Do bacteria also exist in the brain? How do they get into the brain?

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Do bacteria also exist in the brain? How do they get into the brain?

2020-12-13
Rosalinda Roberts, a neuroscientist at the University of Alabama, has been used to seeing strange shapes in the brain. Over the past 30 years, she has observed numerous brain tissues under an electron microscope. She often encounters "unknown objects" - small particles or spheres that should not appear in the tissues, And it doesn't seem to have anything to do with the synapses and other structures she studies. "I'd say, 'OK, I won't pay attention to that,'" and now everything has changed.

Finding bacteria in the brain is often bad news. The human body protects the brain from all kinds of bacteria through the blood-brain barrier, which is also considered a sterile organ. When the barrier is broken, diseases such as encephalitis and meningitis can occur, They were surprised to realize that these unknown objects in the tissue slide were actually bacteria

Many of these bacteria are ready to enter neurons or pass through axons at the moment of "stepping forward". Others are in the process of division. They are also very picky and prefer certain areas of the brain, while the surrounding brain tissue shows no signs of inflammation. When these bacteria exist in the brain, if the person is alive, they are not pathogenic bacteria

If the results can be confirmed - and the possibility of contamination has not been clearly ruled out - then the work opens up a new way to study microbiome and diseases. The team presented their findings at the annual meeting of the society for neuroscience in November

What do you think makes your image attract so many people's attention?

If bacteria actually enter the brain from the gut while a person is alive, that's a real paradigm shift, because the brain has always been considered sterile compared to other organs. Finding bacteria in brain tissue samples that are not traumatic and uninfected is completely unexpected

How did this series of studies begin?

I've been studying schizophrenia for almost all of my career. My research method is to look at synaptic differences and pathological features that may exist in the brains of schizophrenic patients after death. For years, when I see these unknown objects, I ignore them. Then, I have a Ben student, Courtney walker, She was taking an honors course at the University of Alabama. She was studying substantia nigra, an area of the brain that contains dopamine neurons. She's been seeing these objects - we call them "those things" - and she's been talking about it. It's starting to become a puzzle for the lab

How do you know these objects are bacteria?

According to morphological criteria, I began to suspect that they were bacteria. I showed these pictures to a bacteriologist, and he said, "these are bacteria." then we did another ribosomal analysis and found that they were intestinal bacteria. This is very interesting because of the current interest in gut brain research

How much do we know about gut brain behavior?

You can manipulate behavior and cognition, and even structure, by adjusting the microbiota. Take sterile mice, for example, they don't have microbiota. If you put feces from normal mice into their bodies by fecal transplantation, many of their behaviors will be improved, They create new cognitive and behavioral problems. People with different diseases have different fecal microbiota. Parkinson's disease patients have different microbiota than others

What mechanisms have the researchers proposed to describe how microbiota affects the brain?

I haven't seen such a study yet. There may be a lot of speculation about the route through which information enters the brain. One of the hypotheses is that information travels up through a nerve that innervates the stomach, one of which is the vagus nerve, As a result, they can no longer manipulate brain behavior by altering the microbiota. This suggests that whatever they are doing is related to the vagus nerve; as for what they do, they don't say

If bacteria can really get into the brain from the gut, how do they do it?

I'm not a microbiologist, so I can only speculate. If bacteria enter the brain from the vagus nerve, they have to drill into the myelin sheath, transport them internally to the dorsal vagal nucleus, and then leave and enter other areas of the brain. These bacteria may also enter the brain through the blood-brain barrier, This is because the brain sometimes needs to know if you're eating something poisonous, which triggers the vomiting reaction, The blood-brain barrier around the pituitary gland is not very tight. I would like to look more closely at the areas with many holes in the blood-brain barrier to see if there are more bacteria there

Do you see bacteria that prefer certain parts of the brain?

We see that they like to drill into astrocytes around the blood-brain barrier. They also like to drill into axons. Axons are the protruding parts of the brain that carry out information transmission and are covered with lipid rich myelin sheaths. In addition, in mice (not humans), they also like to drill into axons, Bacteria like to enter the nucleus of neurons. It's not clear what that means. Why do they like to invade certain cell types? I know that some bacteria like fat, others like sugars. Myelin contains a lot of lipids, while astrocytes contain sugars. The distribution of bacteria also shows that our observation is not entirely due to pollution, Otherwise we will find bacteria in other places, not just in specific areas

Is it possible that these are bacteria that enter the brain after death?

This is my initial idea. Maybe these bacteria invade the brain after death and begin to feed on brain tissue. However, they also appear in the brains of mice that are immediately fixed at the time of death. There is no post-mortem human intervention or time to allow bacteria to invade. Therefore, this is not a post-mortem anthropogenic change phenomenon. Moreover, in the process of processing, The brain is either in a fixative or frozen. I can't explain why bacteria can get into the brain after being treated artificially. Why do they get into an unfriendly brain fixed in an antibacterial solution?

Can you eliminate other forms of pollution?

Now I can't rule out the possibility of contamination. But even if it's pollution, the distribution of bacteria is very special. They tend to be specific intercellular parts, which is very interesting in itself. We have to eliminate the possibility of contamination through very systematic research, everything is sterilized and autoclaved, and samples of sterile mice, normal mice and human brains are prepared

Should your brain show any signs of inflammation due to bacteria?

These bacteria don't seem to cause inflammation. It's special because you think they will. It means that either the whole thing is post-mortem or post-mortem contamination, or they're just not pathogenic to the brain

Are these bacteria alive?

I think they're alive. Obviously they look healthy. Dead bacteria look a little bit like ghosts, just fragmented cell forms. These bacteria don't look like that. If they were alive at that time and were frozen in their brains after death, it would be very interesting. I wonder if I could grow the bacteria I saw and see if they were really alive, And then do some experiments to understand why they like different parts of the brain. Our 16S microbiome analysis doesn't tell you how many bacteria there are or whether they're alive

Do you see dead bacteria?

I don't see dead bacteria. They are usually engulfed by macrophages or disposed of in lysosomal pathways. I see bacteria with intact structures, many of which have septal cell plates, indicating that they are dividing

The other control you used was the brains of sterile mice. What did you see?

We're looking at four sterile mouse brains. Two of them were examined with 16S microbiome analysis and showed that they didn't have any bacteria. However, microbiological analysis can't tell you how many bacteria there are, only the proportion of different bacteria in a given sample, You can find bacterial fragments that have been killed in food in 16S microbiome analysis. We also need to test the reagents used in 16S analysis to see if any reagents have introduced bacteria

What else do you want to try?

One of the suggestions I got was to transplant labeled bacteria into sterile mice to see how long it took them to get into the brain. I also wanted to look at my postmortem specimens to see if different diseases changed the location or type of bacteria in the brain, I don't see any Helicobacter pylori in my brain. It's a bacterium that claims to cause cognitive impairment

Why did you choose to display the study on posters?

I need to know what the scientific community thinks about the research. I want to see if I can reach out to some microbiologist, or someone else who might be working on this in a way that I can't do. So, that's what it turns out. I've got calls from some scientists saying, "Hey, let's exchange papers and talk about this." it takes a long time for a paper to be published, By the time it's actually published, you may already be doing something else. So, with this (poster) format, you can show the initial work, talk to your peers and get to know what they think, and discuss what to do next, instead of just sitting in your office, scratching your head and asking yourself, "what is this?"
Why do you think only your own laboratory has made this discovery?

There are not so many electron microscopes in the world. Today's neuroscientists want to understand the mechanics of molecular cells and more comprehensive information, Or take a sample of brain tissue that's very, very short after death

The Alabama brain collection you're leading seems to be an important asset for this research?

Yes, but I want to make it clear. For an electron microscope, you need to process the brain within eight hours after death. The current average postmortem interval is close to 24 or 30 hours. So, in fact, only 10% or 15% of the samples tested are suitable for electron microscopy

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