October 6, 2020
Written by: Sarah Reitz
Over the past two decades, the microbiome—the collection of bacteria and other microbes that live in and on our bodies—has been shown to play an important role in everything from digestion1 to immune function1, and even brain function. While some research is focused on the microbiome of adult animals and humans, another branch of research investigates how a mother’s colony of microbes, known as the maternal microbiome, affects her offspring before and during birth.
Past research has shown that the microbiome is important for nervous system development and function2, yet important brain and nervous system development occurs before birth, making the maternal microbiome a prime suspect. In fact, there is already evidence that alterations in the maternal gut microbiome due to infection, diet changes, or stress during pregnancy are associated with abnormalities in offspring brain function and behavior3-6. However, it was unclear whether these abnormalities resulted from the maternal microbiota affecting offspring while in the womb, or if offspring inherited the altered microbiome, which produced changes in brain function and behavior later in life. Additionally, it was not known whether a healthy maternal microbiome, unaffected by outside stress or infection, plays a role in normal brain development of offspring. Now, a new study in mice from a group of researchers at UCLA shows that a normal, healthy maternal microbiome does in fact play a critical role in offspring brain development before they are even born7.
In order to study how a healthy maternal microbiome is involved in brain development, the researchers had to compare offspring of mothers with normal gut microbes to offspring of mothers with no microbiome at all. To do this, they treated some female mice with antibiotics prior to and during pregnancy to kill off their microbiome. They then examined the brains of embryos from antibiotic-treated or untreated mothers during the critical period for brain development.
The first thing the researchers did was examine gene expression differences between the two groups of offspring. They found that removing the maternal microbiome altered expression of 333 different genes, including decreasing expression of many that are involved in the formation and growth of axons, the long projection of a neuron that sends the neuron’s message to other cells. Some of these genes are known to play a role in the development of thalamocortical axons, or axons from thalamus neurons that are connected to neurons in the cortex and are involved in processing sensory information.
Due to these observed differences in gene expression, the researchers examined the thalamocortical axons themselves. They found that offspring of microbiome-free mothers had shorter and thinner axons than offspring of mothers with an intact microbiome, suggesting that a healthy maternal microbiome is needed for proper thalamocortical axon growth in offspring. They also found that these problems with axon growth were due to an inability of the axons to properly respond to growth signals in the brain, rather than an inability of the brain to produce these growth signals. In other words, while the brain was still able to tell the axons when and where to grow, the axons were not properly receiving the message. Together, these results suggest that the healthy maternal microbiome plays an important role in developing neuronal connections between the thalamus and cortex.
Now that they saw that depleting the maternal microbiome impaired axon growth in these thalamocortical neurons, the scientists wondered whether these shorter and smaller axons actually impacted the behavior of the offspring. Since thalamocortical neurons are known to be involved in processing sensory information, they examined the offspring mice in a number of sensory tests. They found that offspring of mothers with no microbiome had impaired tactile, or touch, sensation in their paws compared to offspring of mothers with normal microbiomes. Interestingly, only the sense of touch appeared to be impaired. There were no differences between the two groups of offspring on movement tests, visual sensory tests, or whisker sensory tests.
These results suggest that an altered maternal microbiome during pregnancy has long-lasting impacts on both brain development and tactile sensation. Because the antibiotic treatment wiped out the entire maternal microbiome, the researchers wanted to gain more insight into whether specific types of bacteria were more responsible than others for the axon growth and behavior impairments observed in the offspring. To do this, they replenished the microbiomes of antibiotic-treated females, prior to becoming pregnant, with only a specific family of bacteria, in this case members of either the Firmicutes or Bacteroidetes phyla. They found that the Firmicutes species prevented the impairments in gene expression, axon growth, and tactile sensation in offspring, while replenishing only with Bacteroidetes species only moderately improved axon growth. This shows that certain types of bacteria in the microbiome play a more important role than others in brain development of offspring.
But how are these bacteria in the mother’s gut affecting the brain of their offspring in the womb? The scientists suspected it may be small molecules produced as a by-product of gut microbes digesting food, known as metabolites. It was already known that nutrients from the mother’s blood are passed to the offspring, so it seemed likely that metabolites produced by the mother’s gut bacteria could also be passed alongside these nutrients and ultimately affect brain development.
When the researchers examined the metabolites in the mothers’ blood as well as the offspring’s brains, they found that 8 specific metabolites were decreased in both antibiotic-treated mothers and their offspring compared to mothers with intact microbiomes and their offspring. Not only that, but additional experiments showed that a mixture of 4 of these metabolites—when given to microbiome-deficient mothers during pregnancy—was able to increase axon growth and improve tactile sensory processing in their offspring. Together, this suggests that the maternal microbiome can indeed regulate the developing fetal brain via metabolite signaling.
These experiments provide important evidence to support the role of the maternal microbiome in normal brain development of offspring. While there is already evidence that an altered maternal microbiome can affect offspring in a number of ways, understanding how a healthy microbiome affects brain development is a critical step towards properly supporting brain development in cases where the maternal microbiome is impaired or absent. Hopefully future work will uncover exactly how these microbiome metabolites promote axon growth, and whether other aspects of brain and nervous system development are also supported by a healthy maternal microbiome.
Cover Image by Karsten Paulick via Pixabay
- Jandhyala, SM, Talukdar, R, Subramanyam, C, Vuyyuru, H, Sasikala, M, & Nageshwar, Reddy D (2015) Role of the normal gut microbiota. World J Gastroenterol. 21(29):8787-8803.
- Diaz Heijtz, R, Wang, S, Anuar, F, Qian, Y, Björkholm, B, Samuelsson, A, Hibberd, ML, Forssberg, H, & Pettersson, S (2011) Normal gut microbiota modulates brain development and behavior. PNAS 108: 3047–3052.
- Vuong, HE, Yano, JM, Fung, TC & Hsiao, EY (2017) The microbiome and host behavior. Annu. Rev. Neurosci.40, 21–49.
- Kim, S et al. (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528–532.
- Buffington, SA, et al. (2016) Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775.
- Jašarević, E, et al. (2018) The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus. Nat. Neurosci. 21, 1061–1071.
- Vuong, HE, Pronovost, GN, Williams, DW et al. (2020) The maternal microbiome modulates fetal neurodevelopment in mice. Nature.