Microorganisms that live in our bodies outnumber our own human cells 10 to 1, inhabiting (among other places) the mouth, skin, and gut. Although many of these thousands of species of bacteria help their hosts, most remain poorly understood. Collectively, these bugs and their genes are called the “human microbiome.”
Among them, gut microbes are perhaps the most important. They help to digest food and to train the immune system. Now, new research published in Science Translation Medicine by Viorica Braniste and colleagues at the Karolinska Institutet uncovers another of their functions: helping to seal the blood-brain barrier (BBB) in a developing fetus.
Defending the Brain Against Invaders
The BBB is a network of cells and proteins that form a protective layer between the bloodstream and the nervous system. The barrier defends the brain against infections, ferries away toxins, and controls the flow of nutrients. In fetal mice, who take three weeks to grow in the womb, this barrier usually seals around day 17.
To determine what effect the microbiome has on the BBB, the research team took it away. They raised mice in a completely sterile, germ-free environment. Then, these germ-free mice that lacked gut bacteria had pups of their own. Pups of germ-free mothers had lower levels of tight junction proteins, which help hold the BBB together.
“It’s like when you build with concrete and you put iron sticks between the sections of concrete to hold them together and to stabilize,” explained professor Sven Pettersson, principal investigator of the study, in an interview with Healthline.
As a result, the BBB never fully sealed in the growing germ-free mice, instead staying leaky and letting things into the brain that should never have made it that far. This leaky barrier resulted in a pattern of nerve damage in the brain, particularly in the hippocampus, which is important for controlling stress and forming memories. Other affected brain regions included the frontal cortex, which is responsible for executive control and decision-making, and the striatum, which is necessary for coordinating movement. All of these deficits lasted into adulthood.
Undoing the Brain Damage
Fortunately, the damage to the BBB could be reversed. A fecal transplant of gut microbes from healthy mice into the germ-free mice was enough to undo many of the brain changes. The mice grew new tight junction proteins and the BBB sealed.
To find out which specific bacterial species helped to close the barrier, the researchers seeded mice with single strains of bacteria. Two particular species, Clostridium tyrobutyricum and Bacteroides thetaiotaomicron, caused the BBB to seal. Both bacterial species naturally produce short chain fatty acids, which are necessary for the proper function of tight junction proteins. Directly dosing the mice with short chain fatty acids also repaired the barrier. Whether these changes also reversed the neural damage in the brain remains unclear.
This finding suggests that pregnant women may want to be cautious about using antibiotics that affect gut bacteria, and work with their doctors to evaluate their particular risks.
“The implication is that our gut microbes may influence BBB permeability over the entire lifetime,” said Pettersson. “Moreover, the efficacy of this effect may be dependent on the composition and the diversity of our microbes. Aspects like diet, exercise, and social activity, which can influence the microbiome composition, may thus have effects on the BBB permeability.”