Novel immunotherapeutic approach of heparin and progesterone on preterm birth induced by sterile inflammation

AbstractBackgroundPreterm 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.ResultsWe identified several microbial signatures associated with short cervix, PTB and/or preterm contractions such asLactobacillus jensenii,L. gasseri,Ureaplasma sp. andGardnerella 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.ConclusionsIdentifying 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.

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Role of innate immune cells in preterm birth and miscarriages induced by sterile inflammation in mice and humans

Journal of Reproductive Immunology ◽

10.1016/j.jri.2017.10.007 ◽

2017 ◽

Vol 124 ◽

pp. 73

Author(s):

Yasuyuki Negishi ◽

Tomoko Ichikawa ◽

Yoshio Shima ◽

Toshiyuki Takeshita ◽

Hidemi Takahashi

Keyword(s):

Preterm Birth ◽

Immune Cells ◽

Innate Immune ◽

Sterile Inflammation ◽

Innate Immune Cells

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The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes and preterm birth and neonatal mortality in mice†

Biology of Reproduction ◽

10.1093/biolre/ioab188 ◽

2021 ◽

Author(s):

Kenichiro Motomura ◽

Roberto Romero ◽

Olesya Plazyo ◽

Valeria Garcia-Flores ◽

Meyer Gershater ◽

...

Keyword(s):

Preterm Birth ◽

Neonatal Mortality ◽

Inflammatory Responses ◽

Perinatal Outcomes ◽

Neonatal Morbidity ◽

Causal Link ◽

Sterile Inflammation ◽

Amniotic Cavity ◽

Adverse Perinatal Outcomes

Abstract Sterile inflammation is triggered by danger signals or alarmins released upon cellular stress or necrosis. Sterile inflammation occurring in the amniotic cavity (i.e. sterile intra-amniotic inflammation) is frequently observed in women with spontaneous preterm labor resulting in preterm birth, the leading cause of neonatal morbidity and mortality worldwide, and is associated with increased amniotic fluid concentrations of alarmins. However, the mechanisms whereby alarmins induce sterile intra-amniotic inflammation are still under investigation. Herein, we investigated the mechanisms whereby the alarmin S100A12 induces inflammation of the human chorioamniotic membranes in vitro and used a mouse model to establish a causal link between this alarmin and adverse perinatal outcomes. We report that S100A12 initiates sterile inflammation in the chorioamniotic membranes by upregulating the expression of inflammatory mediators such as pro-inflammatory cytokines and pattern recognition receptors. Importantly, S100A12 induced the priming and activation of inflammasomes, resulting in the activation of caspase-1 and the subsequent release of mature IL-1β by the chorioamniotic membranes. This alarmin also caused the activation of the chorioamniotic membranes by promoting MMP-2 activity and collagen degradation. Lastly, the ultrasound-guided intra-amniotic injection of S100A12 at specific concentrations observed in the majority of women with sterile intra-amniotic inflammation induced preterm birth (rates: 17% at 200 ng/sac; 25% at 300 ng/sac; 25% at 400 ng/sac) and neonatal mortality (rates: 22% at 200 ng/sac; 44% at 300 ng/sac; 31% at 400 ng/sac), demonstrating a causal link between this alarmin and adverse perinatal outcomes. Collectively, our findings shed light on the inflammatory responses driven by alarmins in the chorioamniotic membranes, providing insight into the immune mechanisms leading to preterm birth in women with sterile intra-amniotic inflammation.

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Human Milk Oligosaccharides Modulate the Risk for Preterm Birth in a Microbiome-Dependent and -Independent Manner

mSystems ◽

10.1128/msystems.00334-20 ◽

2020 ◽

Vol 5 (3) ◽

Author(s):

Manuela-Raluca Pausan ◽

Vassiliki Kolovetsiou-Kreiner ◽

Gesa Lucia Richter ◽

Tobias Madl ◽

Elisabeth Giselbrecht ◽

...

Keyword(s):

Preterm Birth ◽

Human Milk ◽

Sterile Inflammation ◽

Vaginal Microbiome ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Short Cervix ◽

Independent Manner ◽

Cross Sectional ◽

Content Type

ABSTRACT Preterm birth (PTB) is one of the leading causes of neonatal mortality. The causes for spontaneous PTB are multifactorial and often remain 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 or without preterm labor and correlated our findings with measurements of metabolites and HMOs in urine and blood. We identified several microbial signatures, such as Lactobacillus jensenii, L. gasseri, Ureaplasma sp., and Gardnerella sp., associated with a short cervix, PTB, and/or preterm contractions. In addition, 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. Since they identify 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 and potentially associated with specific HMO signatures in urine. Our results support current efforts to improve diagnostics and therapeutic strategies in PTB. IMPORTANCE The causes for preterm birth (PTB) often remain elusive. We investigated whether circulating human milk oligosaccharides (HMOs) might be involved in modulating urinary and vaginal microbiome promoting or preventing PTB. We identified here HMOs and key microbial taxa associated with indicators of PTB. Based on our results, we propose two models for how HMOs might modulate risk for PTB: (i) by changes in HMOs associated with sterile inflammation (microbiome-independent) and (ii) by HMO-driven shifts in microbiome (microbiome-dependent). Our findings will guide current efforts to better predict the risk for PTB in seemingly healthy pregnant women and also provide appropriate preventive strategies.

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