Tyramine paradoxically suppresses immune output of the cervicovaginal epithelium: potential mechanisms promoting a Lactobacillus-deplete microbiota

We previously identified alterations in cervicovaginal (CV) tryptophan (Trp) metabolism during pregnancy in association with a Lactobacillus-deplete microbiota, a risk factor for preterm birth (PTB). In the gut, microbial decarboxylation of Trp produces tryptamine (TY), an anti-inflammatory indole metabolite. Immune dysfunction of the CV epithelium contributes to the pathogenesis of PTB. The extent to which TY is bioactive in the CV space remains unknown. This was a secondary analysis of a completed prospective pregnancy cohort. CV fluid was obtained at 16-20 weeks’ gestation. Non-Hispanic Black participants selected for metabolomic profiling were frequency matched by birth outcome and CV microbiota profile (n=40). Bacterial and Trp metabolite abundances were log2 transformed. Linear regression was used to quantify associations between bacterial and metabolite abundances with Bonferroni correction for multiple comparisons. For in vitro studies, ectocervical and endocervical epithelial cells were treated with metabolites for 24 hours. Luminex panels were run on cell media (n=3 per condition). One-way ANOVAs with Dunnett’s multiple comparison tests were performed. TY is positively associated with Gardnerella vaginalis, Atopobium vaginae, and BVAB, microbes prevalent in a Lactobacillus-deficient microbiota (Fig. 1). TY is negatively associated with Lactobacillus crispatus, a healthy commensal microbe. In cervical cells, TY globally suppresses immune output compared to other indole metabolites (indoxyl sulfate and indolelactate) and kynurenine pathway metabolites (kynurenine and kynurenate) (Fig. 2). TY is associated with common opportunistic CV microbes and paradoxically exerts anti-inflammatory effects on the CV epithelium. It is plausible that microbial conversion of Trp to TY blunts host immune defenses, thereby promoting colonization of a Lactobacillus-deplete microbiota. Diversion of Trp decarboxylation to alternative metabolic pathways may offer novel strategies to modify aspects of CV ecosystems and improve reproductive outcomes. SMFM/AAOGF (KG), 5R01NR014784 (ME)View Large Image Figure ViewerDownload Hi-res image Download (PPT)