Fish Have a Brain Microbiome. Could Humans Have One Too?
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Welcome to the Quanta Science Podcast. Each episode, we bring you stories about developments in science and mathematics. I'm Susan Vallett. 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 our ears, mouth, nose, and gut. But scientists have long assumed that bacteria can't survive in the human brain. But can they?

That's next. Quantum Magazine is an editorially independent online publication supported by the Simons Foundation to enhance public understanding of science.

The thinking goes that the powerful blood-brain barrier keeps the brain 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. After all, it's hard to obtain 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, at least in fish. 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 Ohm is a physiologist who studies the human microbiome at the University of Colorado Boulder and wasn't involved in the study. He's inherently skeptical of the idea that populations of microbes could live in the brain, but he finds the new research convincing. This is concrete evidence that

brain microbiomes do exist in vertebrates. And so the idea that humans have a brain microbiome is not outlandish. I mean, obviously, this doesn't tell you anything about the brain microbiome itself, but it does tell you that after this paper, we should be much less surprised if that's what we find and we should dedicate more resources to kind of exploring this idea. I think prior to this paper, it was kind of thought as a little bit out there, this idea that there's a brain microbiome. I just personally know a lot of scientists who just laugh it off as like,

kind of kooks who think that, but I think this gives a lot more firm grasp of that. In many ways, fish physiology is similar to humans, but there are some key differences.

Christopher Link studies the molecular basis of neurodegenerative disease at the University of Colorado Boulder. He wasn't involved in the work. It certainly puts another weight on the scale to think about whether this is relevant to mammals and us. 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. For years, Irene Salinas has been fascinated by a simple physiological fact: that the distance between the nose and the brain is quite small. Salinas is an evolutionary immunologist who works at the University of New Mexico.

She studies mucosal immune systems in fish to better understand how human versions of these systems, such as our intestinal lining and nasal cavity, work. It's clear that the nose is loaded with bacteria. My lab has been working on nasal immunity for a long, long time and how microbiota basically impact olfactory function. And we always had this question in our mind is whether or not this microbiota could work

potentially colonize the olfactory bulb in the brain or maybe other areas of the brain just because of the close proximity right like the nose to the brain is really really close it's like the one-step synapse and it's like the direct route so many many pathogens use this route to invade the brain so in the back of my mind i had this thing that maybe the olfactory bulb is

directly sampling external microbiota, or there was like some of the microbiota directly make it to the olfactory valve. After years of curiosity, she decided to confront her suspicion in her favorite model organisms, fish.

Salinas and her team, including Amir Mani of the University of Chicago Medicine, started by extracting DNA from the olfactory bulbs of trout and salmon. Some of the fish were caught in the wild and some were raised in her lab. They planned to look up the DNA sequences in a database to identify any microbial species. The problem is, these kinds of samples are easily contaminated by bacteria in the lab or from other parts of a fish's body.

That's 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's 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. And in the beginning, you know, we got those data, but we had to go back and redo it many, many times just to be sure, okay, let's now

take from the same animal, the gut from the same animal and the brain from the same animal, just to see if we can match what's in the gut doesn't match with the brain. Little by little, we started to refine our whole system and that took a long time because we've never done this before. 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. I thought the other parts of the brain wouldn't have bacteria, but it turned out that my hypothesis was wrong in the sense that, yes, olfactory bulbs have a little bit of bacteria, but then every part of the brain had, and it actually turned out that they had higher levels than in the olfactory bulb. The fish brains hosted so much bacteria that it took only a few minutes to locate those cells under a microscope.

As an additional step, Salinas's team confirmed that the microbes were actively living in the brain. They weren't dormant or dead.

Ohm was impressed by their thorough approach. I thought it was actually very convincing. I came into this pretty skeptical that I was going to be convinced that there was a brain microbiome. And by the end, I mean, just the amount of different experiments that they performed, all circling the same question from all these different ways, using all these different methods, all of which producing very convincing data that there actually are

living microbes in the brain of salmon. But if there are living microbes in the brain, how did they get there? Researchers have long been skeptical that the brain could have a microbiome because all vertebrates, including fish, have a blood-brain barrier. These blood vessels and surrounding brain cells are fortified to serve as gatekeepers that allow only some molecules in and out of the brain and keep out invaders, especially larger ones like bacteria.

So Salinas naturally wondered how the brains in her study had been colonized. By comparing microbial DNA from the brain to that collected from other organs, her lab found a subset of species that didn't appear elsewhere in the body. Salinas hypothesized that these species may have colonized the fish brains early in their development, before their blood-brain barriers had fully formed. Early on, anything can go in.

It's a free-for-all. But many of the microbial species were also found throughout the body. She suspects that most bacteria in the fish's brain microbiomes originated in their blood and guts and continuously leak into the brain. After that first wave of colonization, you need to have specific features to go in and out. That's how we see it. Salinas was able to identify features that let bacteria make the crossing.

Some could produce molecules, known as polyamines, that can open and close junctions. These are like little doors in the barrier that allow molecules to pass through. Other bacteria could produce molecules that help them evade the body's immune response or compete with other bacteria. Salinas even caught a bacterium in the act.

Looking under the microscope, she captured an image of a bacterium frozen in time within the blood-brain barrier. Half of the bacteria is in the lumen of the blood vessel and half of the bacteria is inside. Like, we literally caught it right in the middle of crossing. It's possible that the microbes don't

live freely in the brain tissue, says physiologist Matthew Ohm. One interesting thing about this paper is they very conclusively show that there are microbes there, but at one point they talk about how they could not conclusively roll out the fact that these microbes are present...

within immune cells. So the most boring interpretation of this paper would be that there are microbes that are consistently living in the brain, but these microbes are actually captured within macrophages or other types of immune systems where, yes, they're technically in the brain, they are technically living, but they are kind of sequestered away from the brain and it is purely...

It's a function of just that they're not able to keep them out of the brain, but instead sequester them kind of like away from everything else in the brain. That would be one interpretation of this data that the authors tried to get at but couldn't conclusively rule out. In that case, it would kind of just point to, okay, well, the salmon can't remove them from the brain, so you just learn to adapt to having them there and not cause problems. But if the bacteria are free-living, they could be involved in the body's processes beyond the brain.

Selina says it's possible that the microbes actively regulate aspects of the creature's physiology, the way human gut microbiomes help regulate the digestive and immune systems. Fish, of course, are not humans, but Selina says they allow a fair comparison. And her work suggests that if fish have microbes living in their brains, it's possible we have them too.

Bacteria have been found living in just about every human organ system. But to many scientists, the brain is a step too far.

Janos Heller studies the blood-brain barrier at Dublin City University and wasn't involved in the new research. It is protective, but it's not this impenetrable barrier or wall that nothing can get through. I mean, it's circadianly regulated, so you do have opening and closing of those tight junctions during the day. There's a monthly cycle as well. Plus, the brain has immune cells working overtime to zap any potentially harmful invaders.

When microbes have been found in the human brain, they're associated with active infections or typically linked to a breakdown in the barrier due to diseases like Alzheimer's.

Scientists challenged that assumption in 2013 when they were studying the neurological impacts of HIV-AIDS. They found genetic hints of bacteria in the brains of both sick and healthy people. The findings were the first to suggest that maybe humans could have a brain microbiome in the absence of disease. Here's Heller. Detection methods have become better.

better. So no one believed it 10 years ago. There haven't been many follow-up studies, and the studies that are out there have been inconclusive. You remember physiologist Matthew Ohm from earlier. There have been a lot of examples in the past where

We, as a scientific community, have thought that we might see low abundances of microbes. I'm most familiar with the debate about humans in utero, like in fetuses. There's this big debate of, does the fetus in humans have a microbiome? Or whenever we sense these signals of microbiome, is it contamination? Because it is very easy to essentially trick yourself into thinking microbes are present because microbial DNA is essentially everywhere. So if you do the most simple experiment of just seeing

sequencing a sample, finding microbes that are there, and assuming that there's a microbiome there. You can do that in things that are very sterile. And so it would take a lot of evidence to convince me that it does exist. The fish experiment did convince Ohm and other researchers that a human brain microbiome is not impossible. What's nearly impossible, though, is confirming that without harming healthy people.

To build a case, Link suggested repeating the fish experiment in rodents. Salinas' team started looking into it. So we actually got the protocol from an expert who works in mouse tumor microbiomes, and they lyse these tumors and they recover bacteria that live in there, and that's the exact same protocol that we use for our brains. This protocol should be able to be adapted really easily to mouse brains.

Salinas' team has found early hints that microbes exist in the olfactory bulbs of healthy mice, and to a lesser extent, throughout the brain. Christopher Link says if microbes have adapted to cross the fish blood-brain barrier and survive in the fish brain, they could do the same in our bodies. It's really not known if there are resident microbes in healthy brains or other lungs or livers or those kind of things.

But there is evidence that they might be there. Interestingly, they clearly seem to be there in fish. It's unlikely that any sort of level of microbes that we would have in our tissues would be comparable to the fish because it seems like there's a lot. But that doesn't mean there's none. And that even small levels of microbes, whether they're bacterial or viruses, could certainly tweak metabolism of our brains or instigate our immune systems to

to a state that is not good for us.

And that's particularly not good for us when we are older. If microbes are truly present, this would suggest an extra layer of neurological regulation that we didn't know existed. We already know that microbes influence our neurobiology. Right now, microbes in your gut are modulating your brain activity through the gut-brain axis by producing metabolites that are sensed by enteric neurons winding through your digestive system.

It's a fascinating, though unproved, proposition that bacteria in the brain are directly impacting our physiology.

However, thanks to research like Selenis', more scientists are open to the idea that healthy human brains might also be home to microbes. Heller wonders why not? A "why" question is always a bit silly in biology, but what beneficial effects does it have? I'm not shocked anymore that they're there, but what do they actually do there? There seems to be a lot of different types.

Are they all there for reason or are they there by mistake?

Arlene Santana helped with this episode. I'm Susan Vallett. For more on this story, read Yasmin Sapakoglu's full article, Fish Have a Brain Microbiome, Could Humans Have One Too?, on our website, quantamagazine.org. Explore math mysteries in the Quanta book, The Prime Number Conspiracy, published by the MIT Press. Available now at amazon.com, barnesandnoble.com, or your local bookstore.