Gut microbial diversity and genus-level differences identified in cervical cancer patients versus healthy controls

doi:10.1016/j.ygyno.2019.09.002

Gynecologic Oncology

Volume 155, Issue 2, November 2019, Pages 237-244

https://doi.org/10.1016/j.ygyno.2019.09.002 Get rights and content

Highlights

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Among cervical cancer patients, bacterial diversity was higher in older women as compared to younger women.
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Compared to controls, women with cervical cancer have distinct differences in their gut microbiota diversity.
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Compared to controls, women with cervical cancer have distinct differences in their gut microbiota composition.
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Currently there is an important gap in studies investigating the gut microbiome and gynecologic cancers.

Abstract

Objectives

The aim of this study was to characterize variation in the gut microbiome of women with locally advanced cervical cancer and compare it to healthy controls.

Methods

We characterized the 16S rDNA fecal microbiome in 42 cervical cancer patients and 46 healthy female controls. Shannon diversity index (SDI) was used to evaluate alpha (within sample) diversity. Beta (between sample) diversity was examined using principle coordinate analysis (PCoA) of unweighted Unifrac distances. Relative abundance of microbial taxa was compared between samples using Linear Discriminant Analysis Effect Size (LEfSe).

Results

Within cervical cancer patients, bacterial alpha diversity was positively correlated with age (p = 0.22) but exhibited an inverse relationship in control subjects (p < 0.01). Alpha diversity was significantly higher in cervical cancer patients as compared to controls (p < 0.05), though stratification by age suggested this relationship was restricted to older women (>50 years; p < 0.01). Beta diversity (unweighted Unifrac; p < 0.01) also significantly differed between cervical cancer patients and controls. Based on age- and race-adjusted LEfSe analysis, multiple taxa significantly differed between cervical cancer patients and controls. Prevotella, Porphyromonas, and Dialister were significantly enriched in cervical cancer patients, while Bacteroides, Alistipes and members of the Lachnospiracea family were significantly enriched in healthy subjects.

Conclusion

Our study suggests differences in gut microbiota diversity and composition between cervical cancer patients and controls. Associations within the gut microbiome by age may reflect etiologic/clinical differences. These findings provide rationale for further study of the gut microbiome in cervical cancer.

Introduction

Cervical cancer continues to be the most common gynecologic cancer globally. The American Cancer Society estimates >13,100 new cases of invasive cervical cancer will be diagnosed in the United States in 2019, resulting in >4250 deaths [1]. A previously published review by Chase et al. highlighted an important gap in studies investigating the association between the gut microbiome and gynecologic cancers [2]. The gut microbiome is proposed to alter host immunity by modulating multiple immunologic pathways, thus impacting cancer risk and treatment outcomes in various malignancies [[3], [4], [5]]; however, the relationship between the gut microbiome and cervical cancer has not been reported.

Previous studies theorized that host-dependent immunologic status and human papillomavirus (HPV)-induced immune evasion are responsible for persistent HPV infection and the subsequent development of cervical dysplasia [6]. Independent of HPV status, the immune system's capability to recognize tumor antigens and clear an oncogenic HPV infection ultimately determines whether a patient develops cervical cancer [7]. The ability of high risk HPV to downregulate interferon signaling favors HPV persistence and the development of cervical cancer and its precursor lesions [7,8]. Previous evidence supports that a more diverse, abundant gut microbiota with distinct composition can lead to improved anti-tumoral immune response by priming anti-tumoral T cell activation [9]. In melanoma patients treated with anti-programmed cell death 1 protein (PD-1) immunotherapy, Gopalakrishnan et al. demonstrated that patients with a favorable baseline gut microbiome (high diversity and abundance of Ruminococcaceae and Faecalibacterium) exhibit enhanced systemic and antitumor immune responses mediated by increased antigen presentation and improved effector T cell function [10]. Noting that gut microbial differences could affect cervical cancer risk and treatment through several pathways, we aimed to characterize variations in the fecal or gut microbiome of women with locally advanced cervical cancer. In doing so, we hope to clarify differences in gut microbial diversity and composition within and between cervical cancer patients as compared to cancer-free controls; laying the groundwork for further research aimed at exploring the role of the gut microbiota in cervical cancer risk and treatment.

Section snippets

Participants and clinical data

Gut microbiome samples for cervical cancer patients were collected on an IRB approved prospective protocol (MDACC 2014–0543) for patients with biopsy-proven carcinoma of the cervix treated at The University of Texas MD Anderson Cancer Center and Harris Health System, Lyndon B. Johnson General Hospital Oncology Clinic between September 22, 2015 and December 21, 2017. Female controls that were comparable to cases in regard to age, race and body mass index (BMI), were derived from the Houston, TX

Results

We characterized the 16S rDNA fecal microbiome in 42 cervical cancer patients. Their clinico-pathologic data are summarized in Table 1. Cervical cancer cases were staged according to the Federation of Gynecology and Obstetrics (FIGO) 2014 staging system. Overall, approximately 64% of the patients (27 of 42) had advanced stage disease (stage IIB, or greater) and the majority of patients had squamous cell cancers with moderate or poor differentiation. With respect to HPV status, HPV-16 was the

Discussion

In this study, we sought to characterize the gut microbiome of women with cervical cancer. We hypothesized that cervical cancer patients would have a microbiome distinct from cancer free controls, which would be more pronounced in higher staged disease. We found that diversity of the fecal microbiome in cervical cancer patients differed between young and older women. We observed significant differences in α and β diversity between cervical cancer patients and controls, suggesting compositional

Research support

This research was supported in part by The University of Texas MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment (CRD), the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant P30CA016672 and the National Institutes of Health T32 grant #5T32 CA101642-13 (TTS). This study was partially funded by The University of Texas MD Anderson Cancer Center HPV-related Cancers Moonshot (AK).

Role of funding sources

The funding sources were not involved in the development of the research hypothesis, study design, data analysis, or manuscript writing. Data access was limited to the authors of this manuscript.

Author contribution

All authors were involved with subject identification and data collection, interpretation of statistical analysis, and review and approval of final manuscript. Study concept was developed by LEC, CRD, AK and TTS. Drafting of manuscript was done by TTS.

Declaration of competing interest

The authors report no conflicts of interest, financial or otherwise, related to the subject matter of the article submitted.

Acknowledgements

This work was supported in part by The University of Texas MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment (CRD), the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant P30CA016672 and the National Institutes of Health T32 grant #5T32 CA101642-13 (TTS). This study was partially funded by The University of Texas MD Anderson Cancer Center HPV-related Cancers Moonshot (AK). The human subjects who participated in this

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Following naringenin treatment, however, the abundances of beneficial bacteria, such as those in the genera Alistipes and Lactobacillus, were increased. The abundance of Alistipes is high in the gut microflora of healthy people but low in cervical cancer patients (Sims et al., 2019). In addition, the abundance of Bacteroides is greatly elevated in the gut microbiota of patients with polycystic ovary syndrome (Qi et al., 2019).
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View full text

Gut microbial diversity and genus-level differences identified in cervical cancer patients versus healthy controls

Highlights

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Section snippets

Participants and clinical data

Results

Discussion

Research support

Role of funding sources

Author contribution

Declaration of competing interest

Acknowledgements

Gynecol. Oncol.

Cancer Cell

Lancet Oncol.

Gynecol. Oncol.

J. Biol. Chem.

Microbiome

AMB Express

Immunity

Cell

Genome Biol.

Gastroenterology

Cancer statistics, 2019

CA Cancer J. Clin.

Commensal bacteria at the interface of host metabolism and the immune system

Nat. Immunol.

Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF- B-responsive genes in cervical keratinocytes

J. Virol.

Commensal <em>Bifidobacterium</em> promotes antitumor immunity and facilitates anti–PD-L1 efficacy

Science (80- )

Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

Science (80- )

Comparison of collection methods for fecal samples in microbiome studies

Am. J. Epidemiol.

Collecting fecal samples for microbiome analyses in epidemiology studies

Cancer Epidemiol. Biomark. Prev.

A framework for human microbiome research

Nature