From gut to gamete: how the microbiome influences fertility and preconception health.

Global fertility rates continue to decline despite advancements in assisted reproductive technologies, highlighting a significant gap in our understanding of the mechanisms underlying preconception physiology. In this commentary, we review a growing body of work demonstrating that the microbiome plays a crucial yet underexplored role in women's reproductive health. This work has shown that microbial communities produce substrates that support metabolic, immune, and hormonal functions during this critical period, affecting fertility, pregnancy outcomes, and offspring health. Women with reproductive disorders, including endometriosis, polycystic ovarian syndrome, primary ovarian insufficiency, and recurrent pregnancy loss, harbor distinct microbial signatures. Animal studies provide key mechanistic insights, showing that disruption of microbiota accelerates ovarian aging, but translating these findings to human preconception health requires careful consideration. While these findings are compelling, this emerging field currently lacks a clear understanding of how microbial signals affect reproductive tissues through metabolites, immune responses, or hormonal pathways. We outline criteria for establishing microbial causation in preconception health, including sufficiency, necessity, specificity, and timing. Moving beyond correlations involves selecting appropriate models, focusing on key developmental windows, conducting longitudinal studies before conception, and investigating how specific microbial metabolites influence reproductive outcomes. Incorporating microbiome research into preconception care could lead to the development of new therapies and interventions. While the principles outlined here primarily address preconception reproductive health, they also offer a framework for microbiome research in general, emphasizing the need for a mechanistic understanding, timely interventions, and progress from association to causation in this rapidly evolving field.