Towards microbiome-informed strategies for predicting and preventing pregnancy complications.

Graphical Abstract: Abstract: Despite the prevalence of pregnancy complications, including miscarriage, stillbirth, preeclampsia (PE), fetal growth restriction (FGR), and preterm birth (PTB), current predictive tools remain limited. This underscores an urgent need for novel molecular biomarkers and mechanistic insights. The microbiome regulates host physiology, and its disruption correlates with adverse pregnancy outcomes, such as PE, PTB, and gestational diabetes mellitus (GDM), and thus holds promise for predictive insights and therapeutic interventions. However, these associations are largely correlative, based on taxonomic rather than protein- or metabolite-based functional changes. In addition, they are often derived from cross-sectional studies, and the underlying mechanisms remain poorly understood. Given the evidence-based view of a sterile intra-uterine environment, understanding the factors that mediate host-microbe interactions is crucial for improving pregnancy outcomes. Maternal immune and hormonal changes can influence the composition and functional capacity of the microbiome, while the microbiome, in turn, modulates immune, neuroendocrine responses, nutrient bioavailability, and metabolic processes, impacting placental development and pregnancy physiology. We explore direct and indirect mediators of host-microbiome interactions and discuss how these may be targeted to improve pregnancy outcomes. We briefly consider the potential influence of the paternal microbiome and maternal preconception microbial states on pregnancy physiology and outcomes. Finally, we critically evaluate existing methodologies and databases for studying microbial variations in pregnancy-related disorders and propose strategies to better harness microbiome-based research for clinical application. By integrating current evidence and identifying key knowledge gaps, this review aims to highlight microbiome-informed strategies for improving pregnancy outcomes and lifelong health. Lay summary: Understanding how microbes influence pregnancy outcomes is essential. Pregnancy complications, such as miscarriage, stillbirth, preeclampsia (PE), Fetal growth restriction (FGR), and preterm birth (PTB), are common, yet we still lack reliable tools to predict who is at risk. This makes it essential to identify new biological markers and better understand the underlying mechanisms. One promising area is the microbiome, the community of microorganisms that live in and on our bodies, including bacteria, viruses, and fungi. The microbiome plays a major role in regulating health, and changes in its composition have been linked to pregnancy disorders, including PE, PTB, and gestational diabetes mellitus (GDM). However, most of what we know comes from studies that only identify which microbes are present, rather than what these microbes are doing. Many studies are also cross-sectional, capturing only a single time point, which limits our ability to understand the cause and effect. Because the uterus is generally considered a sterile environment, the key question is how the maternal body and microbiome communicate. During pregnancy, the immune system and hormone levels change dramatically, and these shifts can alter the composition and function of the microbiome. In turn, the microbiome can influence maternal immunity, hormone signalling, nutrient availability, and metabolism. These interactions may shape how the placenta develops and how the pregnancy progresses. In this review, we examine how the body and the microbiome interact both directly and indirectly and how these pathways might be targeted to improve pregnancy outcomes. We also touch on the possible influence of the father's microbiome and the mother's preconception health on fertility, early development, and long-term pregnancy health.