(21) Vaginal polyamines mitigate inflammasome activation: potential immune mechanisms governing barrier function in preterm birth

Vaginal metabolomics from our group previously identified a role for polyamines in delineating preterm birth (PTB) risk among pregnant individuals with a Lactobacillus-deplete or high-risk microbiota, suggesting that spermine and spermidine may function in a protective capacity. As immune perturbations contribute to barrier dysfunction and tissue remodeling on the pathway to PTB, we sought to explore whether polyamines mitigate these molecular processes. We investigated the innate immune system, including the inflammasome, which is heavily regulated by metabolic cues in other systems and emerging as a key first line of defense in epithelial barriers.


Study Design:

Ectocervical and endocervical epithelial cells were treated with 10⁷ CFUs Gardnerella vaginalis (GV), an anaerobe prevalent in a Lactobacillus-deplete microbiota. THP-1 monocytes were activated into macrophages with PMA and treated with 10⁵ CFUs GV or NLRP3 inflammasome agonist nigericin 5mM. Treatments occurred in the presence or absence of polyamines at concentrations ranging from 50-400uM. Inflammatory cytokine IL-8 and inflammasome activation marker IL-1β were measured in cell culture media by ELISA.  One-way ANOVAs with Dunnet’s multiple comparisons tests were performed.



Results:

Spermidine and spermine partially mitigate GV-induction of IL-8 and IL-1β-in ectocervical and endocervical cells (p <  0.05 for all, Fig. 1A and B). Spermine partially mitigates GV-induction of IL-1β in macrophages (p <  0.001, Fig. 1C). Spermidine and spermine partially mitigate nigericin-activation of NLRP3 as measured by IL-1β induction in macrophages (p <  0.001 for both, Fig. 1D).



Conclusion:

Our data support the paradigm that low concentrations of vaginal spermidine and spermine may contribute to increased inflammation and inflammasome activation in the cervicovaginal space, thereby rendering the barrier more suspectable to microbial challenge. These findings carry translational potential – vaginal polyamine repletion may serve as a novel postbiotic strategy to reduce PTB risk in the setting of a Lactobacillus-deplete microbiota. SMFM-AAOGF Award (KDG)