Metabolic Biosynthesis Pathways Identified from Fecal Microbiome Associated with Prostate Cancer

doi:10.1016/j.eururo.2018.06.033

European Urology

Volume 74, Issue 5, November 2018, Pages 575-582

https://doi.org/10.1016/j.eururo.2018.06.033 Get rights and content

Abstract

Background

The fecal microbiome is associated with prostate cancer risk factors (obesity, inflammation) and can metabolize and produce various products that may influence cancer but have yet to be defined in prostate cancer.

Objective

To investigate gut bacterial diversity, identify specific metabolic pathways associated with disease, and develop a microbiome risk profile for prostate cancer.

Design, setting, and participants

After prospective collection of 133 rectal swab samples 2 wk before the transrectal prostate biopsy, we perform 16S rRNA amplicon sequencing on 105 samples (64 with cancer, 41 without cancer). Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. The p values were adjusted using the false discovery rate. The α- and β-diversity analyses were performed using QIIME. The Mann-Whitney U test was employed to evaluate the statistical significance of β-diversity distances within and between groups of interest, and least absolute shrinkage and selection operator (LASSO) regression analysis was used to determine pathway significance.

Outcome measurements and statistical analysis

The detection of prostate cancer on transrectal prostate needle biopsy and 16s microbiome profile.

Results and limitations

We identified significant associations between total community composition and cancer/non-cancer status (Bray-Curtis distance metric, p < 0.01). We identified significant differences in enrichments of Bacteroides and Streptococcus species in cancer (all p < 0.04). Folate (LDA 3.8) and arginine (LDA 4.1) were the most significantly altered pathways. We formed a novel microbiome–derived risk factor for prostate cancer based on 10 aberrant metabolic pathways (area under curve = 0.64, p = 0.02).

Conclusions

Microbiome analyses on men undergoing prostate biopsy noted mostly similar bacterial species diversity among men diagnosed with and without prostate cancer. The microbiome may have subtle influences on prostate cancer but are likely patient-specific and would require paired analysis and precise manipulation, such as improvement of natural bacterial folate production.

Patient summary

Microbiome evaluation may provide patients with personalized data regarding the presence or absence of particular bacteria that have metabolic functions and implications regarding prostate cancer risk. The study provides a basis to investigate the manipulation of aberrant microbiomes to reduce prostate cancer risk.

Introduction

Each year, there are approximately 1 million prostate cancer diagnoses worldwide and attributed to genetics, race, age, and lifestyle factors (diet/obesity) [1]. The intestinal microbiome has been implicated in lifestyle factors and may impact the availability of various micronutrients on cancer risk [2]. Although some publications report on the urinary microbiome, we focus on the systemic effects from the fecal microbiome to provide insight regarding metabolic pathways to manipulate in the diet for prostate cancer [3], [4], [5].

Intestinal bacteria contain a wealth of information due to their diverse properties, including the ability to produce influential products on cancer development and progression. A reduced diversity profile in the intestinal microbiome can lead to overgrowth of bacteria causing mild systemic inflammation called endotoxemia, contributing to an overall inflammatory state promoting neoplasia in many organ sites [6], [7]. A recent case-control study (n = 20) did suggest differences in fecal microbiome in those men with cancer compared with benign prostate hypertrophy. They found a higher abundance of Bacteroides massiliensis in prostate cancer and higher Faecalibacterium prausnitzii and Eubacterium rectalie in controls and suggested an influence on micronutrients [8]. Groups of other bacteria could also play a role in prostate cancer development by producing and manipulating various proteins, vitamins, minerals, and other substances.

We anticipate differences in those men diagnosed with cancer compared with those without cancer and hypothesize that there could be a particular set of bacteria to target in probiotics for future studies regarding prostate cancer prevention. Herein, we investigate bacterial diversity in patients with or without prostate cancer. Additionally, we examine particular bacterial species differences in the fecal microbiome and their related metabolic pathways associated with prostate cancer.

Section snippets

Patients

We prospectively collected rectal swab samples at least 2 wk prior to a transrectal prostate biopsy. We excluded patients who had any antibiotic therapy in the last 6 mo. All samples were analyzed to identify cancer versus no cancer; however, for the association of future risk of prostate cancer, we excluded men with prostate-specific antigen (PSA) higher than 20.

Rectal swab collection

The rectal swab technique involved the urology provider by using sterile Medline E-Z lubricating jelly and placing the swab

Demographic data

We prospectively collected 133 rectal swab samples at least 2 wk prior to a transrectal prostate biopsy. After excluding patients with any antibiotic therapy in the last 6 mo and low-quality samples, we analyzed 105 samples. To identify the specific target population that could be utilized to alter the microbiome, we were left with 64 men with prostate cancer and 41 without cancer (Fig. 1). Demographics are displayed in Table 1.

Microbiome results

We computed a variety of α-diversity estimators to measure

Discussion

We have identified several factors in which the intestinal microbiome could be involved in men diagnosed with prostate cancer:

1.
Microbiome analysis on men undergoing prostate biopsy noted mostly overlapping bacterial communities between those with and without prostate cancer.
2.
Bacteria associated with carbohydrate metabolism pathways were in abundance, and natural B-vitamin production was lacking in patients with prostate cancer.
3.
The identification of a new 10-microbiome metabolic pathway score may

Conclusions

The fecal microbiome of men undergoing prostate biopsy is similar between cancer and non-cancer groups. The microbiome metabolic pathways provide interesting biological insights; however, it is unlikely to produce a “cancer” microbiome predictive risk profile. The most interesting bacterial metabolic pathways are ones that create natural folate, and other B-vitamins that are more common among those without prostate cancer warrant further investigation.

References (34)

M.C. Wong et al.
Global incidence and mortality for prostate cancer: analysis of temporal patterns and trends in 36 countries
Eur Urol
(2016)
I. Cavarretta et al.
The microbiome of the prostate tumor microenvironment
Eur Urol
(2017)
E. Shrestha et al.
Profiling the urinary microbiome in men with positive versus negative biopsies for prostate cancer
J Urol
(2018)
D.M. Golombos et al.
The role of gut microbiome in the pathogenesis of prostate cancer: a prospective, pilot study
Urology
(2018)
Y. Benjamini et al.
Controlling the false discovery rate in behavior genetics research
Behav Brain Res
(2001)
A.J. Price 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)
H.J. Powers
Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer
J Nutr
(2005)
R. Rodriguez-Melendez et al.
Biotin supplementation increases expression of the cytochrome P450 1B1 gene in Jurkat cells, increasing the occurrence of single-stranded DNA breaks
J Nutr
(2004)
E.S. Amirian et al.
Potential role of gastrointestinal microbiota composition in prostate cancer risk
Infect Agent Cancer
(2013)
K.S. Sfanos et al.
The inflammatory microenvironment and microbiome in prostate cancer development
Nat Rev Urol
(2018)

M.A. Hullar et al.

Gut microbes, diet, and cancer

Cancer Treat Res

(2014)

R.F. Schwabe et al.

The microbiome and cancer

Nat Rev Cancer

(2013)

T. Magoc et al.

FLASH: fast length adjustment of short reads to improve genome assemblies

Bioinformatics

(2011)

A.M. Bolger et al.

Trimmomatic: a flexible trimmer for Illumina sequence data

Bioinformatics

(2014)

J. Kuczynski et al.

Using QIIME to analyze 16S rRNA gene sequences from microbial communities

Curr Protoc Bioinformatics

(2012)

J.G. Caporaso et al.

PyNAST: a flexible tool for aligning sequences to a template alignment

Bioinformatics

(2010)

R.C. Edgar et al.

UCHIME improves sensitivity and speed of chimera detection

Bioinformatics

(2011)

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Published by Elsevier B.V. on behalf of European Association of Urology.

Platinum Priority – Prostate CancerEditorial by Ilaria Cavarretta, Nicasio Mancini and Andrea Salonia on pp. 583–584 of this issueMetabolic Biosynthesis Pathways Identified from Fecal Microbiome Associated with Prostate Cancer

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Patients

Rectal swab collection

Demographic data

Microbiome results

Discussion

Conclusions

Eur Urol

Eur Urol

J Urol

Urology

Behav Brain Res

Eur Urol

J Nutr

J Nutr

Potential role of gastrointestinal microbiota composition in prostate cancer risk

Infect Agent Cancer

The inflammatory microenvironment and microbiome in prostate cancer development

Nat Rev Urol

Gut microbes, diet, and cancer

Cancer Treat Res

The microbiome and cancer

Nat Rev Cancer

FLASH: fast length adjustment of short reads to improve genome assemblies

Bioinformatics

Trimmomatic: a flexible trimmer for Illumina sequence data

Bioinformatics

Using QIIME to analyze 16S rRNA gene sequences from microbial communities

Curr Protoc Bioinformatics

PyNAST: a flexible tool for aligning sequences to a template alignment

Bioinformatics

UCHIME improves sensitivity and speed of chimera detection

Bioinformatics

Platinum Priority – Prostate Cancer
Editorial by Ilaria Cavarretta, Nicasio Mancini and Andrea Salonia on pp. 583–584 of this issue
Metabolic Biosynthesis Pathways Identified from Fecal Microbiome Associated with Prostate Cancer