(841) Gardnerella vaginalis induces biosynthesis of higher order polyamines: mechanisms of an optimal host immune response.

Distinct vaginal metabolomic signatures are associated with an anaerobe-dominant microbiota, a risk factor for preterm birth (PTB). Among individuals with similar microbiota-related risk, select metabolites can further risk stratify. Higher order polyamines, which function as anti-inflammatory molecules in other contexts, are reduced in individuals with an anaerobe-dominant microbiota who have PTB vs term birth. We hypothesize that an effective host immune response to vaginal anaerobes necessitates biosynthesis of polyamines.


Study Design:

Vaginal, ectocervical, and endocervical epithelial cells were treated with 10⁵-10⁷ CFU of Lactobacillus crispatus (LC) or anaerobe Gardnerella vaginalis (GV) for 24h (n=3/condition). Metabolomic profiling of cell culture media was performed and normalized data were analyzed using MetaboAnalyst. Dot plots of log-transformed data were generated (ggplot2 R package). RNA sequencing was conducted on cells. Differential expression analysis of polyamine metabolism genes was performed using DESeq2.


Results:

Metabolomic profiling revealed an increase in higher order polyamine spermidine with a concurrent decrease in the precursor arginine in response to GV compared to LC and NT (Fig. 1). An increase in intermediates along the pathway was observed, with subtle differences across cell lines. To explore the molecular drivers of these metabolic shifts, we examined enzymes involved in polyamine metabolism. GV exposure upregulated ODC1, the rate limiting step in polyamine biosynthesis, and altered expression of additional enzymes including ARG2, AMD1, SRM, SMOX1, PAOX, and SAT1 vs controls (Fig. 2; all adjusted p< 0.05).


Conclusion:

A vaginal anaerobe implicated in PTB induces biosynthesis of higher order polyamines, which may serve to constrain anaerobe-induced inflammation. Modulating the host immune response to vaginal anaerobes, either through activation of enzymatic machinery involved in polyamine biosynthesis or vaginal polyamine repletion, may be leveraged as a future therapeutic to mitigate PTB risk in the setting of an anaerobe-dominant microbiota. 1R01HD114611-01 (KDG)