Preterm birth is associated with xenobiotics and predicted by the vaginal metabolome

Abstract

Spontaneous preterm birth (sPTB) is a leading cause of maternal and neonatal morbidity and mortality, yet its prevention and early risk stratification are limited. Previous investigations have suggested that vaginal microbes and metabolites may be implicated in sPTB. Here we performed untargeted metabolomics on 232 second-trimester vaginal samples, 80 from pregnancies ending preterm. We find multiple associations between vaginal metabolites and subsequent preterm birth, and propose that several of these metabolites, including diethanolamine and ethyl glucoside, are exogenous. We observe associations between the metabolome and microbiome profiles previously obtained using 16S ribosomal RNA amplicon sequencing, including correlations between bacteria considered suboptimal, such as Gardnerella vaginalis, and metabolites enriched in term pregnancies, such as tyramine. We investigate these associations using metabolic models. We use machine learning models to predict sPTB risk from metabolite levels, weeks to months before birth, with good accuracy (area under receiver operating characteristic curve of 0.78). These models, which we validate using two external cohorts, are more accurate than microbiome-based and maternal covariates-based models (area under receiver operating characteristic curve of 0.55–0.59). Our results demonstrate the potential of vaginal metabolites as early biomarkers of sPTB and highlight exogenous exposures as potential risk factors for prematurity.

Microdiversity of the Vaginal Microbiome is Associated with Preterm Birth

“…This result suggests that the more diverse gene pool in G. swidsinskii (PG044) detected in sPTB may be associated with adaptation to drugs present in the environment. This may be consistent with our recent finding that xenobiotics detected in the vaginal environment are strongly associated with sPTB 34 .…”

“…Notably, we found that sPTB-associated purifying selection is particularly strong on genes involved in lipid transportation and metabolism. This is consistent with previous identification of lipid metabolites (e.g., monoacylglycerols and sphingolipids) as signatures of sPTB 34,64,65 . Whether this stronger purifying selection targeting lipid transportation and metabolisms in pregnancy that ended preterm leads to changes in the concentrations of lipid metabolites however requires further experimental testing.…”

“…As in the human gut microbiome [19][20][21] , we show evidence that adaptive evolution also occurs in the vaginal microbiome. Several environmental factors affecting the vaginal ecosystem, such as pH, neutrophil levels, and xenobiotics, have been reported to be associated with sPTB 34,60 . These environmental factors may act as selective stressors that lead to different evolutionary patterns in the vaginal microbiome.…”

“…As in the human gut microbiome 19–21 , we show evidence that adaptive evolution also occurs in the vaginal microbiome. Several environmental factors affecting the vaginal ecosystem, such as pH, neutrophil levels, and xenobiotics, have been reported to be associated with sPTB 34,60 .…”

Small molecule metabolites: discovery of biomarkers and therapeutic targets

“…Major communication between host and gut microbiota takes place through the metabolites, such as acetate, butyrate, and propionate, and via the microbiota composition modulating metabolism processes. 783 – 786 Gut microbiota acts as an “invisible organ” and produces active metabolites via their receptor signal to regulate the host metabolism that affects systemic health, and plays a variety of effects on the host from shaping gut structure and function to the modulation of the host status. The increasing evidence showing that gut environment disorder could affect various organs lead to metabolic diseases.…”