A study led by researchers at Weill Cornell Medicine suggests that gut microbes play a significant role in helping the maternal immune system adapt during pregnancy. The research, published on December 17 in Cell, found that beneficial bacteria in the gut help prevent immune responses that could result in pregnancy loss, at least in mouse models.
The investigators showed 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 tolerating the fetus.
"During pregnancy it's very important that the mom's immune system is trained to recognize that the fetus is not harmful," said Dr. Melody Zeng, senior author and associate professor of immunology in pediatrics at Weill Cornell Medicine. "That prevents the maternal immune system from attacking the fetus, which can lead to recurrent miscarriages or still births."
According to data from the American College of Obstetricians and Gynecologists, more than half of women who experience repeat miscarriage do not have an identified underlying cause. While earlier studies have linked disturbances in gut microbiota to problems with immune function or inflammation, how this happens has remained unclear.
Dr. Zeng's team examined two groups of mice: those bred without exposure to any microbes (germ-free mice) and those treated with antibiotics to disrupt their gut bacteria. Both groups experienced higher levels of inflammation in the placenta and increased fetal death compared to mice with healthy gut microbiomes. In these cases, there were excessive numbers of interferon-gamma-producing T cells and antibodies capable of attacking the fetus. By contrast, pregnant mice with intact microbiomes produced more MDSCs and pTregs—immune cells associated with tolerance toward the fetus.
The researchers also discovered tryptophan-derived metabolites produced by specific gut microbes present in amniotic fluid from healthy pregnancies. These metabolites appear to maintain protective immune cells at the maternal-fetal interface. When germ-free mice received either these metabolites or bacteria capable of producing them, fetal survival rates increased from 50% to 95%. However, introducing unrelated bacteria did not improve outcomes.
The team then analyzed decidual tissue samples from women who had experienced recurrent miscarriages and found lower levels of both tryptophan-derived metabolites and tolerance-inducing immune cells.
"The same immune cells we identified in the mice seem to be important for human pregnancies," said Dr. Julia Brown, first author and postdoctoral associate at Weill Cornell Medicine. "We need to do additional studies to confirm the role of these immune cells and tryptophan metabolites in human pregnancies."
Future work will focus on further investigating how gut microbes promote immune tolerance during pregnancy and whether targeted therapies or supplements could enhance beneficial microbes or their products for better pregnancy outcomes.
"Our research provides new insights about the factors from our microbiome that support immune tolerance during pregnancy," Dr. Zeng said. "We hope to one day leverage those insights to develop therapies that support immune tolerance during pregnancy and help women who may be struggling with infertility or unexplained recurrent miscarriages."
