A multi-omic systems-based approach reveals metabolic markers of bacterial vaginosis and insight into the disease.

Carl J Yeoman,Manolito Torralba,Michael A Smith,Margret E Berg Miller,Sarah Lucas,Steven R Leigh,Mengfei Ho,Karen E Nelson,Marcus Gillis,Melissa Cregger,Brenda A Wilson,Andres Gomez,Susan M Thomas,Alexander V Ulanov,Douglas J Creedon,Jon S Weisbaum,Rebecca Stumpf,Bryan A White,Adam J Ratner

doi:10.1371/journal.pone.0056111

Abstract

BackgroundBacterial vaginosis (BV) is the most common vaginal disorder of reproductive-age women. Yet the cause of BV has not been established. To uncover key determinants of BV, we employed a multi-omic, systems-biology approach, including both deep 16S rRNA gene-based sequencing and metabolomics of lavage samples from 36 women. These women varied demographically, behaviorally, and in terms of health status and symptoms.Principal Findings16S rRNA gene-based community composition profiles reflected Nugent scores, but not Amsel criteria. In contrast, metabolomic profiles were markedly more concordant with Amsel criteria. Metabolomic profiles revealed two distinct symptomatic BV types (SBVI and SBVII) with similar characteristics that indicated disruption of epithelial integrity, but each type was correlated to the presence of different microbial taxa and metabolites, as well as to different host behaviors. The characteristic odor associated with BV was linked to increases in putrescine and cadaverine, which were both linked to Dialister spp. Additional correlations were seen with the presence of discharge, 2-methyl-2-hydroxybutanoic acid, and Mobiluncus spp., and with pain, diethylene glycol and Gardnerella spp.ConclusionsThe results not only provide useful diagnostic biomarkers, but also may ultimately provide much needed insight into the determinants of BV.

Highlights

Mechanistic understandings of a number of diseases that are believed to have microbial axes have escaped conventional biological analyses [1,2,3]
16S rRNA gene profiles We began our multi-omic approach by performing deep sequencing using 454 FLX-titanium technology of the V1-V3 region of 16S rRNA genes amplified from vaginal lavage samples collected from 36 pre-menopausal women of reproductive age
Richness (average species observed per 5000 reads (SOBs5K): high Nugent score median = 920.5 vs. low-moderate Nugent score median = 375.1; Fig. 1A) and diversity analyses using both Shannon’s and Simpson’s diversity indexes indicated a significant increase in diversity (p,0.0003) and richness (p = 0.01) in women with a Nugent score$7 (Fig. 1; Table 1)

Summary

Introduction

Mechanistic understandings of a number of diseases that are believed to have microbial axes have escaped conventional biological analyses [1,2,3]. The application of integrative systems biology approaches exploiting multiple data sources holds much promise in developing a fuller understanding of these diseases [4,5]. BV is discomforting to women, and increases the risks of infertility, pre-term birth and the acquisition of sexually transmitted infections including HIV [8] making it of particular clinical interest. The underlying mechanism that causes BV remains unknown. The cause of BV has not been established. To uncover key determinants of BV, we employed a multi-omic, systems-biology approach, including both deep 16S rRNA gene-based sequencing and metabolomics of lavage samples from 36 women. These women varied demographically, behaviorally, and in terms of health status and symptoms

Methods

Results

Discussion

Conclusion