Gut Microbes Influence Blood-Brain Barrier

In the absence of bacteria, mouse pups are born with a leaky blood brain barrier that persists to adulthood.

AsianScientist (Dec. 30, 2014) – A study published in the journal Science Translational Medicine has shown that the natural microbial flora in the maternal gut appears to influence the closing of the offspring’s blood-brain barrier before birth.

The blood–brain barrier is a highly selective permeability barrier and gateway that controls the passage of molecules and nutrients and shields the brain from unwanted molecules and cells. Previous research had shown that the barrier in mice and in man closes before birth, an important step to ensure proper development and function of the brain.

Led by Professor Sven Pettersson from NTU’s Lee Kong Chian School of Medicine, an international team of researchers compared the development and integrity of the blood-brain barrier between two groups of mice. One group was kept in an environment with exposure to normal microbes, while the second group (the so-called germ-free mice) was raised in a sterile microbe-free environment.

Testing the uptake of certain antibodies and other molecules into the brain, the researchers were able to show that pregnant mice devoid of any microbes had offspring that showed an increased “leakiness” of their blood-brain barrier compared to offspring of mice that had been exposed to microbes.

“For example, we could show that the uptake of a ligand, which binds to the dopamine receptor in the brain, was much higher in mice under germ-free conditions compared to mice exposed to bacteria,” said Pettersson.

The offspring maintained the elevated permeability of the blood-brain barrier into adulthood if kept under germ-free conditions. However, exposing these mice to normal gut microbes at a later stage in life abrogated the leakiness.

“If we took mice that had been raised germ-free and exposed them to bacteria, and then exposed them to the dopamine-receptor ligand again, uptake of the ligand was equivalent to that in mice that had been exposed to microbes all their life,” explained Pettersson.

Though the precise mechanism of how the gut microbes influence the blood brain barrier—a scaffolding of capillary endothelial cells tightly connected by so-called tight junction proteins—is not known yet, the study found important clues. The researchers were able to show that tight junction proteins, which control the permeability of the blood brain barrier, were structurally altered and showed reduced levels of expression in the germ free mice.

Furthermore, the researchers were able to decrease the permeability of the blood-brain barrier by feeding germ-free mice certain short-chained fatty acids—key metabolites of gut bacteria—or by colonizing the mice with bacteria that secrete short-chained fatty acids.

“We conclude that tight junction proteins can be regulated by bacteria, and by regulating the bacteria we believe we are influencing the permeability of the blood-brain barrier,” said Pettersson.

Changes in our internal microbiota might have far-reaching implications for the blood-brain barrier and in consequence for the function and development of the brain. Knowing which microbes and microbial metabolites or signaling molecules play a role in regulating the permeability of the blood brain barrier could potentially be used to regulate the accessibility of the brain for drugs against brain cancer or other brain diseases or could be applied to aid healthy ageing by tightening the barrier against harmful substances.

The article can be found at: Braniste et al. (2014) The Gut Microbiota Influences Blood-Brain Barrier Permeability in Mice.

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Copyright: Asian Scientist Magazine.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Nicola Wittekindt received a PhD in Molecular Toxicology from the Federal Institutes of Technology (ETH) Zürich, Switzerland, and a MSc in Biology from the University of Konstanz, Germany. She is currently a science writer at the Nanyang Technological University in Singapore.

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