Miscarriage and the Microbiome: Host Genetics, Immunity, and the Reproductive Tract Ecosystem

TL;DR

This review explores how the microbiome and host genetics interact to influence miscarriage, highlighting the role of immune-microbial interactions in reproductive health.

Contribution

The paper integrates microbiome, genomics, immunology, and epigenetics to propose a new framework for understanding miscarriage.

Findings

Genetic variation in immune pathways influences susceptibility to miscarriage through interactions with the microbiome.

Microbial metabolites regulate gene expression and immune tolerance in the endometrium and decidua.

Miscarriage may result from disrupted host-microbe communication rather than isolated causes.

Abstract

Background/Objectives: Pregnancy loss is a common and multifactorial complication of human reproduction, traditionally attributed to fetal chromosomal abnormalities, maternal anatomical and endocrine disorders, and immune dysfunction. Growing evidence now indicates that the maternal microbiome, particularly within the reproductive tract, plays a critical role in implantation, placental development, and the maintenance of immune tolerance during early pregnancy. Importantly, the influence of the microbiome on miscarriage appears to be strongly modulated by host genetic background and immune regulation. Methods: This narrative review summarizes current evidence linking alterations in the vaginal, endometrial, placental, and gut microbiomes to miscarriage, with a specific focus on host genetics and immune–microbial interactions. Results: We discuss how genetic variation in innate and adaptive immune pathways, inflammatory signaling, and mucosal barrier function may shape host responses to microbial communities, thereby influencing susceptibility to PL. In addition, we highlight emerging data on microbiome-driven regulation of gene expression and epigenetic modifications in the endometrium and decidua, emphasizing the role of microbial metabolites in immune tolerance and placental function. Conclusions: By integrating findings from microbiome research, host genomics, immunology, and epigenetics, this review proposes a framework in which miscarriage is viewed as a consequence of disrupted host–microbe crosstalk rather than isolated pathology. Finally, we address key methodological challenges and outline future research directions aimed at advancing mechanistic understanding and translational applications.

Figures