Gut microbiota promotes immune tolerance at the maternal-fetal interface

Area of Science:

• Immunology
• Microbiology
• Reproductive Biology

Background:

• Immune tolerance at the maternal-fetal interface is essential for fetal development.
• Dysregulated maternal interferon-gamma (IFN-γ) and interleukin-17 (IL-17) are associated with pregnancy complications.
• Mechanisms regulating maternal immune responses at the maternal-fetal interface are not fully understood.

Purpose of the Study:

• To investigate the role of the gut microbiota in regulating maternal immune responses at the maternal-fetal interface.
• To identify microbial metabolites involved in maintaining immune tolerance during pregnancy.
• To explore the link between gut microbiota, immune dysregulation, and pregnancy complications.

Main Methods:

• Utilized pregnant mouse models, including germ-free mice.
• Analyzed immune cell populations (IFN-γ+, IL-17+ T cells, myeloid-derived suppressor cells (MDSCs), RORγt+ regulatory T cells (Tregs)) at the maternal-fetal interface.
• Assessed the impact of gut microbiota perturbation and specific microbial metabolites (tryptophan derivatives) on pregnancy outcomes.
• Examined human recurrent miscarriage samples for dysregulation of identified pathways.

Main Results:

• Absence or disruption of gut microbiota leads to increased maternal IFN-γ and IL-17 at the maternal-fetal interface, causing fetal resorption in mice.
• Microbiota-dependent tryptophan derivatives suppress pathogenic T cells by activating MDSCs and RORγt+ Tregs.
• Administration of indole-3-carbinol or Lactobacillus murinus restored immune balance and reduced fetal resorption in germ-free mice.
• Dysregulation of MDSCs, RORγt+ Tregs, and tryptophan derivatives was observed in human recurrent miscarriage cases.

Conclusions:

• A gut-placenta immune axis mediated by microbiota-dependent tryptophan derivatives is critical for maternal-fetal immune tolerance.
• These mechanisms are essential for preventing pregnancy complications and ensuring fetal development.
• Dysregulation of this axis contributes to conditions like recurrent miscarriage.