Fish Have a Brain Microbiome. Could Humans Have One Too?

The original version of this story appeared in Quanta Magazine.

Bacteria are in, around and all over us. They thrive in almost every corner of the planet, from deep-sea hydrothermal vents, to high up in the clouds, to the crevices of your ears, mouth, nose and gut. But scientists have long assumed that bacteria can’t survive in the human brain. The powerful blood-brain barrier, the thinking goes, keeps the organ mostly free from outside invaders. But are we sure that a healthy human brain doesn’t have a microbiome of its own?

Over the last decade, initial studies have presented conflicting evidence. The idea has remained controversial, given the difficulty of obtaining healthy, uncontaminated human brain tissue that could be used to study possible microbial inhabitants.

Recently, a study published in Science Advances provided the strongest evidence yet that a brain microbiome can and does exist in healthy vertebrates—fish, specifically. Researchers at the University of New Mexico discovered communities of bacteria thriving in salmon and trout brains. Many of the microbial species have special adaptations that allow them to survive in brain tissue, as well as techniques to cross the protective blood-brain barrier.

Matthew Olm, a physiologist who studies the human microbiome at the University of Colorado, Boulder, and was not involved with the study, is “inherently skeptical” of the idea that populations of microbes could live in the brain, he said. But he found the new research convincing. “This is concrete evidence that brain microbiomes do exist in vertebrates,” he said. “And so the idea that humans have a brain microbiome is not outlandish.”

While fish physiology is, in many ways, similar to humans’, there are some key differences. Still, “it certainly puts another weight on the scale to think about whether this is relevant to mammals and us,” said Christopher Link, who studies the molecular basis of neurodegenerative disease at the University of Colorado, Boulder, and was also not involved in the work.

The human gut microbiome plays a critical role in the body, communicating with the brain and maintaining the immune system through the gut-brain axis. So it isn’t totally far-fetched to suggest that microbes could play an even larger role in our neurobiology.

Fishing for microbes

For years, Irene Salinas has been fascinated by a simple physiological fact: The distance between the nose and the brain is quite small. The evolutionary immunologist, who works at the University of New Mexico, studies mucosal immune systems in fish to better understand how human versions of these systems, such as our intestinal lining and nasal cavity, work. The nose, she knows, is loaded with bacteria, and they’re “really, really close” to the brain—mere millimeters from the olfactory bulb, which processes smell. Salinas has always had a hunch that bacteria might be leaking from the nose into the olfactory bulb. After years of curiosity, she decided to confront her suspicion in her favorite model organisms: fish.

Salinas and a team of researchers including lead author Amir Mani started by extracting DNA from the olfactory bulbs of trout and salmon, some caught in the wild and some raised in her lab. They planned to look up the DNA sequences in a database to identify any microbial species.

These kinds of samples, however, are easily contaminated—by bacteria in the lab or from other parts of a fish’s body—which is why scientists have struggled to study this subject effectively. If they did find bacterial DNA in the olfactory bulb, they would have to convince themselves and other researchers that it truly originated in the brain.

To cover their bases, Salinas’ team studied the fish’s whole-body microbiomes, too. They sampled the rest of the fish’s brains, guts and blood; they even drained blood from the many capillaries of the brain to make sure that any bacteria they discovered resided in the brain tissue itself.

“We had to go back and redo [the experiments] many, many times just to be sure,” Salinas said. The project took five years—but even in the early days it was clear that the fish brains weren’t barren.

As Salinas expected, the olfactory bulb hosted some bacteria. But she was shocked to see that the rest of the brain had even more. “I thought the other parts of the brain wouldn’t have bacteria,” she said. “But it turned out that my hypothesis was wrong.” The fish brains hosted so much that it took only a few minutes to locate bacterial cells under a microscope. As an additional step, her team confirmed that the microbes were actively living in the brain; they weren’t dormant or dead.

Olm was impressed by their thorough approach. Salinas and her team extensively explored “the same question, in numerous different ways, using various methods—all of which generated compelling data indicating the presence of living microbes in the salmon brain,” he stated.

However, the question remains: how did these microbes get there?

Researchers have long doubted the existence of a microbiome in the brain due to the presence of a blood-brain barrier in all vertebrates, including fish. This barrier is designed to only allow certain molecules in and out of the brain, while keeping out invaders like bacteria. Salinas pondered how the brains in her study had been colonized.

By comparing microbial DNA from the brain to that from other organs, her lab identified a subset of species not found elsewhere in the body. Salinas theorized that these species may have colonized the fish brains during early development, before their blood-brain barriers were fully formed. “Early on, anything can enter; it’s a free-for-all,” she explained.

While many microbial species were also found throughout the body, Salinas suspects that most bacteria in the fish brains originated from their blood and guts, continuously leaking into the brain.

“After the initial colonization,” she explained, “specific features are needed for entry and exit.”

Salinas identified features that allowed bacteria to cross, such as the production of polyamines that can open and close junctions in the barrier or molecules that help them evade the immune response.

She even captured an image of a bacterium in the process of crossing the blood-brain barrier under a microscope. “We literally caught it in the act of crossing,” she said.

It is possible that the microbes do not reside freely in the brain tissue but are engulfed by immune cells. However, if the bacteria are free-living, they could be involved in the body’s processes beyond the brain, potentially regulating aspects of the creatures’ physiology similar to human gut microbiomes.

While fish are not humans, they provide a useful comparison. Salinas’ work suggests that if fish can harbor microbes in their brains, it is conceivable that we might as well. It no longer surprises me to see them there,” he remarked. What really piques my curiosity, he added, is whether they all have a purpose for being there or if they ended up there by mistake. This thought-provoking question challenges our understanding of their presence and raises intriguing possibilities about their role in the ecosystem.

This article was first published on QuantaMagazine.org, a platform dedicated to advancing public knowledge of science, independently operated by the Simons Foundation.

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Filed under: Bacteria, Biology, Brain, Fish, Microbes, Bacteria, Viruses, Nervous System.