A preclinical study by Weill Cornell Medicine investigators suggests that gut microbes may influence a mother’s immune system to adapt to the developing fetus during pregnancy. The findings, published December 17 in Cell, indicate that beneficial gut bacteria contribute to preventing immune system reactions that could lead to pregnancy loss in mice.
Research Findings
Investigators demonstrated that metabolites produced by gut microbes promote the recruitment of two types of protective immune cells, myeloid-derived suppressor cells (MDSCs) and RORyt+ regulatory T-cells (pTregs), to the placenta. These cells assist the mother’s immune system in developing tolerance for the fetus.
According to senior author Melody Zeng, associate professor of immunology in pediatrics at Weill Cornell Medicine, the training of the maternal immune system to recognize the fetus as non-harmful is crucial. This mechanism prevents the maternal immune system from attacking the fetus, which can lead to recurrent miscarriages or stillbirths. The American College of Obstetricians and Gynecologists reports that the underlying cause for over half of women experiencing repeat miscarriages remains unidentified.
Methodology and Results
The study examined the maternal immune response during pregnancy in two mouse models: germ-free mice (bred in a sterile environment without exposure to bacteria, fungi, or viruses) and mice treated with antibiotics to disrupt beneficial bacteria. Both germ-free and antibiotic-treated mice exhibited excessive inflammation in the placenta, which resulted in fetal death, in contrast to mice with healthy gut microbiomes. Specifically, these mice developed increased numbers of interferon-gamma-producing T cells and antibodies capable of attacking the developing fetus. Conversely, pregnant mice with healthy gut microbiomes produced both MDSCs and pTregs, contributing to fetal tolerance.
The research team discovered that the amniotic fluid in pregnant mice with healthy gut microbiomes contained tryptophan-derived metabolites, which were produced by specific gut microbes. These metabolites were found to maintain protective immune cells at the maternal-fetal interface, promoting immune tolerance. Administering tryptophan metabolites, or the bacteria that produce them, to germ-free mice increased the proportion of fetal survival from 50% to 95%. In contrast, administering gut bacteria unrelated to this pathway did not improve pregnancy outcomes.
Human Study Correlation and Future Directions
Subsequently, the team analyzed decidual tissue samples, shed from the uterus after pregnancy, from women who had experienced recurrent miscarriages. They identified reduced levels of the tryptophan-derived metabolites and decreased numbers of tolerance-inducing MDSCs and pTregs in these samples.
Julia Brown, a postdoctoral associate in pediatrics at Weill Cornell Medicine and the study’s first author, stated that the immune cells identified in mice appear relevant to human pregnancies. She emphasized the necessity of additional studies to confirm the role of these immune cells and tryptophan metabolites in human pregnancies.
The team plans to continue investigating the role of gut microbes in promoting immune tolerance during pregnancy. These findings are intended to inform the development of targeted therapies. Ultimately, collaboration with physicians is planned to evaluate supplements or interventions that enhance beneficial gut microbes or their metabolites, aiming to improve the chances of a successful full-term pregnancy.
Collaborators and Funding
Dr. Virginia Pascual and Gregory Sonnenberg from Weill Cornell Medicine also contributed to this project. The research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung and Blood Institute, the National Cancer Institute (all part of the National Institutes of Health), the Hartwell Foundation, the Starr Cancer Consortium, a pilot grant from the Friedman Center for Nutrition and Inflammation and the Jill Roberts Institute for Research in IBD at Weill Cornell Medicine, the Weill Cornell Children’s Health Council, and startup support from the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.