Human Milk Oligosaccharides modulate the risk for preterm birth in a microbiome dependent and independent manner

Background Preterm birth is one of the leading causes of neonatal mortality. The causes for spontaneous preterm birth (PTB) are multifactorial and remain often unknown. In this study, we tested the hypothesis that human milk oligosaccharides (HMOs) in blood and urine modulate the maternal urinary and vaginal microbiome and influence the risk for PTB. We analyzed the vaginal and urinary microbiome of a cross-sectional cohort of women with and without preterm labor and correlated our findings with measurements of metabolites and HMOs in urine and blood. Results We identified several microbial signatures associated with short cervix, PTB and/or preterm contractions such as Lactobacillus jensenii , L. gasseri , Ureaplasma sp . and Gardnerella sp.. Additionally, we observed associations between sialylated HMOs, in particular 3’-sialyllactose, with PTB, short cervix and increased inflammation and confirmed an influence of HMOs on the microbiome profile. Conclusions Identifying serum and urinary HMOs and several key microorganisms associated with PTB, our findings point at two distinct processes modulating the risk for PTB. One process seems to be driven by sterile inflammation, characterized by increased concentrations of sialylated HMOs in serum. Another process might be microbiome-mediated, potentially driven by secretor-active HMOs in urine. Our results support current efforts to improve diagnostics and therapeutic strategies.