Differential Host Gene Expression Associated with Non-Lactobacillus-dominant Vaginal Microbiomes During Pregnancy

Background The vaginal microbiome significantly influences gynecological and obstetric health, yet the interrelationship between host vaginal gene expression and the microbiota during pregnancy is understudied—particularly in racioethnically diverse cohorts. Here, we leveraged metatranscriptomic data from 123 participants from the Multi-Omic Microbiome Study-Pregnancy Initiative (MOMS-PI) cohort to perform a novel integrated analysis of human host gene expression and vaginal microbiota composition during pregnancy. We hypothesized that host gene expression at the vaginal-mucosal interface would exhibit distinct transcriptional profiles when colonized by bacteria commonly present in bacterial vaginosis (BV), termed BV-associated vagitypes, compared to Lactobacillus -dominated microbiomes. Such distinct host response would provide evidence linking vaginal inflammation to microbiome composition during pregnancy in a majority Black cohort. By profiling host expression with different BV-associated vagitypes, these host-microbiome signatures could inform clinically actionable biomarkers for microbiome-focused interventions during pregnancy in historically underrepresented populations. Results Host transcriptomic profiles differed significantly between BV-associated and Lactobacillus -dominated vagitypes, with this association remaining significant when analyses were restricted to Black participants. We identified 13 consistently differentially expressed genes in women with BV-associated vagitypes—vaginal microbiomes comprised of high relative abundance of either Gardnerella spp., Candidatus Lachnocurva vaginae, or a mixture of multiple anaerobic taxa—compared to women with Lactobacillus crispatus vagitypes. These differentially expressed genes are involved in host immune response ( DKK1, H2BC21, ILRUN, S100A9 ), oxidative stress response and inflammasome activation ( CSTB ), transcription modulation ( CLK1, PAX9 ), vesicle trafficking ( EXPH5 ), ubiquitination ( FBXO32 ), membrane integrity ( PIEZO1 ), and ion transport ( S100A16, SCNN1A, SLCO4A1 ). Conclusion BV-associated vagitypes are correlated with distinct host immunomodulatory gene expression profiles during pregnancy, independent of self-reported racioethnicity. We demonstrated novel molecular insights into microbiome-host interaction during pregnancy within the context of adverse cervicovaginal health.