A study in mice has found that maternal gut microbiome composition during pregnancy has long-term effects on offspring stem cell growth and development. The researchers, headed by Parag Kundu, PhD, at the Institut Pasteur of Shanghai-Chinese Academy of Sciences, found that treating pregnant mice with the common gut microbe Akkermansia muciniphila 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.
The team showed that Akkermansia muciniphila impacted stem cell growth by altering the abundance of other gut microorganisms and increasing the microbial production of metabolites that cross the placenta and induce stem cell growth and proliferation. Exposing offspring to the bacterium after birth did not result in the same stem cell activation.
“This is a major advancement in developing microbiota-based intervention strategies to improve child health,” said Kundu, who is senior author of the team’s published paper in Cell Stem Cell, titled “Maternal gut microbiota influence stem cell function in offspring.” In their report the team stated, “These results suggest a fundamental role of the maternal microbiome in programming offsprings’ stem cells and represent a promising target for interventions.”
“The maternal microbiome influences child health,” the authors wrote. It’s been established that the maternal microbiome can influence offspring immune- and neuro-development, and metabolic phenotypes, and these will likely have long-term health implications. In contrast, they noted, disruptions to the maternal microbiome can severely affect developmental processes in offspring, which can lead to neuro- and intestinal-developmental disorders and inflammation.
“Together, these findings implicate maternal microbiota as a critical determinant for offspring’s development and health as well as its predisposition to develop disease later in life,” the investigators stated. However, they noted, impact of the maternal microbiome on a given offspring’s stem cells remains poorly understood. “Although several studies have addressed the role of maternal microbiome on offspring’s immune and metabolic health, its influence on the stem cells and associated developmental processes of the offspring remain obscure.”
As cells are responsible for controlling growth, development, and organ maturation during early life, Kundu’s team aimed to investigate whether there is crosstalk between gut microorganisms and fetal stem cells during pregnancy.
For their reported study the researchers focused on Akkermansia muciniphila (Am), a common gut microorganism whose low abundance is associated with obesity, diabetes, and liver steatosis. “We chose Akkermansia muciniphila (Am) for this purpose based on its established capacity to modify the gut microbiota and its potential as a next-generation probiotic,” they stated.
The team treated pregnant mice with Akkermansia muciniphila, and found that this 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. Interestingly, transplantation of altered maternal microbiota into germ-free mice also transmitted these stem cell phenotypes to the recipients’ offspring. “We showed that stem cells in the brain and intestine of the developing offspring responded differently to distinct maternal microbiome signatures,” the researchers wrote.
The changes to stem cell development had a long-term impact on the animals’ 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. “The changes in these stem cell functions, detected as early as three days after birth, were sustained and exerted a significant impact on the offspring’s physiology later in life, including behavior, intestinal permeability, and disease recovery,” the researchers noted.
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,” said 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 progeny of germ-free mice selectively colonized with Akkermansia did not display these stem cell traits, emphasizing the importance of microbiome diversity,” the team noted.
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. “Metabolically more active maternal microbiomes enriched the levels of circulating short-chain fatty acids (SCFAs) and amino acids, leaving distinct transcriptomic imprints on the mTOR pathway of offsprings’ stem cells,” they pointed out. 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. “Blocking mTOR signaling during pregnancy eliminated the maternal-microbiome-mediated effects on stem cells,” they wrote.
The collective findings, the investigators noted, raise “fundamental questions” on whether the maternal microbiome impacts other stem cell types in offspring, such as those in the liver or muscles. “Given that several developmental disorders are linked to early pathogen exposure, it is tempting to speculate that dialogs between microbes and stem cells during early life play a crucial role in maintaining the delicate balance between health and disease.”
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.
In their paper the team concluded, “These findings open avenues to support the 21st century medicine in its attempt to develop microbiota-based intervention strategies to promote child health.” Kundu added, “Promoting child health is a major challenge worldwide, and extrapolating these findings to humans is crucial.”