crossmark The Human Microbiome during Bacterial Vaginosis Andrew B. Onderdonk,a,c Mary L. Delaney,a,c Raina N. Fichorovab,c Department of Pathologya and Department of Obstetrics, Gynecology and Reproductive Biology,b Brigham and Women’s Hospital, and Harvard Medical School,c Boston, Massachusetts, USA SUMMARY ..................................................................................................................................................223 INTRODUCTION ............................................................................................................................................223 Definitions of BV..........................................................................................................................................224 Epidemiological Characteristics of BV ....................................................................................................................225 Definitions of BV Based on Clinical and Microscopic Criteria .............................................................................................225 Definitions Determined by Using Culture-Based Microbiological Criteria ................................................................................226 Non-Culture-Based Methods for Diagnosis of BV.........................................................................................................226 Downloaded from INDIVIDUAL MICROBIAL SPECIES AS POSSIBLE MEDIATORS OF BV AND HOST IMMUNITY..............................................................227 Gardnerella vaginalis ......................................................................................................................................227 Atopobium vaginae .......................................................................................................................................229 Prevotella and Porphyromonas............................................................................................................................229 Anaerobic Cocci ..........................................................................................................................................230 Sneathia (Leptotrichia)....................................................................................................................................230 Mobiluncus ...............................................................................................................................................231 Mycoplasma and Ureaplasma ............................................................................................................................231 BVAB1 to BVAB3 ..........................................................................................................................................232 LINKING IMMUNITY TO BV AND MICROBIAL GROUP PATTERNS .........................................................................................232 http://cmr.asm.org/ Innate Immunity and Cytokines in BV ....................................................................................................................232 Inflammatory Changes and Preterm Birth ................................................................................................................232 HIV Infection and Vaginal Immunity......................................................................................................................233 Host Factors Associated with Vaginal Immune Function.................................................................................................233 CONCLUSION...............................................................................................................................................233 REFERENCES ................................................................................................................................................234 AUTHOR BIOS ..............................................................................................................................................238 on October 6, 2017 by guest SUMMARY cosal inflammation, including vaginal discharge, itching, and Bacterial vaginosis (BV) is the most commonly reported microbi- burning, but was associated with a lack of leukocytic exudate, ological syndrome among women of childbearing age. BV is char- redness, and swelling; therefore, to be distinguished from classic acterized by a shift in the vaginal flora from the dominant Lacto- vaginitis, it was termed vaginosis. This syndrome has been associ- bacillus to a polymicrobial flora. BV has been associated with a ated with a wide array of health issues over the ensuing decades, wide array of health issues, including preterm births, pelvic in- including preterm births, pelvic inflammatory disease, increased flammatory disease, increased susceptibility to HIV infection, and susceptibility to HIV infection, and other chronic health prob- other chronic health problems. A number of potential microbial lems. Taken together, these complications represent an extraordi- pathogens, singly and in combinations, have been implicated narily common complaint among women of childbearing age, in the disease process. The list of possible agents continues to with preterm birth alone affecting over 10% of all pregnancies (1), expand and includes members of a number of genera, includ- and an expensive medical issue for both the women affected and ing Gardnerella, Atopobium, Prevotella, Peptostreptococcus, Mobi- babies born prematurely to mothers with BV. According to a re- luncus, Sneathia, Leptotrichia, Mycoplasma, and BV-associated port from the Institute of Medicine, preterm birth in the United bacterium 1 (BVAB1) to BVAB3. Efforts to characterize BV using States alone cost at least $26.2 billion in 2005, or an average of epidemiological, microscopic, microbiological culture, and se- $51,600 per infant (2). A number of potential microbial patho- quenced-based methods have all failed to reveal an etiology that gens, singly and in combinations, have been implicated in the can be consistently documented in all women with BV. A careful disease process. The list of possible agents continues to expand analysis of the available data suggests that what we term BV is, in and includes members of a number of genera, including Gard- fact, a set of common clinical signs and symptoms that can be nerella, Atopobium, Prevotella, Bacteroides, Peptostreptococcus, provoked by a plethora of bacterial species with proinflammatory characteristics, coupled to an immune response driven by vari- ability in host immune function. Published 10 February 2016 Citation Onderdonk AB, Delaney ML, Fichorova RN. 2016. The human microbiome INTRODUCTION during bacterial vaginosis. Clin Microbiol Rev 29:223–238. doi:10.1128/CMR.00075-15. he clinical syndrome that is currently known as bacterial vagi- Address correspondence to Andrew B. Onderdonk, [email protected]. Tnosis (BV) has been studied extensively for over 60 years. The Copyright © 2016, American Society for Microbiology. All Rights Reserved. originally described syndrome included various symptoms of mu- April 2016 Volume 29 Number 2 Clinical Microbiology Reviews cmr.asm.org 223 Onderdonk et al. facultative and obligately anaerobic organisms with pathogenic potential that may be transiently isolated from the vaginal vault. Culture-based studies have shown that predictable quantitative and qualitative changes in the microbiome occur during the men- strual cycle in overtly healthy women monitored for multiple menstrual cycles, regardless of the type of catamenial protection used (3–6). During menstrual flow, the pH rises, and the numbers of lactobacilli decrease, with a concomitant increase in the num- bers of other facultative and anaerobic species normally present as part of the vaginal microbiome. Following the cessation of men- strual flow, the pH decreases, and the numbers of lactobacilli in- FIG 1 Schematic framework for syndromatic bacterial vaginosis (BV) presen- crease, with a concomitant reduction in the numbers of other tation. The resident microbiome is shaped by host genetics, and in turn, the facultative and obligately anaerobic organisms present. Longitu- microbiome regulates host gene expression, while both vaginal and systemic dinal studies have shown that these quantitative changes in the exposures influence the vaginal microbiome-human genome encounter. The microbiome during the menstrual cycle are consistent from cycle result of these interactions determines symptom severity and disparities within Downloaded from the syndrome known as BV. to cycle for the same subjects as well as for all overtly healthy menarchal women, although there is considerable qualitative sub- ject-to-subject variability in the composition of the vaginal bacte- Mobiluncus, Sneathia, Leptotrichia, Mycoplasma, and recently ge- rial community. Qualitative studies using conventional culture netically characterized organisms of the order Clostridiales (BV- methods have characterized over 100 separate phenotypes that associated bacterium 1 [BVAB1] to BVAB3). A great deal of re- can be isolated from the vaginal microbiome, with some pheno- search has resulted in many excellent reviews of BV describing types always being present in high numbers when assessed longi- both the clinical manifestations and the potentially associated mi- tudinally and some phenotypes being present only sporadically, crobiological agents, with most pointing toward a complex mi- while other phenotypes are consistently present in low