Biogenic Amines Increase the Odds of Bacterial Vaginosis and Affect the Growth of and Lactic Acid Production by Vaginal Lactobacillus spp.

Abstract

Bacterial vaginosis (BV) is the most common vaginal disorder of reproductive-aged women, yet its etiology remains enigmatic. One clinical symptom of BV, malodor, is linked to the microbial production of biogenic amines (BA). Using targeted liquid chromatography mass-spectrometry, we analyzed 149 longitudinally collected vaginal samples to determine the in vivo concentrations of the most common BAs and then assessed their relationship to BV and effect upon the growth kinetics of axenically cultured vaginal Lactobacillus species. Increases in cadaverine, putrescine, and tyramine were associated with greater odds of women transitioning from L. crispatus-dominated vaginal microbiota to microbiota that have a paucity of Lactobacillus spp. and from Nugent scores of 0-3 to Nugent scores of 7-10, consistent with BV. Exposure to putrescine lengthened the lag time and/or slowed the growth of all vaginal Lactobacillus spp., except L. jensenii 62G. L. iners AB107’s lag time was lengthened by cadaverine but reduced in the presence of spermidine and spermine. The growth rate of L. crispatus VPI 3199 was slowed by cadaverine and tyramine and strain-specific responses to spermine and spermidine were observed. BAs were associated with reduced production of D- and L-lactic acid by vaginal Lactobacillus spp. and this effect was independent of their effect upon Lactobacillus spp. growth. The exceptions were higher levels of D- and L-lactic acid by two strains of L. crispatus when grown in the presence of spermine. Results of this study provide evidence of a direct impact of common biogenic amines on vaginal Lactobacillus spp. Importance: Lactobacillus spp. are credited with providing the primary defense against gynecological conditions, including BV, most notably through the acidification of the vaginal microenvironment which results from their production of lactic acid. The microbial production of BAs has been hypothesized to play a mechanistic role in diminishing Lactobacillus spp.-mediated protection, enabling the colonization and outgrowth of diverse anaerobic bacterial species associated with BV. Herein, we demonstrate that in vivo increases in the most commonly observed BAs are associated with a loss of Lactobacillus spp. and the development of BV, measured by Nugent score. Further, we show that BAs formed by amino acid decarboxylase enzymes negatively affect the growth of type-strains of the most common vaginal Lactobacillus spp. and separately alter their production of lactic acid. These results suggest that BAs destabilize vaginal Lactobacillus spp. and may play an important and direct role in diminishing their protection of the vaginal microenvironment.

A non-optimal cervicovaginal microbiota in pregnancy is associated with a distinct metabolomic signature among non-Hispanic Black individuals

“…Notably, our group has established that microbial supernatants from select high-risk vaginal bacteria associated with a non-optimal microbiota can disrupt the cervical epithelial barrier in vitro, and that this process involves cleavage of cell adhesion protein E-cadherin 31 , 39 . Spermine is commonly associated with Lactobacillus -dominated cervicovaginal microbial communities and has been shown to increase production of lactic acid by Lactobacillus 40 . As lactic acid can function in an anti-inflammatory capacity in this space 41 – 44 , it is possible that spermine plays a major role at the cervicovaginal epithelium.…”

“…It is reasonable to conclude that biochemicals belonging to the xenobiotic superpathway arise from microbiota or dietary intake rather than eukaryotic cells. While metabolites of bacterial origin may induce pathologic changes in mucosal immunity and epithelial barrier integrity, these small molecules may also be inhibitory to other bacterial species and alter microbial homeostasis within the cervicovaginal space 40 .…”

Interstrain Variability of Human Vaginal Lactobacillus crispatus for Metabolism of Biogenic Amines and Antimicrobial Activity against Urogenital Pathogens

“…These compounds, commonly produced by urogenital pathogens, are elevated in patients with BV [4] and UTI [10] and are known causes of malodour. Beyond that, large amounts of these compounds increase the risk of vaginal dysbiosis [11]. Therefore, a high abundance of strains that reduce the amounts of biogenic amines are desirable in the vaginal environment.…”

Immunometabolic Analysis of Mobiluncus mulieris and Eggerthella sp. Reveals Novel Insights Into Their Pathogenic Contributions to the Hallmarks of Bacterial Vaginosis

“…We also evaluated the metabolites previously identified in cervicovaginal lavages collected from women with BV ( Srinivasan et al., 2015 ). It is well established that biogenic amines are strongly associated with BV ( Nelson et al., 2015 ) and linked to vaginal odor and elevated pH ( Srinivasan et al., 2015 ; Borgogna et al., 2021 ). Cell culture supernatants from the 3-D cervical cell models infected with Eggerthella sp.…”