Pregnancy transforms the mother’s body to nurture new life, with maternal health shaping the baby’s growth and long-term well-being. Among the many factors influencing a baby’s development, growing evidence from mouse studies highlights the critical role of the gut microbiome. Researchers have shown that the maternal gut microbiome influences immune- and neuro-development in mouse pups.1,2
Now, scientists have discovered a new role: shaping stem cells, which in turn regulate development. In a study published in Cell Stem Cell, researchers found that metabolites produced by the mother’s gut microbiome during pregnancy program offspring stem cells, leaving a lasting impact on their health.3 The results reveal a maternal microbiota-offspring stem cell axis and offer potential therapeutic targets for improving child health.
“When it comes to child health, the first thing that comes to my mind are stem cells,” said Parag Kundu, a researcher who specializes in gut microbiota and stem cell biology at the Chinese Academy of Sciences. “They are responsible for regeneration of cells, growth, development, organ maturation, and so on.”
This prompted Kundu and his team to study whether variations in the composition of the maternal microbiome could influence offspring stem cell function. They manipulated the microbiome of pregnant mice by supplementing their diets with Akkermansia muciniphila (Am), a bacterium recognized for its probiotic properties, throughout their pregnancy.4
Following birth, the researchers examined stem cells from the brain and intestines of the newborn pups. Compared to the offspring of control mice, pups from Am-exposed mothers exhibited increased neurogenesis, or the formation of new neurons from neural stem cells, as well as a higher number of intestinal stem cells. This effect persisted even when the pups were fostered for 21 days by mice unexposed to Am, confirming that the mother’s microbiome during gestation influenced stem cell characteristics.
“We were really surprised when we saw that changing the maternal microbiota can actually influence the stem cell functions,” said Kundu. “Because stem cells are robust. They are not subject to much change.”
Given the long-lived nature of stem cells, the researchers wondered whether alterations to the maternal microbiome could have lasting effects on the pups. At 10 months old, which corresponds to middle age in mice, pups born to Am-exposed mothers showed greater level of neurogenesis and more intestinal stem cells than offsprings of control mothers did.
Kundu and his team investigated the effects of more stem cells and their activity on the pups’ health. They subjected two-month-old mice to a series of behavioral tests, and observed that mice born to Am-exposed mothers showed higher exploratory behavior and lower anxiety levels than the progeny of control mice. When the researchers induced colitis in the mice, offspring of Am-fed mothers regenerated intestinal cells faster, leading to a quicker recovery.
The researchers analyzed the metagenomes of control and Am-exposed mothers to understand the mechanisms driving the differences in stem cell characteristics. This revealed significant differences in microbiota composition and the activation of distinct genes programs that drive growth and metabolic pathways. Using metabolomic analyses, the researchers discovered different metabolic signatures in Am-exposed and control mothers. For example, mice exposed to Am had higher levels of short-chain fatty acids in their serum, which suggests increased metabolic activity.
Building on these observations, the team hypothesized that maternally-produced metabolites, some of which can cross the placenta, could reprogram offspring stem cells.5 They used human-derived brain and intestinal organoids to test this and found that the mini-organs treated with serum from Am-exposed mice exhibited increased cell proliferation.
To pinpoint the pathway regulating the maternal microbiota-offspring stem cell axis, the researchers carried out RNA sequencing on stem cells from the offspring of Am-exposed mothers. The analysis revealed increased activity in genes associated with the mammalian target of rapamycin pathway, which regulates cell growth and metabolism. Inhibiting this signaling pathway during pregnancy eliminated maternal microbiome-mediated effects on offspring stem cells.
“This is a beautiful study to demonstrate directly that colonization of particular microbes can lead to altered stem cell function,” said Liza Konnikova, a maternal and child health expert at Yale School of Medicine who was not involved in the study. Given the long-standing hypothesis that a mother’s microbiome influences offspring stem cells, she was not particularly surprised by the results. “I was actually very excited to see this.”
While she noted that there is circumstantial evidence regarding such an axis in humans, it is technically and ethically difficult to conduct such a study in people. But, if proven conclusively in humans, this can have huge implications in maternal and child health, she said.
Kundu agreed. “This [study] is just the first step,” he said. To study how the findings might apply to humans, his team plans to transplant microbiota from probiotic-exposed pregnant individuals into germ-free mice and study how the offspring of these animals respond.
- Gomez de Aguero M, et al. The maternal microbiota drives early postnatal innate immune development. Science. 2016;351(6279):1296-1302.
- Vuong HE, et al. The maternal microbiome modulates fetal neurodevelopment in mice. Nature. 2020;586(7828):281-286.
- Dang H, et al. Maternal gut microbiota influence stem cell function in offspring. Cell Stem Cell. 2024:S1934-5909(24)00365-5.
- Cani PD, et al. Akkermansia muciniphila: Paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol.[MK3] 2022;19(10):625-637.
- Aleksi Husso, et al. Impacts of maternal microbiota and microbial metabolites on fetal intestine, brain, and placenta. BMC Biol. 2023;21(1):207.
