochemistry, PCR, and DNA sequencing	Presence of H. pylori DNA in prostatic tissue of prostate cancer and BPH [²⁶²]
Fecal swab from prostate cancer patients	DNA sequencing	Significant difference between gut microbiome of prostate cancer patients compared to controls Higher abundance of Bacteriodes massiliensis in prostate cancer patients in comparison with benign controls Higher abundance of Faecalibacterium prausnitzii and Eubacterium rectalie among controls compared to cancer patients [⁸⁷]
Pre- and post transrectal biopsy urine, and fecal samples	16S rRNA gene NGS⁵	Alteration of urinary microbiome after prostate biopsy, suggesting introduction of fecal bacteria into the urinary tract through prostate biopsy [²⁶³]

Tab.1 Studies evaluating the microbiome in prostate cancer patients

1	RL Siegel, KD Miller, A Jemal. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1): 7–30 https://doi.org/10.3322/caac.21442 pmid: 29313949
2	MM Center, A Jemal, J Lortet-Tieulent, E Ward, J Ferlay, O Brawley, F Bray. International variation in prostate cancer incidence and mortality rates. Eur Urol 2012; 61(6): 1079–1092 https://doi.org/10.1016/j.eururo.2012.02.054 pmid: 22424666
3	T Kimura, S Egawa. Epidemiology of prostate cancer in Asian countries. Int J Urol 2018; 25: 524–531 https://doi.org/10.1111/iju.13593
4	MR Nowroozi, SA Momeni, S Ohadian Moghadam, E Ayati, A Mortazavi, S Arfae, H Jamshidian, M Taherimahmoudi, M Ayati. Prostate-specific antigen density and gleason score predict adverse pathologic features in patients with clinically localized prostate cancer. Nephrourol Mon Nephrourol Mon 2016; 8(6): e39984 https://doi.org/10.5812/numonthly.39984 pmid: 27896239
5	F Moradpour, Z Fatemi. Estimation of the projections of the incidence rates, mortality and prevalence due to common cancer site in Isfahan, Iran. Asian Pac J Cancer Prev 2013; 14(6): 3581–3585 https://doi.org/10.7314/APJCP.2013.14.6.3581 pmid: 23886149
6	KS Sfanos, WB Isaacs, AM De Marzo. Infections and inflammation in prostate cancer. Am J Clin Exp Urol 2013; 1(1): 3–11 pmid: 25110720
7	SF Peisch, EL Van Blarigan, JM Chan, MJ Stampfer, SA Kenfield. Prostate cancer progression and mortality: a review of diet and lifestyle factors. World J Urol 2017; 35(6): 867–874 https://doi.org/10.1007/s00345-016-1914-3 pmid: 27518576
8	PJ Turnbaugh, RE Ley, M Hamady, CM Fraser-Liggett, R Knight, JI Gordon. The human microbiome project. Nature 2007; 449(7164): 804–810 https://doi.org/10.1038/nature06244 pmid: 17943116
9	N Uemura, S Okamoto, S Yamamoto, N Matsumura, S Yamaguchi, M Yamakido, K Taniyama, N Sasaki, RJ Schlemper. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001; 345(11): 784–789 https://doi.org/10.1056/NEJMoa001999 pmid: 11556297
10	A Sheh, JG Fox. The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes 2013; 4(6): 505–531 https://doi.org/10.4161/gmic.26205 pmid: 23962822
11	AK DeGruttola, D Low, A Mizoguchi, E Mizoguchi. Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis 2016; 22(5): 1137–1150 https://doi.org/10.1097/MIB.0000000000000750 pmid: 27070911
12	AV Hartstra, KE Bouter, F Bäckhed, M Nieuwdorp. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 2015; 38(1): 159–165 https://doi.org/10.2337/dc14-0769 pmid: 25538312
13	F Carbonero, AC Benefiel, AH Alizadeh-Ghamsari, HR Gaskins. Microbial pathways in colonic sulfur metabolism and links with health and disease. Front Physiol 2012; 3: 448 https://doi.org/10.3389/fphys.2012.00448 pmid: 23226130
14	MM Huycke, HR Gaskins. Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models. Exp Biol Med (Maywood) 2004; 229(7): 586–597 https://doi.org/10.1177/153537020422900702 pmid: 15229352
15	X Wang, MM Huycke. Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells. Gastroenterology 2007; 132(2): 551–561 https://doi.org/10.1053/j.gastro.2006.11.040 pmid: 17258726
16	X Wang, Y Yang, DR Moore, SL Nimmo, SA Lightfoot, MM Huycke. 4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by enterococcus faecalis-infected macrophages. Gastroenterology 2012; 142: 543–551 https://doi.org/10.1053/j.gastro.2011.11.020
17	D Nesić, Y Hsu, CE Stebbins. Assembly and function of a bacterial genotoxin. Nature 2004; 429: 429–433 https://doi.org/10.1038/nature02532
18	W Liang, N Ferrara. The complex role of neutrophils in tumor angiogenesis and metastasis. Cancer Immunol Res 2016; 4: 83–91 https://doi.org/10.1158/2326-6066.CIR-15-0313
19	K Mima, Y Cao, AT Chan, ZR Qian, JA Nowak, Y Masugi, et al.. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location. Clin Transl Gastroenterol 2016; 7: e200 https://doi.org/10.1038/ctg.2016.53
20	A Cougnoux, G Dalmasso, R Martinez, E Buc, J Delmas, L Gibold, et al.. Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype. Gut 2014; 63: 1932–1942 https://doi.org/10.1136/gutjnl-2013-305257.
21	Q Zhang, N Yu, C Lee. Mysteries of TGF-β paradox in benign and malignant cells. Front Oncol 2014; 4: 94 https://doi.org/10.3389/fonc.2014.00094
22	BE Menzies. The role of fibronectin binding proteins in the pathogenesis of Staphylococcus aureus infections. Curr Opin Infect Dis 2003; 16: 225–229 https://doi.org/10.1097/01.qco.0000073771.11390.75
23	N Li, A Ren, X Wang, X Fan, Y Zhao, GF Gao, P Cleary, B Wang. Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors. Proc Natl Acad Sci USA 2015; 112(1): 238–243 https://doi.org/10.1073/pnas.1414422112 pmid: 25535343
24	SB Jakowlew. Transforming growth factor-β in cancer and metastasis. Cancer Metastasis Rev 2006; 25(3): 435–457 https://doi.org/10.1007/s10555-006-9006-2
25	DG Bostwick, G de la Roza, P Dundore, FA Corica, KA Iczkowski. Intraepithelial and stromal lymphocytes in the normal human prostate. Prostate 2003; 55: 187–193 https://doi.org/10.1002/pros.10224
26	D Dikov, S Bachurska, D Staikov, V Sarafian. Intraepithelial lymphocytes in relation to NIH category IV prostatitis in autopsy prostate. Prostate 2015; 75(10): 1074–1084 https://doi.org/10.1002/pros.22991 pmid: 25917232
27	T Fujii, K Shimada, O Asai, N Tanaka, K Fujimoto, K Hirao, N Konishi. Immunohistochemical analysis of inflammatory cells in benign and precancerous lesions and carcinoma of the prostate. Pathobiology 2013; 80(3): 119–126 https://doi.org/10.1159/000342396 pmid: 23328608
28	KS Sfanos, S Yegnasubramanian, WG Nelson, AM De Marzo. The inflammatory microenvironment and microbiome in prostate cancer development. Nat Rev Urol 2018; 15: 11–24 https://doi.org/10.1038/nrurol.2017.167
29	E Shrestha, JR White, SH Yu, I Kulac, O Ertunc, AM De Marzo, S Yegnasubramanian, LA Mangold, AW Partin, KS Sfanos. Profiling the urinary microbiome in men with positive versus negative biopsies for prostate cancer. J Urol 2018; 199(1): 161–171 https://doi.org/10.1016/j.juro.2017.08.001 pmid: 28797714
30	R Virchow. An address on the value of pathological experiments. Br Med J 1881; 2(1075): 198–203 https://doi.org/10.1136/bmj.2.1075.198
31	SI Grivennikov, FR Greten, M Karin. Immunity, inflammation, and cancer. Cell 2010; 140(6): 883–899 https://doi.org/10.1016/j.cell.2010.01.025
32	NB Delongchamps, G de la Roza, V Chandan, R Jones, R Sunheimer, G Threatte, et al.. Evaluation of prostatitis in autopsied prostates—is chronic inflammation more associated with benign prostatic hyperplasia or cancer? J Urol 2008; 179(5): 1736–1740 https://doi.org/10.1016/j.juro.2008.01.034
33	T Stark, L Livas, N Kyprianou. Inflammation in prostate cancer progression and therapeutic targeting. Transl Androl Urol 2015; 4(4): 455–463 https://doi.org/10.3978/j.issn.2223-4683.2015.04.12
34	CL Maynard, CO Elson, RD Hatton, CT Weaver. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012; 489(7415): 231–241 https://doi.org/10.1038/nature11551
35	H Goris, F de Boer, D van der Waaij. Myelopoiesis in experimentally contaminated specific-pathogen-free and germfree mice during oral administration of polymyxin. Infect Immun 1985; 50(2): 437–441 pmid: 2997040
36	A Khosravi, A Yáñez, JG Price, A Chow, M Merad, HS Goodridge, et al.. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 2014; 15(3): 374–381 https://doi.org/10.1016/j.chom.2014.02.006
37	RF Schwabe, C Jobin. The microbiome and cancer. Nat Rev Cancer 2013; 13(11): 800–812 https://doi.org/10.1038/nrc3610
38	AM Sheflin, AK Whitney, TL Weir. Cancer-promoting effects of microbial dysbiosis. Curr Oncol Rep 2014; 16(10): 406 https://doi.org/10.1007/s11912-014-0406-0
39	C Horbinski, C Mojesky, N Kyprianou. Live free or die: tales of homeless (cells) in cancer. Am J Pathol 2010; 177: 1044–1052 https://doi.org/10.2353/ajpath.2010.091270
40	MR Galdiero, E Bonavita, I Barajon, C Garlanda, A Mantovani, S Jaillon. Tumor associated macrophages and neutrophils in cancer. Immunobiology 2013; 218(11): 1402–1410 https://doi.org/10.1016/j.imbio.2013.06.003
41	M Puhr, A De Marzo, W Isaacs, MS Lucia, K Sfanos, S Yegnasubramanian, et al.. Inflammation, microbiota, and prostate cancer. Eur Urol Focus 2016; 2(4): 374–382 https://doi.org/10.1016/j.euf.2016.08.010
42	DA Barron, DR Rowley. The reactive stroma microenvironment and prostate cancer progression. Endocr Relat Cancer 2012; 19(6): R187–204 https://doi.org/10.1530/ERC-12-0085
43	SM Frisch, RA Screaton. Anoikis mechanisms. Curr Opin Cell Biol 2001; 13(5): 555–562 https://doi.org/10.1016/S0955-0674(00)00251-9 pmid: 11544023
44	H Armstrong, M Bording-Jorgensen, S Dijk, E Wine. The complex interplay between chronic inflammation, the microbiome, and cancer: understanding disease progression and what we can do to prevent it. Cancers (Basel) 2018; 10(3): 83 https://doi.org/10.3390/cancers10030083
45	F Balkwill, A Mantovani. Inflammation and cancer: back to Virchow? Lancet 2001; 357: 539–545 https://doi.org/10.1016/S0140-6736(00)04046-0
46	LM Coussens, Z Werb. Inflammation and cancer. Nature 2002; 420(6917): 860–867 https://doi.org/10.1038/nature01322
47	F Colotta, P Allavena, A Sica, C Garlanda, A Mantovani. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009; 30(7): 1073–1081 https://doi.org/10.1093/carcin/bgp127
48	R Francescone, V Hou, SI Grivennikov. Microbiome, inflammation, and cancer. Cancer J 2014; 20(3): 181–189 https://doi.org/10.1097/PPO.0000000000000048
49	A Dzutsev, JH Badger, E Perez-Chanona, S Roy, R Salcedo, CK Smith, G Trinchieri. Microbes and cancer. Annu Rev Immunol 2017; 35(1): 199–228 https://doi.org/10.1146/annurev-immunol-051116-052133 pmid: 28142322
50	PH Schatteman, L Hoekx, JJ Wyndaele, W Jeuris, E Van Marck. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density. Eur Urol 2000; 37(4): 404–412 https://doi.org/10.1159/000020161
51	B Gurel, MS Lucia, IM Jr Thompson, PJ Goodman, CM Tangen, AR Kristal, et al.. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev 2014; 23(5): 847–856 https://doi.org/10.1158/1055-9965.EPI-13-1126
52	C De Nunzio, G Kramer, M Marberger, R Montironi, W Nelson, F Schröder, et al.. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol 2011; 60(1): 106–117 https://doi.org/10.1016/j.eururo.2011.03.055
53	DB Shinohara, AM Vaghasia, SH Yu, TN Mak, H Brüggemann, WG Nelson, et al.. A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. Prostate 2013; 73(9): 1007–1015 https://doi.org/10.1002/pros.22648
54	JE Elkahwaji, W Zhong, WJ Hopkins, W Bushman. Chronic bacterial infection and inflammation incite reactive hyperplasia in a mouse model of chronic prostatitis. Prostate 2007; 67(1): 14–21 https://doi.org/10.1002/pros.20445
55	PS Pelouze. Gonorrhea in the male and female: a book for practitioners. Philadelphia: W. B. Saunders Company, 1935
56	F Poletti, MC Medici, A Alinovi, MG Menozzi, P Sacchini, G Stagni, et al.. Isolation of Chlamydia trachomatis from the prostatic cells in patients affected by nonacute abacterial prostatitis. J Urol 1985; 134(4): 691–693 https://doi.org/10.1016/s0022-5347(17)47387-3
57	RB Hayes, LM Pottern, H Strickler, C Rabkin, V Pope, GM Swanson, et al.. Sexual behavior, STDs and risks for prostate cancer. Br J Cancer 2000; 82(3): 718–725 https://doi.org/10.1054/bjoc.1999.0986
58	H Maeda, T Akaike. Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 1998; 63(7): 854–865 pmid: 9721338
59	AM De Marzo, EA Platz, S Sutcliffe, J Xu, H Grönberg, CG Drake, Y Nakai, WB Isaacs, WG Nelson. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007; 7(4): 256–269 https://doi.org/10.1038/nrc2090
60	SJ Bultman. Emerging roles of the microbiome in cancer. Carcinogenesis 2014; 35(2): 249–255 https://doi.org/10.1093/carcin/bgt392
61	CM Buchta Rosean, MR Rutkowski. The influence of the commensal microbiota on distal tumor-promoting inflammation. Semin Immunol 2017; 32: 62–73 https://doi.org/10.1016/j.smim.2017.06.002
62	M Schirmer, SP Smeekens, H Vlamakis, M Jaeger, M Oosting, EA Franzosa, et al.. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 2016; 167(4): 1125–1136.e8 https://doi.org/10.1016/j.cell.2016.10.020
63	WM Chu. Tumor necrosis factor. Cancer Lett 2013; 328: 222–225 https://doi.org/10.1016/j.canlet.2012.10.014
64	J Suh, AB Rabson. NF-κB activation in human prostate cancer: important mediator or epiphenomenon? J Cell Biochem 2004; 91: 100–117 https://doi.org/10.1002/jcb.10729
65	CH Lee, YT Jeon, SH Kim, YS Song. NF-κB as a potential molecular target for cancer therapy. Biofactors 2007; 29(1): 19–35 https://doi.org/10.1002/biof.5520290103 pmid: 17611291
66	S Ohadian Moghadam, MR Nowroozi. Toll-like receptors: the role in bladder cancer development, progression and immunotherapy. Scand J Immunol 2019: e12818 https://doi.org/10.1111/sji.12818
67	JH Harmey, CD Bucana, W Lu, AM Byrne, S McDonnell, C Lynch, et al.. Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 2002; 101(5): 415–422 https://doi.org/10.1002/ijc.10632
68	F Simon, R Fernández. Early lipopolysaccharide-induced reactive oxygen species production evokes necrotic cell death in human umbilical vein endothelial cells. J Hypertens. 2009; 27(6): 1202–1216 https://doi.org/10.1097/HJH.0b013e328329e31c
69	XL Xu, RT Lee, HM Fang, YM Wang, R Li, H Zou, Y Zhu, Y Wang. Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 2008; 4(1): 28–39 https://doi.org/10.1016/j.chom.2008.05.014
70	ML Maneval, KA Eckert. Effects of oxidative and alkylating damage on microsatellite instability in nontumorigenic human cells. Mutat Res 2004; 546: 29–38 https://doi.org/10.1016/j.mrfmmm.2003.10.001
71	AK Cheema, I Maier, T Dowdy, Y Wang, R Singh, PM Ruegger, et al.. Chemopreventive metabolites are correlated with a change in intestinal microbiota measured in A-T mice and decreased carcinogenesis. PLoS One 2016; 11: e0151190 https://doi.org/10.1371/journal.pone.0151190
72	Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486(7402): 207–214 https://doi.org/10.1038/nature11234 pmid: 22699609
73	TA van der Meulen, H Harmsen, H Bootsma, F Spijkervet, F Kroese, A Vissink. The microbiome-systemic diseases connection. Oral Dis 2016; 22(8): 719–734 https://doi.org/10.1111/odi.12472 pmid: 26953630
74	O Pabst. Correlation, consequence, and functionality in microbiome-immune interplay. Immunol Rev 2017; 279(1): 4–7 https://doi.org/10.1111/imr.12584 pmid: 28856741
75	M Arumugam, J Raes, E Pelletier, D Le Paslier, T Yamada, DR Mende, et al.. Enterotypes of the human gut microbiome. Nature 2011; 473: 174–180 https://doi.org/10.1038/nature09944
76	E Rinninella, P Raoul, M Cintoni, F Franceschi, GAD Miggiano, A Gasbarrini, et al.. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019; 7(1): 14 https://doi.org/10.3390/microorganisms7010014
77	C Huggins, CV Hodges. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 2002; 167(2 Pt 2): 948–952 https://doi.org/10.1016/S0022-5347(02)80307-X pmid: 11905923
78	FJ Strobl, JE Levine. Estrogen inhibits luteinizing hormone (LH), but not follicle-stimulating hormone secretion in hypophysectomized pituitary-grafted rats receiving pulsatile LH-releasing hormone infusions. Endocrinology 1988; 123(1): 622–630 https://doi.org/10.1210/endo-123-1-622
79	R Geier, S Adler, G Rashid, A Klein. The synthetic estrogen diethylstilbestrol (DES) inhibits the telomerase activity and gene expression of prostate cancer cells. Prostate 2010; 70(12): 1307–1312 https://doi.org/10.1002/pros.21166
80	P Thelen, W Wuttke, H Jarry, M Grzmil, RH Ringert. Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J Urol 2004; 171(5): 1934–1938 https://doi.org/10.1097/01.ju.0000121329.37206.1b
81	CS Plottel, MJ Blaser. Microbiome and malignancy. Cell Host Microbe 2011; 10: 324–335 https://doi.org/10.1016/j.chom.2011.10.003
82	E Cavalieri, D Chakravarti, J Guttenplan, E Hart, J Ingle, R Jankowiak, P Muti, E Rogan, J Russo, R Santen, T Sutter. Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta 2006; 1766(1): 63–78 https://doi.org/10.1016/j.bbcan.2006.03.001 pmid: 16675129
83	JM Baker, L Al-Nakkash, MM Herbst-Kralovetz. Estrogen-gut microbiome axis: physiological and clinical implications. Maturitas 2017; 103: 45–53 https://doi.org/10.1016/j.maturitas.2017.06.025
84	JL Nelles, WY Hu, GS Prins. Estrogen action and prostate cancer. Expert Rev Endocrinol Metab 2011; 6: 437–451 https://doi.org/10.1586/eem.11.20
85	D Gadelle, P Raibaud, E Sacquet. β-glucuronidase activities of intestinal bacteria determined both in vitro and in vivo in gnotobiotic rats. Appl Environ Microbiol 1985; 49(3): 682–685 pmid: 3994372
86	K Gloux, O Berteau, H Oumami, F Beguet, M Leclerc, J Dore. A metagenomic β-glucuronidase uncovers a core adaptive function of the human intestinal microbiome. Proc Natl Acad Sci USA 2011; 108: 4539–4546 https://doi.org/10.1073/pnas.1000066107
87	DM Golombos, A Ayangbesan, P O’Malley, P Lewicki, L Barlow, CE Barbieri, C Chan, C DuLong, G Abu-Ali, C Huttenhower, DS Scherr. The role of gut microbiome in the pathogenesis of prostate cancer: a prospective, pilot study. Urology 2018; 111: 122–128 https://doi.org/10.1016/j.urology.2017.08.039 pmid: 28888753
88	SH Duncan, A Barcenilla, CS Stewart, SE Pryde, HJ Flint. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl Environ Microbiol 2002; 68(10): 5186–5190 https://doi.org/10.1128/AEM.68.10.5186-5190.2002 pmid: 12324374
89	DW Cockburn, NI Orlovsky, MH Foley, KJ Kwiatkowski, CM Bahr, M Maynard, B Demeler, NM Koropatkin. Molecular details of a starch utilization pathway in the human gut symbiont Eubacterium rectale. Mol Microbiol 2015; 95(2): 209–230 https://doi.org/10.1111/mmi.12859 pmid: 25388295
90	HM Hamer, D Jonkers, K Venema, S Vanhoutvin, FJ Troost, RJ Brummer. The role of butyrate on colonic function. Aliment Pharmacol Ther 2008; 27: 104–119 https://doi.org/10.1111/j.1365-2036.2007.03562.x
91	H Sokol, B Pigneur, L Watterlot, O Lakhdari, LG Bermúdez-Humarán, JJ Gratadoux, S Blugeon, C Bridonneau, JP Furet, G Corthier, C Grangette, N Vasquez, P Pochart, G Trugnan, G Thomas, HM Blottière, J Dorv, P Marteau, P Seksik, P Langella. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008; 105(43): 16731–16736 https://doi.org/10.1073/pnas.0804812105 pmid: 18936492
92	M Kwa, CS Plottel, MJ Blaser, S Adams. The intestinal microbiome and estrogen receptor-positive female breast cancer. J Natl Cancer Inst 2016; 22: 108 https://doi.org/10.1093/jnci/djw029
93	MA Hullar, AN Burnett-Hartman, JW Lampe. Gut microbes, diet, and cancer. Cancer Treat Res 2014; 159: 377–399 https://doi.org/10.1007/978-3-642-38007-5_22 pmid: 24114492
94	RF Schwabe, C Jobin. The microbiome and cancer. Nat Rev Cancer 2013; 13(11): 800–812 https://doi.org/10.1038/nrc3610 pmid: 24132111
95	AJ Price, RC Travis, PN Appleby, D Albanes, A Barricarte Gurrea, T Bjørge, et al.. Circulating folate and vitamin B12 and risk of prostate cancer: a collaborative analysis of individual participant data from six cohorts including 6875 cases and 8104 controls. Eur Urol 2016; 70: 941–951 https://doi.org/10.1016/j.eururo.2016.03.029
96	R Wang, Y Zheng, JY Huang, AQ Zhang, YH Zhou, JN Wang. Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies. BMC Public Health 2014; 14: 1326 https://doi.org/10.1186/1471-2458-14-1326
97	I Cavarretta, R Ferrarese, W Cazzaniga, D Saita, R Lucianò, ER Ceresola, I Locatelli, L Visconti, G Lavorgna, A Briganti, M Nebuloni, C Doglioni, M Clementi, F Montorsi, F Canducci, A Salonia. The microbiome of the prostate tumor microenvironment. Eur Urol 2017; 72(4): 625–631 https://doi.org/10.1016/j.eururo.2017.03.029 pmid: 28434677
98	MA Liss, JR White, M Goros, J Gelfond, R Leach, T Johnson-Pais, Z Lai, E Rourke, J Basler, D Ankerst, DP Shah. Metabolic biosynthesis pathways identified from fecal microbiome associated with prostate cancer. Eur Urol 2018; 74(5): 575–582 https://doi.org/10.1016/j.eururo.2018.06.033 pmid: 30007819
99	SJ James, AG Basnakian, BJ Miller. In vitro folate deficiency induces deoxynucleotide pool imbalance, apoptosis, and mutagenesis in Chinese hamster ovary cells. Cancer Res 1994; 54(19): 5075–5080 pmid: 7923120
100	SN Wickramasinghe, S Fida. Misincorporation of uracil into the DNA of folate- and B12-deficient HL60 cells. Eur J Haematol 1993; 50(3): 127–132 https://doi.org/10.1111/j.1600-0609.1993.tb00080.x pmid: 8472808
101	SJ Duthie, A Hawdon. DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J 1998; 12(14): 1491–1497 https://doi.org/10.1096/fasebj.12.14.1491 pmid: 9806758
102	A Pompei, L Cordisco, A Amaretti, S Zanoni, D Matteuzzi, M Rossi. Folate production by bifidobacteria as a potential probiotic property. Appl Environ Microbiol 2007; 73(1): 179–185 https://doi.org/10.1128/AEM.01763-06 pmid: 17071792
103	R Rodriguez-Melendez, JB Griffin, J Zempleni. Biotin supplementation increases expression of the cytochrome P450 1B1 gene in Jurkat cells, increasing the occurrence of single-stranded DNA breaks. J Nutr 2004; 134(9): 2222–2228 https://doi.org/10.1093/jn/134.9.2222 pmid: 15333708
104	FE Dewhirst, T Chen, J Izard, BJ Paster, AC Tanner, WH Yu, A Lakshmanan, WG Wade. The human oral microbiome. J Bacteriol 2010; 192(19): 5002–5017 https://doi.org/10.1128/JB.00542-10 pmid: 20656903
105	DS Michaud, J Izard, CS Wilhelm-Benartzi, DH You, VA Grote, A Tjønneland, CC Dahm, K Overvad, M Jenab, V Fedirko, MC Boutron-Ruault, F Clavel-Chapelon, A Racine, R Kaaks, H Boeing, J Foerster, A Trichopoulou, P Lagiou, D Trichopoulos, C Sacerdote, S Sieri, D Palli, R Tumino, S Panico, PD Siersema, PH Peeters, E Lund, A Barricarte, JM Huerta, E Molina-Montes, M Dorronsoro, JR Quirós, EJ Duell, W Ye, M Sund, B Lindkvist, D Johansen, KT Khaw, N Wareham, RC Travis, P Vineis, HB Bueno-de-Mesquita, E Riboli. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut 2013; 62(12): 1764–1770 https://doi.org/10.1136/gutjnl-2012-303006 pmid: 22990306
106	JD Beck, S Offenbacher. Systemic effects of periodontitis: epidemiology of periodontal disease and cardiovascular disease. J Periodontol 2005; 76(11S): 2089–2100 https://doi.org/10.1902/jop.2005.76.11-S.2089
107	KJ Joshipura, EB Rimm, CW Douglass, D Trichopoulos, A Ascherio, WC Willett. Poor oral health and coronary heart disease. J Dent Res 1996; 75(9): 1631–1636 https://doi.org/10.1177/00220345960750090301 pmid: 8952614
108	S Offenbacher, HL Jared, PG O’Reilly, SR Wells, GE Salvi, HP Lawrence, SS Socransky, JD Beck. Potential pathogenic mechanisms of periodontitis associated pregnancy complications. Ann Periodontol 1998; 3(1): 233–250 https://doi.org/10.1902/annals.1998.3.1.233 pmid: 9722707
109	PP Hujoel, M Drangsholt, C Spiekerman, NS Weiss. An exploration of the periodontitis-cancer association. Ann Epidemiol 2003; 13(5): 312–316 https://doi.org/10.1016/S1047-2797(02)00425-8 pmid: 12821269
110	P Famili, JA Cauley, SL Greenspan. The effect of androgen deprivation therapy on periodontal disease in men with prostate cancer. J Urol 2007; 177(3): 921–924 https://doi.org/10.1016/j.juro.2006.10.067 pmid: 17296376
111	JN Krieger, L Nyberg Jr, JC Nickel. NIH consensus definition and classification of prostatitis. JAMA 1999; 282(3): 236–237 https://doi.org/10.1001/jama.282.3.236 pmid: 10422990
112	S Offenbacher. Periodontal diseases: pathogenesis. Ann Periodontol 1996; 1(1): 821–878 https://doi.org/10.1902/annals.1996.1.1.821 pmid: 9118282
113	TL Jang, AJ Schaeffer. The role of cytokines in prostatitis. World J Urol 2003; 21(2): 95–99 https://doi.org/10.1007/s00345-003-0335-2 pmid: 12783173
114	TE Van Dyke, AJ van Winkelhoff. Infection and inflammatory mechanisms. J Periodontol 2013; 84(4 Suppl): S1–S7 https://doi.org/10.1902/jop.2013.1340018 pmid: 23631571
115	N Joshi, NF Bissada, D Bodner, GT Maclennan, S Narendran, R Jurevic, R Skillicorn. Association between periodontal disease and prostate-specific antigen levels in chronic prostatitis patients. J Periodontol 2010; 81(6): 864–869 https://doi.org/10.1902/jop.2010.090646 pmid: 20450358
116	N Alwithanani, NF Bissada, N Joshi. Periodontal treatment improves prostate symptoms and lowers serum PSA in men with high PSA and chronic periodontitis. Dentistry 2015; 5: 1–4 https://doi.org/10.4172/2161-1122.1000284
117	Y Hasui, K Marutsuka, Y Asada, H Ide, S Nishi, Y Osada. Relationship between serum prostate specific antigen and histological prostatitis in patients with benign prostatic hyperplasia. Prostate 1994; 25(2): 91–96 https://doi.org/10.1002/pros.2990250206 pmid: 7518599
118	E Kandirali, C Boran, E Serin, A Semercioz, A Metin. Association of extent and aggressiveness of inflammation with serum PSA levels and PSA density in asymptomatic patients. Urology 2007; 70(4): 743–747 https://doi.org/10.1016/j.urology.2007.06.1102 pmid: 17991548
119	B Noack, RJ Genco, M Trevisan, S Grossi, JJ Zambon, E De Nardin. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 2001; 72(9): 1221–1227 https://doi.org/10.1902/jop.2000.72.9.1221 pmid: 11577954
120	J Estemalik, C Demko, NF Bissada, N Joshi, D Bodner, E Shankar, S Gupta. Simultaneous detection of oral pathogens in subgingival plaque and prostatic fluid of men with periodontal and prostatic diseases. J Periodontol 2017; 88(9): 823–829 https://doi.org/10.1902/jop.2017.160477 pmid: 28548883
121	T Kadowaki, K Nakayama, F Yoshimura, K Okamoto, N Abe, K Yamamoto. Arg-gingipain acts as a major processing enzyme for various cell surface proteins in Porphyromonas gingivalis. J Biol Chem 1998; 273(44): 29072–29076 https://doi.org/10.1074/jbc.273.44.29072 pmid: 9786913
122	FR Saglie, A Marfany, P Camargo. Intragingival occurrence of Actinobacillus actinomycetemcomitans and Bacteroides gingivalis in active destructive periodontal lesions. J Periodontol 1988; 59(4): 259–265 https://doi.org/10.1902/jop.1988.59.4.259 pmid: 3290428
123	X Fan, AV Alekseyenko, J Wu, BA Peters, EJ Jacobs, SM Gapstur, MP Purdue, CC Abnet, R Stolzenberg-Solomon, G Miller, J Ravel, RB Hayes, J Ahn. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut 2018; 67(1): 120–127 https://doi.org/10.1136/gutjnl-2016-312580 pmid: 27742762
124	PG Stathopoulou, MR Benakanakere, JC Galicia, DF Kinane. The host cytokine response to Porphyromonas gingivalis is modified by gingipains. Oral Microbiol Immunol 2009; 24(1): 11–17 https://doi.org/10.1111/j.1399-302X.2008.00467.x pmid: 19121064
125	L Duncan, M Yoshioka, F Chandad, D Grenier. Loss of lipopolysaccharide receptor CD14 from the surface of human macrophage-like cells mediated by Porphyromonas gingivalis outer membrane vesicles. Microb Pathog 2004; 36(6): 319–325 https://doi.org/10.1016/j.micpath.2004.02.004 pmid: 15120158
126	SA Whiteside, H Razvi, S Dave, G Reid, JP Burton. The microbiome of the urinary tract—a role beyond infection. Nat Rev Urol 2015; 12(2): 81–90 https://doi.org/10.1038/nrurol.2014.361 pmid: 25600098
127	AJ Wolfe, E Toh, N Shibata, R Rong, K Kenton, M Fitzgerald, et al.. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 2012; 50: 1376–1383 https://doi.org/10.1128/JCM.05852-11
128	EE Hilt, K McKinley, MM Pearce, AB Rosenfeld, MJ Zilliox, ER Mueller, et al.. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 2014; 52: 871–876 https://doi.org/10.1128/JCM.02876-13
129	DA Lewis, R Brown, J Williams, P White, SK Jacobson, JR Marchesi, et al.. The human urinary microbiome; bacterial DNA in voided urine of asymptomatic adults. Front Cell Infect Microbiol 2013; 3: 41 https://doi.org/10.3389/fcimb.2013.00041
130	CM Porter, E Shrestha, LB Peiffer, KS Sfanos. The microbiome in prostate inflammation and prostate cancer. Prostate Cancer Prostatic Dis 2018; 21: 345–354 https://doi.org/10.1038/s41391-018-0041-1
131	RS Kirby, D Lowe, MI Bultitude, KE Shuttleworth. Intra-prostatic urinary reflux: an aetiological factor in abacterial prostatitis. Br J Urol 1982; 54(6): 729–731 https://doi.org/10.1111/j.1464-410X.1982.tb13635.x pmid: 7150931
132	DE Fouts, R Pieper, S Szpakowski, H Pohl, S Knoblach, MJ Suh, et al.. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J Transl Med 2012; 28: 174 https://doi.org/10.1186/1479-5876-10-174
133	DE Nelson, B Van Der Pol, Q Dong, KV Revanna, B Fan, S Easwaran, et al.. Characteristic male urine microbiomes associate with asymptomatic sexually transmitted infection. PLoS One 2010; 5: e14116 https://doi.org/10.1371/journal.pone.0014116
134	Q Dong, DE Nelson, E Toh, L Diao, X Gao, JD Fortenberry, et al.. The microbial communities in male first catch urine are highly similar to those in paired urethral swab specimens. PLoS One 2011; 6: e19709 https://doi.org/10.1371/journal.pone.0019709
135	RJ Cohen, BA Shannon, JE McNeal, T Shannon, KL Garrett. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution? J Urol 2005; 173(6): 1969–1974 https://doi.org/10.1097/01.ju.0000158161.15277.78 pmid: 15879794
136	KS Sfanos, J Sauvageot, HL Fedor, JD Dick, AM De Marzo, WB Isaacs. A molecular analysis of prokaryotic and viral DNA sequences in prostate tissue from patients with prostate cancer indicates the presence of multiple and diverse microorganisms. Prostate 2008; 68(3): 306–320 https://doi.org/10.1002/pros.20680 pmid: 18163428
137	TN Mak, SH Yu, AM De Marzo, H Brüggemann, KS Sfanos. Multi-locus sequence typing (MLST) analysis of Propionibacterium acnes isolates from radical prostatectomy specimens. Prostate 2013; 73: 770–777 https://doi.org/10.1002/pros.22621
138	KS Sfanos, WB Isaacs. An evaluation of PCR primer sets used for detection of Propionibacterium acnes in prostate tissue samples. Prostate 2008; 68: 1492–1495 https://doi.org/10.1002/pros.20820
139	S Davidsson, P Mölling, JR Rider, M Unemo, MG Karlsson, J Carlsson, et al.. Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer. Infect Agent Cancer 2016; 11: 26 https://doi.org/10.1186/s13027-016-0074-9
140	CM Brede, DA Shoskes. The etiology and management of acute prostatitis. Nat Rev Urol 2011; 8: 207–212 https://doi.org/10.1038/nrurol.2011.22
141	M Sasaki, C Yamaura, Y Ohara-Nemoto, S Tajika, Y Kodama, T Ohya, R Harada, S Kimura. Streptococcus anginosus infection in oral cancer and its infection route. Oral Dis 2005; 11(3): 151–156 https://doi.org/10.1111/j.1601-0825.2005.01051.x pmid: 15888105
142	K Shiga, M Tateda, S Saijo, T Hori, I Sato, H Tateno, K Matsuura, T Takasaka, T Miyagi. Presence of Streptococcus infection in extra-oropharyngeal head and neck squamous cell carcinoma and its implication in carcinogenesis. Oncol Rep 2001; 8(2): 245–248 https://doi.org/10.3892/or.8.2.245 pmid: 11182034
143	WF Fricke, C Maddox, Y Song, JS Bromberg. Human microbiota characterization in the course of renal transplantation. Am J Transplant 2014; 14: 416–427 https://doi.org/10.1111/ajt.12588
144	H Siddiqui, K Lagesen, AJ Nederbragt, SL Jeansson, KS Jakobsen. Alterations of microbiota in urine from women with interstitial cystitis. BMC Microbiol 2012; 12: 205 https://doi.org/10.1186/1471-2180-12-205
145	AE Stapleton. Urinary tract infection pathogenesis: host factors. Infect Dis Clin North Am 2014; 28: 149–159 https://doi.org/10.1016/j.idc.2013.10.006
146	B Ragnarsdóttir, N Lutay, J Grönberg-Hernandez, B Köves, C Svanborg. Genetics of innate immunity and UTI susceptibility. Nat Rev Urol 2011; 8: 449–468 https://doi.org/10.1038/nrurol.2011.100
147	C Gottschick, ZL Deng, M Vital, C Masur, C Abels, DH Pieper, I Wagner-Döbler. The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome 2017; 5: 99 https://doi.org/10.1186/s40168-017-0305-3
148	MM Pearce, EE Hilt, AB Rosenfeld, MJ Zilliox, K Thomas-White, C Fok, et al.. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. MBio 2014; 5: e01283–14 https://doi.org/10.1128/mBio.01283-14
149	V Nienhouse, X Gao, Q Dong, DE Nelson, E Toh, K McKinley, et al.. Interplay between bladder microbiota and urinary antimicrobial peptides: mechanisms for human urinary tract infection risk and symptom severity. PLoS One 2014; 9: e114185 https://doi.org/10.1371/journal.pone.0114185
150	H Siddiqui, AJ Nederbragt, K Lagesen, SL Jeansson, KS Jakobsen. Assessing diversity of the female urine microbiota by high throughput sequencing of 16S rDNA amplicons. BMC Microbiol 2011; 11: 244 https://doi.org/10.1186/1471-2180-11-244
151	A Micheli, R Ciampichini, W Oberaigner, L Ciccolallo, E de Vries, I Izarzugaza, et al.. The advantage of women in cancer survival: an analysis of EUROCARE-4 data. Eur J Cancer 2009; 45: 1017–1027 https://doi.org/10.1016/j.ejca.2008.11.008
152	S Sutcliffe, JM Zenilman, KG Ghanem, RA Jadack, LJ Sokoll, DJ Elliott, et al.. Sexually transmitted infections and prostatic inflammation/cell damage as measured by serum prostate specific antigen concentration. J Urol 2006; 175: 1937–1942 https://doi.org/10.1016/S0022-5347(05)00892-X
153	WY Huang, R Hayes, R Pfeiffer, RP Viscidi, FK Lee, YF Wang, D Reding, D Whitby, JR Papp, CS Rabkin. Sexually transmissible infections and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2008; 17(9): 2374–2381 https://doi.org/10.1158/1055-9965.EPI-08-0173 pmid: 18768506
154	DA Shoskes, J Altemus, AS Polackwich, B Tucky, H Wang, C Eng. The urinary microbiome differs significantly between patients with chronic prostatitis/chronic pelvic pain syndrome and controls as well as between patients with different clinical phenotypes. Urology 2016; 92: 26–32 https://doi.org/10.1016/j.urology.2016.02.043 pmid: 26970449
155	H Yu, H Meng, F Zhou, X Ni, S Shen, UN Das. Urinary microbiota in patients with prostate cancer and benign prostatic hyperplasia. Arch Med Sci 2015; 11(2): 385–394 https://doi.org/10.5114/aoms.2015.50970 pmid: 25995756
156	E Holmes, JV Li, T Athanasiou, H Ashrafian, JK Nicholson. Understanding the role of gut microbiome-host metabolic signal disruption in health and disease. Trends Microbiol 2011; 19: 349–359 https://doi.org/10.1016/j.tim.2011.05.006
157	AJ Cox, NP West, AW Cripps. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol 2015; 3: 207–215 https://doi.org/10.1016/S2213-8587(14)70134-2.
158	L Zitvogel, L Galluzzi, S Viaud, M Vétizou, R Daillère, M Merad, G Kroemer. Cancer and the gut microbiota: an unexpected link. Sci Transl Med 2015; 7(271): 271ps1 https://doi.org/10.1126/scitranslmed.3010473 pmid: 25609166
159	R Mandar. Microbiota of male genital tract: impact on the health of man and his partner. Pharmacol Res 2013; 69: 32–41 https://doi.org/10.1016/j.phrs.2012.10.019
160	S Keay, CO Zhang, BR Baldwin, RB Alexander. Polymerase chain reaction amplification of bacterial 16s rRNA genes in prostate biopsies from men without chronic prostatitis. Urology 1999; 53(3): 487–491 https://doi.org/10.1016/S0090-4295(98)00553-6 pmid: 10096371
161	JN Krieger, DE Riley, RL Vesella, DC Miner, SO Ross, PH Lange. Bacterial DNA sequences in prostate tissue from patients with prostate cancer and chronic prostatitis. J Urol 2000; 164(4): 1221–1228 https://doi.org/10.1016/S0022-5347(05)67145-5 pmid: 10992370
162	MA Yow, SN Tabrizi, G Severi, DM Bolton, J Pedersen; BioResource Australian Prostate Cancer, GG Giles, MC Southey. Characterisation of microbial communities within aggressive prostate cancer tissues. Infect Agent Cancer 2017; 12(1): 4 https://doi.org/10.1186/s13027-016-0112-7 pmid: 28101126
163	SJ Salter, MJ Cox, EM Turek, ST Calus, WO Cookson, MF Moffatt, et al.. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol 2014; 12: 87 https://doi.org/10.1186/s12915-014-0087-z
164	A Glassing, SE Dowd, S Galandiuk, B Davis, RJ Chiodini. Inherent bacterial DNA contamination of extraction and sequencing reagents may affect interpretation of microbiota in low bacterial biomass samples. Gut Pathog 2016; 8(1): 24 https://doi.org/10.1186/s13099-016-0103-7 pmid: 27239228
165	M Alfano, F Canducci, M Nebuloni, M Clementi, F Montorsi, A Salonia. The interplay of extracellular matrix and microbiome in urothelial bladder cancer. Nat Rev Urol 2016; 13(2): 77–90 https://doi.org/10.1038/nrurol.2015.292 pmid: 26666363
166	S Caini, S Gandini, M Dudas, V Bremer, E Severi, A Gherasim. Sexually transmitted infections and prostate cancer risk: a systematic review and meta-analysis. Cancer Epidemiol 2014; 38: 329–338 https://doi.org/10.1016/j.canep.2014.06.002
167	BI Yoon, S Kim, DS Han, US Ha, SJ Lee, HW Kim, CH Han, YH Cho. Acute bacterial prostatitis: how to prevent and manage chronic infection? J Infect Chemother 2012; 18(4): 444–450 https://doi.org/10.1007/s10156-011-0350-y pmid: 22215226
168	WR Fair, RF Parrish. Antibacterial substances in prostatic fluid. Prog Clin Biol Res 1981; 75A: 247–264 pmid: 7041133
169	SH Hall, KG Hamil, FS French. Host defense proteins of the male reproductive tract. J Androl 2002; 23(5): 585–597 pmid: 12185087
170	OA Alexeyev, I Marklund, B Shannon, I Golovleva, J Olsson, C Andersson, I Eriksson, R Cohen, F Elgh. Direct visualization of Propionibacterium acnes in prostate tissue by multicolor fluorescent in situ hybridization assay. J Clin Microbiol 2007; 45(11): 3721–3728 https://doi.org/10.1128/JCM.01543-07 pmid: 17881550
171	JB Drott, O Alexeyev, P Bergström, F Elgh, J Olsson. Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells. BMC Microbiol 2010; 10(1): 126–132 https://doi.org/10.1186/1471-2180-10-126 pmid: 20420679
172	ST Palayoor, MY Youmell, SK Calderwood, CN Coleman, BD Price. Constitutive activation of IκB kinase α and NF-κB in prostate cancer cells is inhibited by ibuprofen. Oncogene 1999; 18(51): 7389–7394 https://doi.org/10.1038/sj.onc.1203160 pmid: 10602496
173	LB Mora, R Buettner, J Seigne, J Diaz, N Ahmad, R Garcia, T Bowman, R Falcone, R Fairclough, A Cantor, C Muro-Cacho, S Livingston, J Karras, J Pow-Sang, R Jove. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res 2002; 62(22): 6659–6666 pmid: 12438264
174	L Fassi Fehri, TN Mak, B Laube, V Brinkmann, LA Ogilvie, H Mollenkopf, M Lein, T Schmidt, TF Meyer, H Brüggemann. Prevalence of Propionibacterium acnes in diseased prostates and its inflammatory and transforming activity on prostate epithelial cells. Int J Med Microbiol 2011; 301(1): 69–78 https://doi.org/10.1016/j.ijmm.2010.08.014 pmid: 20943438
175	S Ogino, R Nishihara, TJ VanderWeele, M Wang, A Nishi, P Lochhead, et al.. The role of molecular pathological epidemiology in the study of neoplastic and non-neoplastic diseases in the era of precision medicine. Epidemiology 2016; 27(4): 602–611 https://doi.org/10.1097/EDE.0000000000000471
176	S Ogino, P Lochhead, AT Chan, R Nishihara, E Cho, BM Wolpin, et al.. Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease. Mod Pathol 2013; 26(4): 465–484 https://doi.org/10.1038/modpathol.2012.214
177	PC Kashyap, N Chia, H Nelson, E Segal, E Elinav. Microbiome at the frontier of personalized medicine. Mayo Clin Proc 2017; 92(12): 1855–1864 https://doi.org/10.1016/j.mayocp.2017.10.004
178	T Hamada, JA Nowak, DA Jr Milner. M Song, S Ogino. Integration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms. J Pathol 2019; 247(5): 615–628 https://doi.org/10.1002/path.5236
179	S Ogino, JA Nowak, T Hamada, DA Jr Milner, R Nishihara. Insights into pathogenic interactions among environment, host, and tumor at the crossroads of molecular pathology and epidemiology. Annu Rev Pathol 2019; 14: 83–103 https://doi.org/10.1146/annurev-pathmechdis-012418-012818
180	S Ogino, AT Chan, CS Fuchs, E Giovannucci. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut 2011; 60: 397–411 https://doi.org/10.1136/gut.2010.217182
181	T Hamada, N Keum, R Nishihara, S Ogino. Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis. J Gastroenterol 2017; 52: 265–275 https://doi.org/10.1007/s00535-016-1272-3
182	NJ Whitaker, WK Glenn, A Sahrudin, MM Orde, W Delprado, JS Lawson. Human papillomavirus and Epstein Barr virus in prostate cancer: koilocytes indicate potential oncogenic influences of human papillomavirus in prostate cancer. Prostate 2013; 73(3): 236–241 https://doi.org/10.1002/pros.22562
183	YD Nam, HJ Kim, JG Seo, SW Kang, JW Bae. Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing. PLoS One 2013; 8(12): e82659 https://doi.org/10.1371/journal.pone.0082659 pmid: 24367534
184	S Banerjee, JC Alwine, Z Wei, T Tian, N Shih, C Sperling, et al.. Microbiome signatures in prostate cancer. Carcinogenesis 2019; 40(6): 749–764 https://doi.org/10.1093/carcin/bgz008
185	A Zambrano, M Kalantari, A Simoneau, JL Jensen, LP Villarreal. Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. Prostate 2002; 53(4): 263–276 https://doi.org/10.1002/pros.10157
186	RA Blaheta , E Weich , D Marian , J Bereiter-Hahn , J Jones , D Jonas , M Michaelis , HW Doerr , J Jr Cinatl . Human cytomegalovirus infection alters PC3 prostate carcinoma cell adhesion to endothelial cells and extracellular matrix. Neoplasia 2006; 8(10): 807–816
187	AP Bhatt, MR Redinbo, SJ Bultman. The role of the microbiome in cancer development and therapy. CA Cancer J Clin 2017; 67(4): 326–344 https://doi.org/10.3322/caac.21398 pmid: 28481406
188	ES Amirian, JF Petrosino, NJ Ajami, Y Liu, MP Mims, ME Scheurer. Potential role of gastrointestinal microbiota composition in prostate cancer risk. Infect Agent Cancer 2013; 8(1): 42 https://doi.org/10.1186/1750-9378-8-42
189	HJ Haiser, PJ Turnbaugh. Developing a metagenomic view of xenobiotic metabolism. Pharmacol Res 2013; 69(1): 21–31 https://doi.org/10.1016/j.phrs.2012.07.009
190	RJ Dutton, PJ Turnbaugh. Taking a metagenomic view of human nutrition. Curr Opin Clin Nutr Metab Care 2012; 15(5): 448–454 https://doi.org/10.1097/MCO.0b013e3283561133
191	NB La Thangue, DJ Kerr. Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nat Rev Clin Oncol 2011; 8(10): 587–596 https://doi.org/10.1038/nrclinonc.2011.121
192	SH Wong, TNY Kwong, CY Wu, J Yu. Clinical applications of gut microbiota in cancer biology. Semin Cancer Biol 2019; 55: 28– 36 https://doi.org/10.1016/j.semcancer.2018.05.003 pmid: 29782923
193	Y Shetty, P Prabhu, B Prabhakar. Emerging vistas in theranostic medicine. Int J Pharm 2019; 558: 29–42 https://doi.org/10.1016/j.ijpharm.2018.12.068
194	A Behrouzi, AH Nafari, SD Siadat. The significance of microbiome in personalized medicine. Clin Transl Med 2019; 8(1): 16 https://doi.org/10.1186/s40169-019-0232-y
195	S Alanee, A El-Zawahry, D Dynda, A Dabaja, K McVary, M Karr, et al.. A prospective study to examine the association of the urinary and fecal microbiota with prostate cancer diagnosis after transrectal biopsy of the prostate using 16sRNA gene analysis. Prostate 2019; 79(1): 81–87 https://doi.org/10.1002/pros.23713
196	Y Feng, W Jaratlerdsiri, SM Patrick, RJ Lyons, AM Haynes. CC Collins, et al.. Metagenomic analysis reveals a rich bacterial content in high-risk prostate tumors from African men. Prostate 2019; 79(15): 1731–1738 https://doi.org/10.1002/pros.23897
197	Y Feng, VR Ramnarine, R Bell, S Volik, E Davicioni. VM Hayes, et al.. Metagenomic and metatranscriptomic analysis of human prostate microbiota from patients with prostate cancer. BMC Genomics 2019; 20(1): 146 https://doi.org/10.1186/s12864-019-5457-z
198	X Ma, C Chi, L Fan, B Dong, X Shao, S Xie, et al.. The microbiome of prostate fluid is associated with prostate cancer. Front Microbiol 2019; 10: 1664 https://doi.org/10.3389/fmicb.2019.01664
199	D Rea, G Coppola, G Palma, A Barbieri, A Luciano, P Del Prete. Microbiota effects on cancer: from risks to therapies. Oncotarget 2018; 9(25): 17915–17927 https://doi.org/10.18632/oncotarget.24681
200	KM Wilson, EL Giovannucci, LA Mucci. Lifestyle and dietary factors in the prevention of lethal prostate cancer. Asian J Androl 2012; 14: 365–374 https://doi.org/10.1038/aja.2011.142
201	S Punnen, J Hardin, I Cheng, EA Klein, JS Witte. Impact of meat consumption, preparation, and mutagens on aggressive prostate cancer. PLoS One 2011; 6: e27711 https://doi.org/10.1371/journal.pone.0027711
202	HL Newmark, RP Heaney. Dairy products and prostate cancer risk. Nutr Cancer 2010; 62: 297–299 https://doi.org/10.1080/01635580903407221
203	EL Richman, SA Kenfield, MJ Stampfer, EL Giovannucci, JM Chan. Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate-specific antigen-era: incidence and survival. Cancer Prev Res (Phila) 2011; 4(12): 2110–2121 https://doi.org/10.1158/1940-6207.CAPR-11-0354
204	P Astorg. Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence. Cancer Causes Control 2004; 15: 367–386 https://doi.org/10.1023/B:CACO.0000027498.94238.a3
205	AD Joshi, R Corral, C Catsburg, JP Lewinger, J Koo, EM John, et al.. Red meat and poultry, cooking practices, genetic susceptibility and risk of prostate cancer: results from a multiethnic case–control study. Carcinogenesis 2012; 33: 2108–2118 https://doi.org/10.1093/carcin/bgs242
206	RC Travis, PN Appleby, A Siddiq, NE Allen, R Kaaks, F Canzian, et al.. Genetic variation in the lactase gene, dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutrition. Int J Cancer 2013; 132(8): 1901–1910 https://doi.org/10.1002/ijc.27836
207	ES Amirian, MM Ittmann, ME Scheurer. Associations between arachidonic acid metabolism gene polymorphisms and prostate cancer risk. Prostate 2011; 71(13): 1382–1389 https://doi.org/10.1002/pros.21354
208	F Massari, V Mollica, V Di Nunno, L Gatto, M Santoni, M Scarpelli, et al.. The human microbiota and prostate cancer: friend or foe? Cancers (Basel) 2019; 11(4):459 https://doi.org/10.3390/cancers11040459
209	P Kundu, E Blacher, E Elinav, S Pettersson. Our gut microbiome: the evolving inner self. Cell 2017; 171(7): 1481–1493 https://doi.org/10.1016/j.cell.2017.11.024
210	M Blaser. Antibiotic overuse: stop the killing of beneficial bacteria. Nature 2011; 476(7361): 393–394 https://doi.org/10.1038/476393a
211	B Boursi, R Mamtani, K Haynes, YX Yang. Recurrent antibiotic exposure may promote cancer formation—another step in understanding the role of the human microbiota? Eur J Cancer 2015; 51(17): 2655–2664 https://doi.org/10.1016/j.ejca.2015.08.015
212	G Musso, R Gambino, M Cassader. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care 2010; 33(10): 2277–2284 https://doi.org/10.2337/dc10-0556
213	V Iebba, M Nicoletti, S Schippa. Gut microbiota and the immune system: an intimate partnership in health and disease. Int J Immunopathol Pharmacol 2012; 25(4): 823–833 https://doi.org/10.1177/039463201202500401
214	JM Ridlon, S Ikegawa, JM Alves, B Zhou, A Kobayashi, T Iida, et al.. Clostridium scindens: a human gut microbe with a high potential to convert glucocorticoids into androgens. J Lipid Res 2013; 54(9): 2437–2449 https://doi.org/10.1194/jlr.M038869
215	JE Bisanz, MK Enos, JR Mwanga, J Changalucha, JP Burton, GB Gloor, et al.. Randomized open-label pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. MBio 2014; 5(5): e01580–1514 https://doi.org/10.1128/mBio.01580-14
216	S Maleki Vareki, RM Chanyi, K Abdur-Rashid, L Brennan, JP Burton. Moving on from Metchnikoff: thinking about microbiome therapeutics in cancer. Ecancermedicalscience 2018; 12: 867 https://doi.org/10.3332/ecancer.2018.867
217	N Namasivayam. Chemoprevention in experimental animals. Ann N Y Acad Sci 2011; 1215: 60–71 https://doi.org/10.1111/j.1749-6632.2010.05873.x
218	R Flores, J Shi, B Fuhrman, X Xu, TD Veenstra, MH Gail, et al.. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J Transl Med 2012; 10: 253 https://doi.org/10.1186/1479-5876-10-253
219	E Cavalieri, E Rogan. The molecular etiology and prevention of estrogeninitiated cancers. Mol Aspects Med 2014; 36: 1–55 https://doi.org/10.1016/j.mam.2013.08.002
220	H Akaza. Prostate cancer chemoprevention by soy isoflavones: role of intestinal bacteria as the “second human genome”. Cancer Sci 2012; 103(6): 969–975 https://doi.org/10.1111/j.1349-7006.2012.02257.x
221	H Tsuji, K Moriyama, K Nomoto, N Miyanaga, H Akaza. Isolation and characterization of the equol-producing bacterium Slackia sp. Strain NATTS. Arch Microbiol 2010; 192(4): 279–287 https://doi.org/10.1007/s00203-010-0546-z
222	MI El-Demiry, TB Hargreave, A Busuttil, K James, AW Ritchie, GD Chisholm. Lymphocyte sub-populations in the male genital tract. Br J Urol 1985; 57(6): 769–774 https://doi.org/10.1111/j.1464-410X.1985.tb07051.x pmid: 3910154
223	S McClinton, ID Miller, O Eremin. An immunohistochemical characterisation of the inflammatory cell infiltrate in benign and malignant prostatic disease. Br J Cancer 1990; 61(3): 400–403 https://doi.org/10.1038/bjc.1990.87 pmid: 1691655
224	N Iida, A Dzutsev, CA Stewart, L Smith, N Bouladoux, RA Weingarten, DA Molina, R Salcedo, T Back, S Cramer, RM Dai, H Kiu, M Cardone, S Naik, AK Patri, E Wang, FM Marincola, KM Frank, Y Belkaid, G Trinchieri, RS Goldszmid. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013; 342(6161): 967–970 https://doi.org/10.1126/science.1240527 pmid: 24264989
225	S Viaud, F Saccheri, G Mignot, T Yamazaki, R Daillère, D Hannani, et al.. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013; 342: 971–976 https://doi.org/10.1126/science.1240537
226	A Sivan, L Corrales, N Hubert, JB Williams, K Aquino-Michaels, ZM Earley, FW Benyamin, YM Lei, B Jabri, ML Alegre, EB Chang, TF Gajewski. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264): 1084–1089 https://doi.org/10.1126/science.aac4255 pmid: 26541606
227	TC Johnstone, GY Park, SJ Lippard. Understanding and improving platinum anticancer drugs—phenanthriplatin. Anticancer Res 2014; 34(1): 471–476 pmid: 24403503
228	B Routy, E Le Chatelier, L Derosa, CPM Duong, MT Alou, R Daillère, A Fluckiger, M Messaoudene, C Rauber, MP 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, JR 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, JC Soria, E Deutsch, Y Loriot, F Ghiringhelli, G Zalcman, F Goldwasser, B Escudier, MD Hellmann, A Eggermont, D Raoult, L Albiges, G Kroemer, L Zitvogel. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91–97 https://doi.org/10.1126/science.aan3706 pmid: 29097494
229	V Gopalakrishnan, CN Spencer, L Nezi, A Reuben, MC Andrews, TV Karpinets, PA Prieto, D Vicente, K Hoffman, SC Wei, AP Cogdill, L Zhao, CW Hudgens, DS Hutchinson, T Manzo, M Petaccia de Macedo, T Cotechini, T Kumar, WS Chen, SM Reddy, R Szczepaniak Sloane, J Galloway-Pena, H Jiang, PL Chen, EJ Shpall, K Rezvani, AM Alousi, RF Chemaly, S Shelburne, LM Vence, PC Okhuysen, VB Jensen, AG Swennes, F McAllister, E Marcelo Riquelme Sanchez, Y Zhang, E Le Chatelier, L Zitvogel, N Pons, JL Austin-Breneman, LE Haydu, EM Burton, JM Gardner, E Sirmans, J Hu, AJ Lazar, T Tsujikawa, A Diab, H Tawbi, IC Glitza, WJ Hwu, SP Patel, SE Woodman, RN Amaria, MA Davies, JE Gershenwald, P Hwu, JE Lee, J Zhang, LM Coussens, ZA Cooper, PA Futreal, CR Daniel, NJ Ajami, JF Petrosino, MT Tetzlaff, P Sharma, JP Allison, RR Jenq, JA Wargo. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359(6371): 97–103 https://doi.org/10.1126/science.aan4236 pmid: 29097493
230	RV Parry, JM Chemnitz, KA Frauwirth, AR Lanfranco, I Braunstein, SV Kobayashi, PS Linsley, CB Thompson, JL Riley. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543–9553 https://doi.org/10.1128/MCB.25.21.9543-9553.2005 pmid: 16227604
231	BT Fife, KE Pauken, TN Eagar, T Obu, J Wu, Q Tang, M Azuma, et al.. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009; 10: 1185–1192 https://doi.org/10.1038/ni.1790
232	JN Graff, JJ Alumkal, CG Drake, GV Thomas, WL Redmond, M Farhad, JP Cetnar, FS Ey, RC Bergan, R Slottke, TM Beer. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 2016; 7(33): 52810–52817 https://doi.org/10.18632/oncotarget.10547 pmid: 27429197
233	MP Kuczma, ZC Ding, T Li, T Habtetsion, T Chen, Z Hao, et al.. The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells. Oncotarget 2017; 8(67): 111931–111942 https://doi.org/10.18632/oncotarget.22953
234	J Vande Voorde, S Sabuncuoğlu, S Noppen, A Hofer, F Ranjbarian, S Fieuws, J Balzarini, S Liekens. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine. J Biol Chem 2014; 289(19): 13054–13065 https://doi.org/10.1074/jbc.M114.558924 pmid: 24668817
235	S Ladoire, JC Eymard, S Zanetta, G Mignot, E Martin, I Kermarrec, E Mourey, F Michel, L Cormier, F Ghiringhelli. Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res 2010; 30(10): 4317–4323 pmid: 21036758
236	RS Kerbel, BA Kamen. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004; 4(6): 423–436 https://doi.org/10.1038/nrc1369
237	F Ghiringhelli, C Menard, PE Puig, S Ladoire, S Roux, F Martin, et al.. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T-cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007; 56(5): 641–648 https://doi.org/10.1007/s00262-006-0225-8
238	A Nicolini, P Mancini, P Ferrari, L Anselmi, G Tartarelli, V Bonazzi, et al.. Oral low-dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC). Biomed Pharmacother 2004; 58(8): 447–450 https://doi.org/10.1016/j.biopha.2004.08.006
239	B Hellerstedt, KJ Pienta, BG Redman, P Esper, R Dunn, J Fardig, et al.. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer 2003; 98(8): 1603–1610 https://doi.org/10.1002/cncr.11686
240	S Bracarda, M Tonato, P Rosi, V De Angelis, E Mearini, S Cesaroni, P Fornetti, M Porena. Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer 2000; 88(6): 1438–1444 https://doi.org/10.1002/(SICI)1097-0142(20000315)88:6<1438::AID-CNCR23>3.0.CO;2-O pmid: 10717628
241	TC Johnstone, K Suntharalingam, SJ Lippard. The next generation of platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem Rev 2016; 116(5): 3436–3486 https://doi.org/10.1021/acs.chemrev.5b00597
242	S Viaud, R Daillère, IG Boneca, P Lepage, P Langella, M Chamaillard, MJ Pittet, F Ghiringhelli, G Trinchieri, R Goldszmid, L Zitvogel. Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ 2015; 22(2): 199–214 https://doi.org/10.1038/cdd.2014.56 pmid: 24832470
243	EL Westman, MJ Canova, IJ Radhi, K Koteva, I Kireeva, N Waglechner, et al.. Bacterial inactivation of the anticancer drug doxorubicin. Chem Biol 2012; 19(10): 1255–1264 https://doi.org/10.1016/j.chembiol.2012.08.011
244	N Harada, R Hanaoka, H Horiuchi, T Kitakaze, T Mitani, H Inui, R Yamaji. Castration influences intestinal microflora and induces abdominal obesity in high-fat diet-fed mice. Sci Rep 2016; 6(1): 23001 https://doi.org/10.1038/srep23001 pmid: 26961573
245	M Fijlstra, M Ferdous, AM Koning, EH Rings, HJ Harmsen, WJ Tissing. Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model. Support Care Cancer 2015; 23(6): 1513– 1522 https://doi.org/10.1007/s00520-014-2487-6
246	KS Sfanos, MC Markowski, LB Peiffer, SE Ernst, JR White, KJ Pienta, et al.. Compositional differences in gastrointestinal microbiota in prostate cancer patients treated with androgen axis-targeted therapies. Prostate Cancer Prostatic Dis 2018; 21(4): 539–548 https://doi.org/10.1038/s41391-018-0061-x
247	HB Bode, B Zeggel, B Silakowski, SC Wenzel, H Reichenbach, R Müller. Steroid biosynthesis in prokaryotes: identification of myxobacterial steroids and cloning of the first bacterial 2,3(S)-oxidosqualene cyclase from the myxobacterium Stigmatella aurantiaca. Mol Microbiol 2003; 47: 471–481 https://doi.org/10.1046/j.1365-2958.2003.03309.x
248	V Matson, J Fessler, R Bao, T Chongsuwat, Y Zha, ML Alegre, JJ Luke, TF Gajewski. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371): 104–108 https://doi.org/10.1126/science.aao3290 pmid: 29302014
249	I Chitapanarux, T Chitapanarux, P Traisathit, S Kudumpee, E Tharavichitkul, V Lorvidhaya. Randomized controlled trial of live Lactobacillus acidophilus plus Bifidobacterium bifidum in prophylaxis of diarrhea during radiotherapy in cervical cancer patients. Radiat Oncol 2010; 5(1): 31 https://doi.org/10.1186/1748-717X-5-31 pmid: 20444243
250	DV Seidel, MA Azcárate-Peril, RS Chapkin, ND Turner. Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk. Semin Cancer Biol 2017; 46: 191–204 https://doi.org/10.1016/j.semcancer.2017.06.009
251	MA Conlon, AR Bird. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 2014; 7(1): 17–44 https://doi.org/10.3390/nu7010017
252	M Vétizou, JM Pitt, R Daillère, P Lepage, N Waldschmitt, C Flament, S Rusakiewicz, B Routy, MP Roberti, CP 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, DP Enot, M Bérard, J Nigou, P Opolon, A Eggermont, PL Woerther, E Chachaty, N Chaput, C Robert, C Mateus, G Kroemer, D Raoult, IG Boneca, F Carbonnel, M Chamaillard, L Zitvogel. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264): 1079–1084 https://doi.org/10.1126/science.aad1329 pmid: 26541610
253	F Guarner, JR Malagelada. Gut flora in health and disease. Lancet 2003; 361: 512–519 https://doi.org/10.1016/S0140-6736(03)12489-0
254	M Horinaka. T Yoshida, A Kishi, K Akatani, T Yasuda, J Kouhara, et al.. Lactobacillus strains induce TRAIL production and facilitate natural killer activity against cancer cells. FEBS Lett 2010; 584(3): 577–582 https://doi.org/10.1016/j.febslet.2009.12.004
255	ME Sanders, TR Klaenhammer. The scientific basis of Lactobacillus acidophilus NCFM functionality as a probiotic. J Dairy Sci 2001; 84: 319–331 https://doi.org/10.3168/jds.S0022-0302(01)74481-5
256	RG Montes, TM Bayless, JM Saavedra, JA Perman. Effect of milks inoculated with Lactobacillus acidophilus or a yogurt starter culture in lactosemaldigesting children. J Dairy Sci 1995; 78: 1657–1664 https://doi.org/10.3168/jds.S0022-0302(95)76790-X
257	D Davani-Davari, M Negahdaripour, I Karimzadeh, M Seifan, M Mohkam, SJ Masoumi, et al.. Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods 2019; 8(3): 92 https://doi.org/10.3390/foods8030092
258	H Wang, MS Geier, GS Howarth. Prebiotics: a potential treatment strategy for the chemotherapy-damaged gut? Crit Rev Food Sci Nutr 2016; 56(6): 946–956 https://doi.org/10.1080/10408398.2012.741082
259	M Sambi, L Bagheri, MR Szewczuk. Current challenges in cancer immunotherapy: multimodal approaches to improve efficacy and patient response rates. J Oncol 2019; 2019: 4508794 https://doi.org/10.1155/2019/4508794
260	M Arora, J Weuve, K Fall, NL Pedersen, LA Mucci. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. Am J Epidemiol 2010; 171(2): 253–259 https://doi.org/10.1093/aje/kwp340
261	M Miyake, K Ohnishi, S Hori, A Nakano, R Nakano, H Yano, et al.. Mycoplasma genitalium infection and chronic inflammation in human prostate cancer: detection using prostatectomy and needle biopsy specimens. Cells 2019; 8(3): 212 https://doi.org/10.3390/cells8030212
262	MS Al-Marhoon, A Ouhtit, AO Al-Abri, KP Venkiteswaran, Q Al-Busaidi, J Mathew, et al.. Molecular evidence of Helicobacter pylori infection in prostate tumors. Curr Urol 2015; 8(3): 138–143 https://doi.org/10.1159/000365705
263	S Alanee, A El-Zawahry, D Dynda, K McVary, M Karr, A Braundmeier-Fleming. Prospective examination of the changes in the urinary microbiome induced by transrectal biopsy of the prostate using 16S rRNA gene analy sis. Prostate Cancer Prostatic Dis 2019; 22(3): 446–452 https://doi.org/10.1038/s41391-018-0120-3.

[1]	Cenyi Shao, Shijian Li, Feng Zhu, Dahai Zhao, Hui Shao, Haixiao Chen, Zhiruo Zhang. Taizhou’s COVID-19 prevention and control experience with telemedicine features[J]. Front. Med., 2020, 14(4): 506-510.
[2]	Ke Sheng. Artificial intelligence in radiotherapy: a technological review[J]. Front. Med., 2020, 14(4): 431-449.
[3]	Min Zhou, Xinxin Zhang, Jieming Qu. Coronavirus disease 2019 (COVID-19): a clinical update[J]. Front. Med., 2020, 14(2): 126-135.
[4]	Tung Huynh, Ke-Qin Hu. Direct acting antiviral-induced dynamic reduction of serum α fetoprotein in hepatitis C patients without hepatocellular carcinoma[J]. Front. Med., 2019, 13(6): 658-666.
[5]	Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li. NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation inhibition[J]. Front. Med., 2019, 13(6): 646-657.
[6]	Tianyuan Li, Renbing Jia, Xianqun Fan. Classification and treatment of orbital venous malformations: an updated review[J]. Front. Med., 2019, 13(5): 547-555.
[7]	Yuqiu Han, Xiangyang Jiang, Qi Ling, Li Wu, Pin Wu, Ruiqi Tang, Xiaowei Xu, Meifang Yang, Lijiang Zhang, Weiwei Zhu, Baohong Wang, Lanjuan Li. Antibiotics-mediated intestinal microbiome perturbation aggravates tacrolimus-induced glucose disorders in mice[J]. Front. Med., 2019, 13(4): 471-481.
[8]	Weiqi Rong, Yang Zhang, Lei Yang, Lin Feng, Baojun Wei, Fan Wu, Liming Wang, Yanning Gao, Shujun Cheng, Jianxiong Wu, Ting Xiao. Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma[J]. Front. Med., 2019, 13(2): 250-258.
[9]	Jing Yue, Bo Zhang, Mingyue Wang, Junning Yao, Yifan Zhou, Ding Ma, Lei Jin. Effect of antitubercular treatment on the pregnancy outcomes and prognoses of patients with genital tuberculosis[J]. Front. Med., 2019, 13(1): 121-125.
[10]	Eun Young Lee, Kun-Ho Yoon. Epidemic obesity in children and adolescents: risk factors and prevention[J]. Front. Med., 2018, 12(6): 658-666.
[11]	Minhong Shen, Yibin Kang. Complex interplay between tumor microenvironment and cancer therapy[J]. Front. Med., 2018, 12(4): 426-439.
[12]	Chenyang Wang, Qiurong Li, Jieshou Li. Gut microbiota and its implications in small bowel transplantation[J]. Front. Med., 2018, 12(3): 239-248.
[13]	Kuo Yang, Runshun Zhang, Liyun He, Yubing Li, Wenwen Liu, Changhe Yu, Yanhong Zhang, Xinlong Li, Yan Liu, Weiming Xu, Xuezhong Zhou, Baoyan Liu. Multistage analysis method for detection of effective herb prescription from clinical data[J]. Front. Med., 2018, 12(2): 206-217.
[14]	Qingmeng Zhang, Fengmin Zhang, Baofeng Yang. Pneumonic plague epidemic in Northeast China in 1910–1911: Dr. Wu Lien-Teh’s epidemic preventive system for plague control[J]. Front. Med., 2018, 12(1): 113-115.
[15]	Zongming Zhang, Zhuo Liu, Limin Liu, Mengmeng Song, Chong Zhang, Hongwei Yu, Baijiang Wan, Mingwen Zhu, Zixu Liu, Hai Deng, Haiming Yuan, Haiyan Yang, Wenping Wei, Yue Zhao. Strategies of minimally invasive treatment for intrahepatic and extrahepatic bile duct stones[J]. Front. Med., 2017, 11(4): 576-589.

Viewed

Full text

Abstract

Cited

Shared

Discussed