Lacking a strong blood-brain barrier, germ-free mice (left) can't prevent a radioactive tracer (yellow) from entering the brain the way that mice with microbes (middle) can. But adding microbes to germ-free mice (right) restores the blood-brain barrier.

Lacking a strong blood-brain barrier, germ-free mice (left) can't prevent a radioactive tracer (yellow) from entering the brain the way that mice with microbes (middle) can. But adding microbes to germ-free mice (right) restores the b

Miklós Tóth/Karolinkska Institutet

Body's bacteria may keep our brains healthy

The microbes that live in your body outnumber your cells 10 to one. Recent studies suggest these tiny organisms help us digest food and maintain our immune system. Now, researchers have discovered yet another way microbes keep us healthy: They are needed for closing the blood-brain barrier, a molecular fence that shuts out pathogens and molecules that could harm the brain.

The findings suggest that a woman's diet or exposure to antibiotics during pregnancy may influence the development of this barrier. The work could also lead to a better understanding of multiple sclerosis, in which a leaky blood-brain barrier may set the stage for a decline in brain function.

The first evidence that bacteria may help fortify the body’s biological barriers came in 2001. Researchers discovered that microbes in the gut activate genes that code for gap junction proteins, which are critical to building the gut wall. Without these proteins, gut pathogens can enter the bloodstream and cause disease.

In the new study, intestinal biologist Sven Pettersson and his postdoc Viorica Braniste of the Karolinska Institute in Stockholm decided to look at the blood-brain barrier, which also has gap junction proteins. They tested how leaky the blood-brain barrier was in developing and adult mice. Some of the rodents were brought up in a sterile environment and thus were germ-free, with no detectable microbes in their bodies. Braniste then injected antibodies—which are too big to get through the blood-brain barrier—into embryos developing within either germ-free moms or moms with the typical microbes, or microbiota.

The studies showed that the blood-brain barrier typically forms a tight seal a little more than 17 days into development. Antibodies infiltrated the brains of all the embryos younger than 17 days, but they continued to enter the brains of embryos of germ-free mothers well beyond day 17, the team reports online today in Science Translational Medicine. Embryos from germ-free mothers also had fewer intact gap junction proteins, and gap junction protein genes in their brains were less active, which may explain the persistent leakiness. (The researchers didn’t look at the mice’s guts.)

Germ-free mice even have leaky blood-brain barriers as adults. But those leaks closed after the researchers gave the animals the microbes from normal mice for 2 weeks, Pettersson says.

The microbes have “a striking effect,” says Elaine Hsiao, a neurobiologist at the California Institute of Technology in Pasadena who was not involved in the study. The work suggests "a role for the [microbes] in regulating brain development and function.”

But how? In the gut, bacteria may influence the gut wall’s integrity through one of their byproducts, energy-laden molecules called short-chain fatty acids. So Pettersson and his colleagues infected germ-free mice with either bacteria that made these fatty acids or ones that did not. The blood-brain barrier improved only when the bacteria made these fatty acids, Pettersson says. He thinks that these molecules may get into the blood and stimulate gene activity that leads to the closure of the barrier.

The study is not perfect. "Germ-free mice are useful tools for studying the microbiota, but the germ-free condition is artificial and involves widespread disruptions” in how the body functions, such as impaired immunity and loss of gut integrity, Hsiao says. So these results in germ-free mice need to be confirmed in humans.

But at the very least, the findings point toward a new understanding of human health and disease, says Lora Hooper, an immunologist at the University of Texas Southwestern Medical Center in Dallas who was not involved in the work. With multiple sclerosis, neurobiologists are at a loss to explain why the disease progresses so erratically, so the idea that changes in the body's microbes may alter the blood-brain barrier to make the brain more vulnerable to damage is appealing, Pettersson notes.

Scientists, Hooper adds, should also investigate whether microbes help spur the development of the human fetus’s blood-brain barrier. It could be that taking antibiotics at the wrong time during pregnancy is creating abnormalities in the blood-brain barrier of the child, she says.

*Correction, 21 November, 11:22 a.m.: A misspelled name has been corrected and two attributions have been eliminated.

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