Maternal immune modulations are critical for fetal development. Without tolerance of fetal markers there is a risk of complications, such as preterm birth and miscarriage. It is known that the gut microbiome helps shape the immune system in healthy individuals and that dysbiosis can drive inflammation and potentially autoimmune diseases. However, in the context of pregnancy the role that the microbiome plays in maternal-fetal tolerance is unclear. A recent publication by Dr. Melody Zeng’s group focused on how the maternal microbiome regulates maternal-fetal tolerance.
In this study, they demonstrate that pregnancy alters the microbiome significantly. Bacterial diversity is reduced and there are increased regulatory T cell populations in the small intestine of pregnant dams compared to non-pregnant females. The vast majority of immune cells detected in the placenta are of maternal origin, therefore alterations in the microbiome have a direct impact on maternal-fetal tolerance. In pregnant germ-free mice there was an increase in interferon (IFN)-gamma positive T cells in the placenta and uterus. It is known that low levels of IFN is important during pregnancy however, exacerbated IFN responses are linked to poor outcomes including pregnancy loss. Such is the case for germ-free dams in this study, which had significantly higher rates of fetal resorption. Additionally, germ-free dams had a reduction in myeloid-derived suppressor cells, which seem to regulate immune tolerance, as well as a reduction of RORγt+Treg, that are peripherally generated Tregs, at the maternal-fetal interface. Taken together, this suggests that the maternal microbiome drives maternal-fetal tolerance.
To further elucidate the role that the gut microbiome plays in maternal-fetal tolerance, the researchers used metabolomic analysis of plasma and amniotic fluid taken from germ-free pregnant mice compared to control pregnant dams. Germ-free dams had significantly reduced tryptophan levels as well as lower levels of kynurenine and kynurenic acid. Interestingly, bacterial-derived tryptophan metabolites were increased in pregnant control dams, including 3-indolepropionic acid, indolelactic acid, and indole. These metabolites have been shown to be anti-inflammatory and promote Treg development. Here they demonstrate that aryl hydrocarbon receptor (AhR) signaling is significantly reduced in germ-free and vancomycin-treated pregnant dams. When germ-free mice are treated with indole-3-carbinol (an AhR agonist), fetal resorption incidence is decreased. Furthermore, they observed less fetal resorption, higher levels of RORγt+Tregs, and reduced IFN levels when germ-free mice were recolonized with a tryptophan-metabolizing bacteria (Lactobacillus murinus). This suggests that bacterial-derived tryptophan metabolism contributes to maternal tolerance during pregnancy.
Additionally, maternal microbiome alterations due to diet have also been linked to long-term disorders in offspring including metabolic dysfunction-associated steatotic liver disease (MASLD). Dr. Jacob Friedman’s group recently showed that treating Western-style fed pregnant dams with indole reduced hepatic steatosis and fibrosis of adult offspring. AhR signaling was activated in the offspring of dams treated with indole, which provided protection against MASLD-like symptoms. Taken together, targeting the microbiome and increasing bacterial-derived tryptophan-metabolites may improve pregnancy outcomes in individuals who have recurrent miscarriages, as well as have a potential long-term health benefit against metabolic diseases like MASLD. Further research is needed to validate this therapeutic strategy with careful consideration of the potential long-term effects that maternal targeted therapy may have on offspring.