Research reveals how the gut microbiome supports successful pregnancy

Gut microbes may play a key role in training a mother's immune system to adapt to the developing fetus during pregnancy, according to a preclinical study by Weill Cornell Medicine investigators.

The findings, published Dec. 17 in Cell, show that beneficial gut bacteria help prevent immune system reactions that can lead to pregnancy loss in mice. The investigators demonstrated that metabolites produced by gut microbes promote the recruitment of two types of protective immune cells, called myeloid-derived suppressor cells (MDSCs) and RORyt+ regulatory T-cells (pTregs), to the placenta and help the mother's immune system learn to tolerate the fetus.

During pregnancy it's very important that the mom's immune system is trained to recognize that the fetus is not harmful. That prevents the maternal immune system from attacking the fetus, which can lead to recurrent miscarriages or still births."

Dr. Melody Zeng, senior author, associate professor of immunology in pediatrics and member of the Gale and Ira Drukier Institute for Children's Health, Weill Cornell Medicine

For more than half of women who experience repeat miscarriage the underlying cause has not been identified, according to the American College of Obstetricians and Gynecologists. Previous studies have linked gut microbiota disturbances to immune system dysfunction or inflammatory conditions; but the mechanistic underpinnings remain unclear. Dr. Zeng and her team looked at the potential role of the gut microbiota in maternal-fetal immune tolerance and pregnancy outcomes.

Dr. Virginia Pascual, the Gale and Ira Drukier Director of Children's Health Research and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine, and Dr. Gregory Sonnenberg, associate vice chair for research in the Department of Medicine and the Henry R. Erle, M.D.-Roberts Family Professor of Medicine, also contributed to this collaborative, multidisciplinary project.

Gut microbes are beneficial in model systems

Dr. Zeng and her colleagues looked at the maternal immune response during pregnancy in two mouse models: mice bred in a sterile environment with no exposure to bacteria, fungi and viruses, called germ-free mice, and mice treated with antibiotics to disrupt beneficial bacteria. They found that the germ-free and antibiotic-treated mice experienced excessive inflammation in the placenta that led to fetal death compared with mice with healthy gut microbiomes. Specifically, they developed excessive numbers of interferon-gamma-producing T cells and antibodies that can attack the developing fetus. However, pregnant mice with healthy gut microbiomes produced both types of protective immune cells, MDSCs and pTregs, that help build tolerance toward the fetus.

The team discovered that the amniotic fluid in the pregnant mice with healthy gut microbiomes contained metabolites derived from the amino acid tryptophan, which were produced by specific gut microbes. These metabolites maintain protective immune cells at the maternal-fetal interface to promote immune tolerance. Giving germ-free mice tryptophan metabolites, or the bacteria that produce them, increased the proportion of fetal survival from 50% to 95%. By contrast, giving these mice gut bacteria unrelated to this pathway did not improve pregnancy outcomes.

Human tissue samples correlate with animal studies

Next, the team looked at samples of tissue shed from the uterus after the end of the pregnancy, called decidual tissue, from women who had experienced recurrent miscarriages. They found reduced levels of the tryptophan-derived metabolites and reduced numbers of tolerance-inducing MDSCs and pTregs.  

"The same immune cells we identified in the mice seem to be important for human pregnancies," said the study's first author Dr. Julia Brown, a postdoctoral associate in pediatrics 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 directions

The team will investigate the role of gut microbes in promoting immune tolerance during pregnancy and use these findings to develop targeted therapies. Ultimately, they plan to collaborate with physicians to evaluate supplements or interventions that enhance beneficial gut microbes or their metabolites to improve the chances of a successful full-term pregnancy.

"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."