Gut microbiome composition during pregnancy has long-term effects on offspring stem cell growth and development, researchers report December 11 in the Cell Press journal Cell Stem Cell. Treating pregnant mice with a common gut microbe resulted in offspring that had more active stem cells in both the brain and intestinal tract. As a result, the offspring were less anxious and recovered quicker from colitis, and these differences were still evident at 10 months of age.
Exposing offspring to the microbe after birth did not result in the same stem cell activation. The team showed that the microbe impacted stem cell growth by altering the abundance of other gut microbes and increasing the microbial production of metabolites that cross the placenta and induce stem cell growth and proliferation.
"This is a major advancement in developing microbiota-based intervention strategies to improve child health," says senior author Parag Kundu of the Institut Pasteur of Shanghai.
Researchers treated the pregnant mice with Akkermansia muciniphila, a common gut microbe whose low abundance is associated with obesity, diabetes, and liver steatosis.
Previous studies have shown that the maternal microbiome is associated with offspring immunity, metabolism, and neurological development, but how gut microbes impact these processes is unclear. Since stem cells are responsible for controlling growth, development, and organ maturation during early life, Kundu's team decided to investigate whether there is crosstalk between gut microbes and fetal stem cells during pregnancy.
To do this, they treated pregnant mice with Akkermansia muciniphila and found that prenatal exposure had big impacts on the offspring's stem cells. The offspring of Akkermansia-exposed mothers had more stem cells in their brains and intestines, and these stem cells were also more active compared to the stem cells of mice that were not exposed to Akkermansia in utero.
These changes to stem cell development had long-term impacts on the mice's behavior and health. In behavioral tests, the offspring of Akkermansia-exposed mothers were less anxious and more exploratory. They also rebounded faster from chemically induced intestinal inflammation due to faster regeneration and turnover of intestinal epithelial cells.
Treating newborn mice with Akkermansia did not have the same impact on stem cell development as prenatal exposure.
"When we exposed the offspring postnatally to Akkermansia, we saw some differences in differentiation, but we didn't see the entire phenomena what we observed when mothers were exposed to Akkermansia during pregnancy," says Kundu. "That's why we think that this pregnancy period is critical, and microbiome alterations during this period can really do miracles."
The effect appears to be Akkermansia specific, since treating pregnant mice with a different gut microbe, Bacteroidetes thetaiotaomicron, did not impact offspring stem cell development. However, Akkermansia was only able to exert its effects in the presence of an otherwise complex gut microbiome.
The team showed that Akkermansia altered the abundance of other species of gut microbe and promoted other gut microbes to become more metabolically active to produce larger quantities of metabolites like short-chain fatty acids and amino acids. Unlike gut microbes, these metabolites can cross the placenta, and they're known to stimulate cell growth and proliferation via a protein called mTOR. When the researchers treated pregnant mice with both Akkermansia and rapamycin, a chemical that inhibits mTOR, they no longer saw any impacts on the offspring's stem cells.
Looking ahead, the researchers plan to further study how microbiome metabolites influence stem cells. To test whether this phenomenon also occurs in humans, they're planning to create "humanized mice" by transplanting human microbiota into mice and to examine human cohorts who consume probiotics during pregnancy.
"Promoting child health is a major challenge worldwide, and extrapolating these findings to humans is crucial," says Kundu.
