> Matthew Olm (opens a new tab), 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.”
It's interesting to me that it would ever have been considered outlandish. In light of everything we now know about microbiomes and microbiology in general, it seems to me as a layman that the more radical proposition would be that the blood-brain barrier would be 100% effective at keeping out all bacteria, rather than the proposition that it probably isn't but that the bacteria it does let in tend to be symbiotic.
> it seems to me as a layman that the more radical proposition would be that the blood-brain barrier would be 100% effective at keeping out all bacteria,
Bacteria is not usually found in most organs in the body though. Even more so in an organ as important as the brain that even our own immune system doesn't have access. The brain has its own cells to do that job. In order for bacteria to cross the blood brain barrier you need bacteria in the blood first, where they aren't normally found without getting under fire.
Having bacteria in the gut is more obvious and makes more sense.
Agreed. Additionally, one of the mechanisms keeping the gut bacteria from taking over the rest of the body is an oxygen gradient: anaerobic bacteria in the gut are unlikely to be interested in an exploration of the aerobic environment of the body. Oxygen diffuses freely across the blood brain barrier, so it would not serve as an analogous containment mechanism.
The lungs, mammary glands, uterus, ovaries, vagina, placenta, semen, eyes, skin, and nasal cavity all have their own documented microbiome so far, and we've been finding out about new microbiomes about once a year. They are not a thing that is reserved for the digestive tract.
If you were to simplify the human body to a sphere (or torus... or whatever corresponds with the number of orifices that a human has), then all of the microbiomes you've listed would be on the exterior. The brain (and heart and kidneys and liver and bones and...) would not be.
The microflora would need to have gotten there somehow, something analogous to endosymbiosis. But unless they're somehow getting from brain-to-egg-to-brain that's hard to explain. As for the others, they're easier, all being along the surfaces. Even the gut is on the "outside" in that membranes need not be crossed in order to access it.
Although counterpoint: the same argument would apply to a fish so I guess it's not impossible. Just more surprising.
We already know of harmful pathogens that can infect the brain, such as Borreliosis. The only jump now is the fact that there could also exist harmless bacteria.
Spirochetes are much more efficient than most bacteria at moving through very viscous media, which include the obstacles encountered when moving through an animal body.
Thus, both the spirochetes causing Lyme disease and those causing syphilis have high chances of reaching even the brain, while traveling through the body.
Fortunately, for the bacteria employing other means of locomotion it is usually more difficult to pass through many of the internal body tissues, as long as those are intact.
> But unless they're somehow getting from brain-to-egg-to-brain that's hard to explain.
There are pathways from the outside to the brain - most notably the nose and the eyes. The former have a known pathogen pathway (naegleria fowleri, a virtually 100% fatal parasite), the latter are actually an immunoprivileged site [1] and investigations are ongoing what the role of eyes is in the transmission of H5N1 bird flu.
The brain is _unusually_ protected though. There's nothing like the blood brain barrier basically anywhere else. Most the the tissues you mentioned are exposed to the environment in some way. There aren't many ways to reach the brain without getting inside the body first(sensory organs being the obvious pathway, but even that is a stretch).
Not saying it's impossible, just that the skepticism is warranted.
Indeed, those organs expose to the outside world have reason to cultivate friendly bacteria for no other reason than to take up space, to stop hostile bacteria having a place to take hold.
This is unrelated to your main point, more to clarify an edge case for those interested in learning more: B cells can breach the BBB under certain conditions.
At least one pathogen, Epstein-Barr virus, is known to inhabit B cells.
From what I understand about the BBB, it's practically impermeable to anything the size of a bacteria (mainly intended for gating small molecules like fats and drugs), until an individual has some sort of disease or other health problem that effects the BBB's integrity. But I can easily imagine that some bacteria (harmful, or helpful) could have exactly the right surface proteins to indicate it's permitted.
CSF sampling is a routine investigation in most hospitals. We don't typically see bacteria in these samples, when we do, its in the form of bacterial meningitis, hence the skepticism.
And the article itself says "... 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."
Is it the blood brain barrier that keeps out bacteria or your immune system? Admittedly I know little about biology, but I thought bacteria growing inside your body was generally considered a “bad thing” (topologically speaking, your digestive system is outside your body).
Indeed. In order to even try to cross the blood brain barrier, an organism would have to be in the blood already. If that's unexpected, the immune system certainly won't like it. Large compounds and even immune cells aren't supposed to cross it. Usually brain infections are from tiny viruses because of that, unless they found another way (like ear, nose or eye infections, all of them effectively brain 'appendages').
Now, it could be the case that in a person with a compromised immune system AND a compromised blood brain barrier, that organisms would be able to live long enough to reach the brain. Once there, they would be mostly shielded from the immune system, except for brain glial cells (and I guess antibodies; usually the blood brain barrier stops most of them)
I like to think that the bacteria are only on the outermost layer of the body, i.e. skin. It just happens so that the respiratory and the digestive systems are the exterior part of the body which are inside our body. In other words epithelial cells mark the boundary of inside and outside and bacteria are usually tolerated on the outside and not inside.
Pure intuition, nothing more. I think we're just beginning to understand the microbiome and the brain does so much, has so many ports, and requires so many resources, that I think there are probably hundreds or thousands of heretofore unknown critters it relies on.
A few years ago my team mounted what I think was the largest-(to-date) scale search for this in electron microscopy brain tissue volumes [1].
I STRONGLY believe there is a substantial central nervous system microbiome, but (spoiler alert) no evidence found in that search :)
If you're excited about this work, the datasets are all freely available from BossDB [2] — well over a dozen petavoxels of it! I'd be so curious if models these days could pick up on something we missed!
Microbes are CRAZY. They're everywhere. Thermal vent-friendly microbes. Space-friendly microbes. Vacuum-resilient, heat-resilient, acid-resilient. Microbe-free-environment-friendly microbes [1]. It seems hard to imagine that a blood-brain barrier could really keep the brain sterile.
We're lucky to live in a scientific era during which a "gut microbiome" is taken for granted (heck, even FDA-approved treatments depend on it! Google FMT, but don't click "images" from your work laptop), but it wasn't so long ago that we felt microbes were unlikely to live endogenously and harmlessly anywhere in the body.
There were also some hypotheses (untested, if memory serves) that COVID-19 influenced olfactory neurons through direct infection. Don't tell the blood-brain barrier, but if I were a bacterium, the nasal palate would be my ingress strategy. Or maybe the gums or gut — one of the cranial nerves, certainly.
[edit] I should clarify — covid is viral, not bacterial, but it does show that this is a potential entry vector.
The central nervous system is incredibly complicated, and our symbiotic relationship with microbes is extraordinary. I think it does a disservice to bacteria to suppose they DON'T get involved in an organ :)
Our defenses are also crazy. For example, the inner mucus layer of the colon is able to keep trillions of bacteria at bay the vast majority of the time (unless there is inflammation or takeover by specific mucus-eating bacteria). Many of the proteins in the secreted mucus layers are still unknown in function, like FCGBP which comprises up to 40% of the protein content of mucus.
Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis
https://gut.bmj.com/content/63/2/281
So I think without trillions of bacteria to exclude, in the absence of any other issues excluding bacteria from the brain seems pretty doable.
Many viruses infect neurons, but they are way smaller than bacteria.
Absence of proof is not proof of absence. I would imagine that it would take a lot of negative searches by many people trying different approaches to rule it out. The searches are likely to be carried out by people who believe in the idea rather than those that are skeptical they will find something (the skeptics will work on reproducing any positive results).
It should be noted that absence of proof is evidence for absence. And since in the physical sciences, unlike mathematics, actual proof of absence is impossible, absence of evidence (after thorough searches) is the best we've got to form a belief for absence of the phenomenon.
That is, we believe, very strongly, that it's impossible for two masses to repel each other gravitationally, for example, but we will never have actual proof it's impossible.
None of this to say that it's irrational to believe in a brain microbiome despite this search seeming fruitless, as there are good a priori arguments for expecting one to exist.
But evidence of absence is, and in this case we have a lot.
For the last 400 years, pathologists on every country had filleted and put, lets say tens thousands of human brains and human guts under the microscope. One of them has systematically a microbiome, easy to see. The other don't, except when is diseased or rotten. The sample token here is huge, maybe millions.
If we would had searched 400 years for this chocolate teapot without finding it, we could conclude with a solid suspicion that there is not such thing.
This is very different than just saying "I don't think that there is bacteria in the brain but I never searched for it". All pathology science is based in searching for it. We created gram staining dyes, scanners, tags, gold coated plates for electronic microscopes, DNA analysis... exactly for that.
If there really is a microbiome living in each healthy brain, we should have found it 150 years ago.
> For the last 400 years, pathologists on every country had filleted and put, lets say tens thousands of human brains and human guts under the microscope. One of them has systematically a microbiome, easy to see. The other don't, except when is diseased or rotten. The sample token here is huge, maybe millions.
Is that really the case? By my understanding of the article, we find plenty of bacteria whenever we look at human brain samples. The problem is that it's very hard to tell if that bacteria was already present in the brain, or if it got in through the process of cutting the brain open (especially by contamination with other tissues), or if it was indeed present before the procedure, but only because the individual was very old or had a disease.
Yeah exactly. It’s not an unreasonable search and we don’t have confidence our search methods work. Hell, the Ryugu sample was contaminated while in a hermetically sealed clean room filled with nitrogen gas. Either the blood brain barrier is even more effective or maybe the story isn’t quite so clear. This is not an unreasonable hypothesis nor do have we exhausted search. Hell, we’re literally talking about it in response to a related find in another species. So it’s definitely not a wild theory or one that conflicts with known theories.
The chocolate teapot example is a non sequiter as it fails both Occam’s razor and the principle that extraordinary claims require extraordinary evidence not to mention that it wouldn’t follow any laws of known science and it’s existence very well would upend quite a few of those. The scientific method isn’t something you get to apply piecemeal.
Unfortunately many people claim an absence of evidence _without_a_thorough_search_ is evidence of absence. As in "I have haven't seen it so it must not exist". Many people who are experts do this. There needs to be some new terminology here, just saying "there is no evidence" is meaningless, people need to start saying "there is no evidence after <these> kinds of searches" to qualify their statements. Like "I haven't seen any evidence, but I haven't really looked", or "I asked some of my collegues and none had seen any relevant papers", or "I did a PubMed search and found no papers on that topic", or "I did a PubMed search and found 10 low quality studies that showed no evidence of that". Otherwise it is completely reasonable to interpret "there is no evidence" as "I don't know".
Also (and this is a pet peeve of mine), we're talking about evidence not proof. They're not the same thing. Just because there's evidence that something happened, it doesn't mean that it happened.
Evidence is a thing that you claim could be part of an valid argument that something happened ("is consistent with"). This isn't a universal definition, but there's got to be some separation between proof and evidence. When there's evidence admitted into a court case, it doesn't necessarily mean that someone is guilty. When there's a lot of evidence and still no proof, you can and should (and will) still make a probabilistic case that something did happen.
So I'd agree with and disagree with you. There's no evidence (that you know of) that Russell's Teapot is there, which is why you do not believe it is there. If somebody does believe it is there, but admits that they have no proof that it is there, it would be reasonable to ask what evidence makes them believe that it is there.
Where I obviously agree with is that "belief" can't mean just something you want to think for no particular reason. Or if it does, it's certainly not worth talking about.
What makes a hypothetical brain microbiome so hard to find? I would think that once you’re doing microscopy on brain slices that a biome would show you quite fast. But if you’re still optimistic after a negative search I assume there must be many reasons why a brain microbiome could exist but still be hard to detect.
I once saw a video about using a scanning tunneling microscope. I wanted to get a handle on how hard it was, so I scanned an area the size of 4 football fields and found a single dime. It takes a long time just to figure out what you are looking for. We have literally not even scratched the surface.
I would bet that your search was interesting, and that eventually you will find something.
Mikelson-Morely went looking for ether, and Einstein found relitivity.
Cool! Has anything similar been attempted in tumor tissue, given the many claims of microbes in tumors? Especially tumors not in contact with the exterior.
As far as I know, most of the tumor microbiome claims haven't held up very well. For example, the 2020 Nature paper "Microbiome analyses of blood and tissues suggest cancer diagnostic approach" was retracted this past year [1].
Given the ease of contamination of tissues (and databases), I tend to be pretty skeptical of tumor microbiome claims -- especially the wide-ranging claims of microbes being present in all tumors.
I know nothing about this, so I guess I'm asking "why can't we do this?": take some brain, throw it in a blender, and look for DNA the same way the ancient environmental DNA people do?
You can't find out this way. Removing brains exposes it to an outside environment where there are microbes. You can't tell if they arrived before or after you removed the material.
Maybe the first point you make is also the argument for why our brain might have a microbiome, as our body is not in any way hermetically enclosed, and e.g. amoebas are able to infect our brains just by going through our nose.
More nitpickfully, one of the big things we care about is if the bacteria are living _harmlessly_ in the brain. i.e., site of microbes, and a lack of inflammation, will answer more than just "are there microbes around".
Since I don't have enough information on the topic... how would one distinguish a microbiome that was present while the organism was alive, from contamination after death?
That's a question more suited to a microbiologist or bacteriologist than to me, but my educated guess, at least in the electron microscopy case, is that you'll see the bacteria inside the depth of the slices, rather than sitting "atop" the slices. i.e., if you cut open an apple and find half a worm, the worm was in the apple. If you cut open an apple and then see a worm on top of the slice, it's possible it arrived post-cut.
Two months ago we had almost the same topic here on HN and I posted a question that no one seemed to be able to answer:
> I mentioned Adam Savage's "Scariest [Podcast] Episode Yet" in a different context the other day[0] in which I remember Joe DeRisi[1] saying something along the lines of brain & spinal fluid being "absolutely pristine" when it comes to the presence/absence of a microbiome (in healthy individuals) and that it'd be real problem if there were one.
> I'm just a layman but can anyone ELI5 how this can be squared with the OP, specifically with statements like
> > It turns out our grey matter is teeming with bacteria, viruses and fungi
Probably the vast majority of studies are correct and a few misinterpret artefacts, and then a journalist uses an evocative word like "teeming" without knowing that what they're saying doesn't pass the sniff test. Same reason these papers languish for years and don't pass peer review in rigorous journals
I was very surprised that just last year, 2023, we discovered a whole ass thin membrane covering the brain we didn't know was there.
The thin membrane discovered, again, just last year, is called the Subarachnoid Lymphatic-like Membrane (SLYM), and apparently acts as a protective barrier separating "clean" and "dirty" cerebrospinal fluid among potentially other things.
Just how much we still don’t know about the brain and its protective systems... It’s crazy to think that a major part of the brain’s anatomy was essentially hiding in plain sight for all these years.
How much of the thinking/feeling would be due to this microbiome? Is this how people develop mental illnesses? Such an interesting topic! I hope it gets the funding it needs!
Aren’t viruses much harder to detect than bacteria? Viruses are generally smaller and are completely inert without a host cell. Bacteria, besides be larger, also have their own metabolic processes and distinct structures you can do things like grow them in a laboratory culture until the colony is much obvious.
Your comment makes it sound like bacteria are harder to detect but if we’re already identifying viruses, locating bacteria seems easier.
(Though some viruses are bigger than the smallest bacteria, like Mycoplasma at 200nm, viruses are generally smaller)
That rather speaks against it being a microbiome - it could just be incidental contamination the body is in the process of cleaning up. To be a microbiome I would expect to a diverse, well-adapted quorum of species that find some type of symbioses.
Absent that evidence, well biology is probability - something is always happening somewhere just by chance and statistics, but it doesn't make it a feature.
Dr Salinas is awesome. She did an interview on "The Children's Hours" about lung fish that was so interesting. Her fish research is leading to a ton of human immunology understanding.
Aren’t there some kinds of amoeba that can cross the BBB and take up residence in the brain? And fungal infections? (Or am I just thinking of horror movie plots?)
Why hasn't it passed peer review yet? Maybe because they only used techniques prone to artefacts. IMO if a brain microbiome exists in healthy people it would have been seen already, with all the microscopy and sequencing done
The whole microbiome thing is way overblown. It's like studying a great city by looking at rats in the sewer. And yeah, maybe some people have rats in their houses too. That's doesn't really tell you much about the city.
that a bacteria decided to "lemme make this dude ask a question on HN". On a serious note, it's already answered in the article - it means that our behavior is not only influenced by the gut bacteria (already proven), but the brain ones too.
I’m skeptical but there’s plenty of intracellular bacterial pathogens. Perhaps there’s an intracellular commensal bacteria/symbiote.
I think if it was extracellular we would see it more often in CSF - which is collected quite a bit in healthcare. Regular histology/pathology slices and staining would detect as well.
I could imagine an intracellular commensal bacteria that is small and virtually indistinguishable from an organelle like a mitochondria or lysosome that may exist.
Mitochondria were already bacteria at one point. Could there be another endosymbiont?
Mitochondria have circular DNA and phage like polymerase. Perhaps our secret symbiont can be found through DNA studies.
Most people will read this headline as a question. I read it like a proposition for bio weapon lab research. Post covid.
Parasites can live there. I think, Toxoplasma gondii and malaria and a brain eating ameba exists.
If you planted a bean in the brain of a beagle, it would grow too. Though I hope we don't ever do that.
In case it helps others: to find out what the above comment’s “huge impact on human behavior” is supposed to refer to, you’ll need to dig into references/footnotes #23, #25, #27, #28 and #29 on the linked Wikipedia entry.
Let's not jump to conclusions. That guardian article is about a pre-print study that used frozen brain samples from a single tissue bank, and RNA sequencing was done on a single machine.
There's a lot of controversy around this[1], because contamination is possible and it's known that the blood brain barrier weakens with age. The sample are all from older individuals.
Contamination is possible, but it's hard to explain the results that way. Definitely needs replication, of course.
I don't see the point of the samples all being from older individuals. Even if it exclusively occurs in older individuals (unlikely), it would still mean that the blood-brain barrier is not 100% effective (which we already know to be true).
> When microbes have been found in the human brain, they are associated with active infections or typically linked to a breakdown in the barrier due to diseases such as Alzheimer’s.
I think the question is whether there is a brain microbiome in healthy people, which seems to still be an open question.
I mean, we know about all kinds of microbes that can be in the brains of "unhealthy" people, and we've known that for ages (taxoplasmosis and CJD come to mind).
The association in the article isn't a case of "we didn't find it in healthy people", but "we found it in more in unhealthy people".
From the article: "It found that, while there was a remarkable diversity of species in the control brains, there were often overgrowths of certain bugs in Alzheimer’s brains."
Evidence is scarce and the article is talking about brains with active illnesses. It could be that there isn't any microbiome normally but if the safety mechanisms fail and bacteria colonize the brain, that would cause the illnesses described.
> Evidence is scarce and the article is talking about brains with active illnesses.
They compared them to control brains, which also had microbes.
> It could be that there isn't any microbiome normally but if the safety mechanisms fail and bacteria colonize the brain, that would cause the illnesses described.
That would describe a scenario where the blood-brain barrier isn't 100% effective, no? If it's not 100% effective (which we know to be true), it is also seems unlikely that 100% of the things that cross the blood-brain barrier cause something that we currently consider a disease. Heck, in healthy individuals, latent taxoplasmosis' effects are often so minimial I don't think we'd call it a disease (otherwise 30%+ of the world has the disease).
> Matthew Olm (opens a new tab), 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.”
It's interesting to me that it would ever have been considered outlandish. In light of everything we now know about microbiomes and microbiology in general, it seems to me as a layman that the more radical proposition would be that the blood-brain barrier would be 100% effective at keeping out all bacteria, rather than the proposition that it probably isn't but that the bacteria it does let in tend to be symbiotic.
> it seems to me as a layman that the more radical proposition would be that the blood-brain barrier would be 100% effective at keeping out all bacteria,
Bacteria is not usually found in most organs in the body though. Even more so in an organ as important as the brain that even our own immune system doesn't have access. The brain has its own cells to do that job. In order for bacteria to cross the blood brain barrier you need bacteria in the blood first, where they aren't normally found without getting under fire.
Having bacteria in the gut is more obvious and makes more sense.
Agreed. Additionally, one of the mechanisms keeping the gut bacteria from taking over the rest of the body is an oxygen gradient: anaerobic bacteria in the gut are unlikely to be interested in an exploration of the aerobic environment of the body. Oxygen diffuses freely across the blood brain barrier, so it would not serve as an analogous containment mechanism.
The lungs, mammary glands, uterus, ovaries, vagina, placenta, semen, eyes, skin, and nasal cavity all have their own documented microbiome so far, and we've been finding out about new microbiomes about once a year. They are not a thing that is reserved for the digestive tract.
If you were to simplify the human body to a sphere (or torus... or whatever corresponds with the number of orifices that a human has), then all of the microbiomes you've listed would be on the exterior. The brain (and heart and kidneys and liver and bones and...) would not be.
The microflora would need to have gotten there somehow, something analogous to endosymbiosis. But unless they're somehow getting from brain-to-egg-to-brain that's hard to explain. As for the others, they're easier, all being along the surfaces. Even the gut is on the "outside" in that membranes need not be crossed in order to access it.
Although counterpoint: the same argument would apply to a fish so I guess it's not impossible. Just more surprising.
We already know of harmful pathogens that can infect the brain, such as Borreliosis. The only jump now is the fact that there could also exist harmless bacteria.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8232152/
Spirochetes are much more efficient than most bacteria at moving through very viscous media, which include the obstacles encountered when moving through an animal body.
Thus, both the spirochetes causing Lyme disease and those causing syphilis have high chances of reaching even the brain, while traveling through the body.
Fortunately, for the bacteria employing other means of locomotion it is usually more difficult to pass through many of the internal body tissues, as long as those are intact.
Michael Stevens of VSauce fame has you covered with his "How Many Holes Does a Human Have?" video:
https://www.youtube.com/watch?v=egEraZP9yXQ
Thanks for mentioning this. I really enjoyed the video and learned a thing or two. Would recommend!
I think it depends a bit on how you count but I've heard it is an 8 holed donut
It also differs between individuals (e.g. one can develop a fistula).
Or get a piercing.
So getting pierced, puts one topological outside of baseline humanity?
I suppose it does. Be careful, you wouldn't want to end up homeomorphic to the wrong crowd.
Aren’t tattoos injective?
If I met a 8 holed donut I'd tear it a new one.
I expect I'd start by tearing it one fewer: now a seven holed donut with some stubs.
> But unless they're somehow getting from brain-to-egg-to-brain that's hard to explain.
There are pathways from the outside to the brain - most notably the nose and the eyes. The former have a known pathogen pathway (naegleria fowleri, a virtually 100% fatal parasite), the latter are actually an immunoprivileged site [1] and investigations are ongoing what the role of eyes is in the transmission of H5N1 bird flu.
[1] https://www.aao.org/eye-health/tips-prevention/eye-immune-pr...
[2] https://www.unmc.edu/healthsecurity/transmission/2024/06/04/...
The brain is _unusually_ protected though. There's nothing like the blood brain barrier basically anywhere else. Most the the tissues you mentioned are exposed to the environment in some way. There aren't many ways to reach the brain without getting inside the body first(sensory organs being the obvious pathway, but even that is a stretch).
Not saying it's impossible, just that the skepticism is warranted.
> There's nothing like the blood brain barrier basically anywhere else.
There is. The placenta and, oddly, prostate as well.
Those are all organs that are directly exposed to outside materials.
For the more internal organs, bacteria would have to travel across a skin of digestive tract barrier.
Unless they're present in the womb as the fetus starts growing, I guess.
Indeed, those organs expose to the outside world have reason to cultivate friendly bacteria for no other reason than to take up space, to stop hostile bacteria having a place to take hold.
> Having bacteria in the gut is more obvious and makes more sense.
It probably has to do with the fact that, topologically speaking, the stomach (and the whole GI tract) is technically on the outside of our bodies.
> even our own immune system doesn't have access
I thought that was recently found to be false? Or at least it isn't the full picture. see for example: https://www.science.org/doi/10.1126/science.abo7649
It is certainly true as a rule of thumb, although there may be more going on locally that was previously thought
But bacteria are incredibly adaptable
This is unrelated to your main point, more to clarify an edge case for those interested in learning more: B cells can breach the BBB under certain conditions.
At least one pathogen, Epstein-Barr virus, is known to inhabit B cells.
From what I understand about the BBB, it's practically impermeable to anything the size of a bacteria (mainly intended for gating small molecules like fats and drugs), until an individual has some sort of disease or other health problem that effects the BBB's integrity. But I can easily imagine that some bacteria (harmful, or helpful) could have exactly the right surface proteins to indicate it's permitted.
I guess this review/writeup https://asm.org/articles/2020/april/how-pathogens-penetrate-... covers most of the known mechanisms for traveral of the BBB by pathogens.
CSF sampling is a routine investigation in most hospitals. We don't typically see bacteria in these samples, when we do, its in the form of bacterial meningitis, hence the skepticism.
A start: do fish have a blood brain barrier that’s similar to humans?
This is indeed the first question to ask. According to ChatGpt (don't beat me up)
>>> Yes, fish brains have a blood-brain barrier (BBB)
You can't just say "don't beat me up" and expect not to be beaten up.
Anyway there's a pdf here that probably tells what kind of a BBB zebrafish have.
https://www.mdpi.com/1422-0067/22/22/12111
And the article itself says "... 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."
ha, I guess you are right
https://en.wikipedia.org/wiki/Self-fulfilling_prophecy
Is it the blood brain barrier that keeps out bacteria or your immune system? Admittedly I know little about biology, but I thought bacteria growing inside your body was generally considered a “bad thing” (topologically speaking, your digestive system is outside your body).
Indeed. In order to even try to cross the blood brain barrier, an organism would have to be in the blood already. If that's unexpected, the immune system certainly won't like it. Large compounds and even immune cells aren't supposed to cross it. Usually brain infections are from tiny viruses because of that, unless they found another way (like ear, nose or eye infections, all of them effectively brain 'appendages').
Now, it could be the case that in a person with a compromised immune system AND a compromised blood brain barrier, that organisms would be able to live long enough to reach the brain. Once there, they would be mostly shielded from the immune system, except for brain glial cells (and I guess antibodies; usually the blood brain barrier stops most of them)
> It's interesting to me that it would ever have been considered outlandish
Not so long ago we thought fish or even human babies didn't feel pain, we take a lot of things for granted. https://hms.harvard.edu/news/long-life-early-pain
I like to think that the bacteria are only on the outermost layer of the body, i.e. skin. It just happens so that the respiratory and the digestive systems are the exterior part of the body which are inside our body. In other words epithelial cells mark the boundary of inside and outside and bacteria are usually tolerated on the outside and not inside.
When something seems obvious to me but scientists in the field disagree, I usually take this a sign I need to improve my own understanding.
Unfortunately as often as not this doesn't seem to be the case. Expertise in a field often seems to create blinders.
So, what does that say about the possibility of fungal symbiotes?
And I think the brain, like other organs, might have its own microbial community, even if it’s a small or specialized one.
I am skeptical that the brain wouldn't have a microbiome
There are regions of the body that almost certainly do not have a microbiome, for example the viteous humor
I’m talking about the brain in particular. A lot goes on and it consumes a ton of resources.
> A lot goes on and it consumes a ton of resources.
But why should this be taken a sign of a brain microbiome? I fail to see the connection you're implying.
Pure intuition, nothing more. I think we're just beginning to understand the microbiome and the brain does so much, has so many ports, and requires so many resources, that I think there are probably hundreds or thousands of heretofore unknown critters it relies on.
A few years ago my team mounted what I think was the largest-(to-date) scale search for this in electron microscopy brain tissue volumes [1].
I STRONGLY believe there is a substantial central nervous system microbiome, but (spoiler alert) no evidence found in that search :)
If you're excited about this work, the datasets are all freely available from BossDB [2] — well over a dozen petavoxels of it! I'd be so curious if models these days could pick up on something we missed!
[1]: https://www.biorxiv.org/content/10.1101/2022.07.12.499807v1 [2]: https://bossdb.org
> I STRONGLY believe there is a substantial central nervous system microbiome, but (spoiler alert) no evidence found in that search :)
What gave you reason to believe this if you found no evidence of it in your own search?
Microbes are CRAZY. They're everywhere. Thermal vent-friendly microbes. Space-friendly microbes. Vacuum-resilient, heat-resilient, acid-resilient. Microbe-free-environment-friendly microbes [1]. It seems hard to imagine that a blood-brain barrier could really keep the brain sterile.
We're lucky to live in a scientific era during which a "gut microbiome" is taken for granted (heck, even FDA-approved treatments depend on it! Google FMT, but don't click "images" from your work laptop), but it wasn't so long ago that we felt microbes were unlikely to live endogenously and harmlessly anywhere in the body.
There were also some hypotheses (untested, if memory serves) that COVID-19 influenced olfactory neurons through direct infection. Don't tell the blood-brain barrier, but if I were a bacterium, the nasal palate would be my ingress strategy. Or maybe the gums or gut — one of the cranial nerves, certainly. [edit] I should clarify — covid is viral, not bacterial, but it does show that this is a potential entry vector.
The central nervous system is incredibly complicated, and our symbiotic relationship with microbes is extraordinary. I think it does a disservice to bacteria to suppose they DON'T get involved in an organ :)
[1] https://www.space.com/ryugu-asteroid-sample-earth-life-colon...
Our defenses are also crazy. For example, the inner mucus layer of the colon is able to keep trillions of bacteria at bay the vast majority of the time (unless there is inflammation or takeover by specific mucus-eating bacteria). Many of the proteins in the secreted mucus layers are still unknown in function, like FCGBP which comprises up to 40% of the protein content of mucus.
The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria https://pubmed.ncbi.nlm.nih.gov/18806221/
Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis https://gut.bmj.com/content/63/2/281
So I think without trillions of bacteria to exclude, in the absence of any other issues excluding bacteria from the brain seems pretty doable.
Many viruses infect neurons, but they are way smaller than bacteria.
Absence of proof is not proof of absence. I would imagine that it would take a lot of negative searches by many people trying different approaches to rule it out. The searches are likely to be carried out by people who believe in the idea rather than those that are skeptical they will find something (the skeptics will work on reproducing any positive results).
It should be noted that absence of proof is evidence for absence. And since in the physical sciences, unlike mathematics, actual proof of absence is impossible, absence of evidence (after thorough searches) is the best we've got to form a belief for absence of the phenomenon.
That is, we believe, very strongly, that it's impossible for two masses to repel each other gravitationally, for example, but we will never have actual proof it's impossible.
None of this to say that it's irrational to believe in a brain microbiome despite this search seeming fruitless, as there are good a priori arguments for expecting one to exist.
> It should be noted that absence of proof is evidence for absence.
Exactly. Like the apocryphal small chocolate teapot orbiting the Earth
But evidence of absence is, and in this case we have a lot.
For the last 400 years, pathologists on every country had filleted and put, lets say tens thousands of human brains and human guts under the microscope. One of them has systematically a microbiome, easy to see. The other don't, except when is diseased or rotten. The sample token here is huge, maybe millions.
If we would had searched 400 years for this chocolate teapot without finding it, we could conclude with a solid suspicion that there is not such thing.
This is very different than just saying "I don't think that there is bacteria in the brain but I never searched for it". All pathology science is based in searching for it. We created gram staining dyes, scanners, tags, gold coated plates for electronic microscopes, DNA analysis... exactly for that.
If there really is a microbiome living in each healthy brain, we should have found it 150 years ago.
> For the last 400 years, pathologists on every country had filleted and put, lets say tens thousands of human brains and human guts under the microscope. One of them has systematically a microbiome, easy to see. The other don't, except when is diseased or rotten. The sample token here is huge, maybe millions.
Is that really the case? By my understanding of the article, we find plenty of bacteria whenever we look at human brain samples. The problem is that it's very hard to tell if that bacteria was already present in the brain, or if it got in through the process of cutting the brain open (especially by contamination with other tissues), or if it was indeed present before the procedure, but only because the individual was very old or had a disease.
Yeah exactly. It’s not an unreasonable search and we don’t have confidence our search methods work. Hell, the Ryugu sample was contaminated while in a hermetically sealed clean room filled with nitrogen gas. Either the blood brain barrier is even more effective or maybe the story isn’t quite so clear. This is not an unreasonable hypothesis nor do have we exhausted search. Hell, we’re literally talking about it in response to a related find in another species. So it’s definitely not a wild theory or one that conflicts with known theories.
The chocolate teapot example is a non sequiter as it fails both Occam’s razor and the principle that extraordinary claims require extraordinary evidence not to mention that it wouldn’t follow any laws of known science and it’s existence very well would upend quite a few of those. The scientific method isn’t something you get to apply piecemeal.
Unfortunately many people claim an absence of evidence _without_a_thorough_search_ is evidence of absence. As in "I have haven't seen it so it must not exist". Many people who are experts do this. There needs to be some new terminology here, just saying "there is no evidence" is meaningless, people need to start saying "there is no evidence after <these> kinds of searches" to qualify their statements. Like "I haven't seen any evidence, but I haven't really looked", or "I asked some of my collegues and none had seen any relevant papers", or "I did a PubMed search and found no papers on that topic", or "I did a PubMed search and found 10 low quality studies that showed no evidence of that". Otherwise it is completely reasonable to interpret "there is no evidence" as "I don't know".
This might be too nitpicky, but isn't believe exactly what one has in absence of evidence?
They're is no evidence that Russell's Teapot is floating out in space in orbit around the sun, AND I don't believe that it's there.
If I said "I STRONGLY believe that a teapot is out there," it would be reasonable to ask me why.
Also (and this is a pet peeve of mine), we're talking about evidence not proof. They're not the same thing. Just because there's evidence that something happened, it doesn't mean that it happened.
Evidence is a thing that you claim could be part of an valid argument that something happened ("is consistent with"). This isn't a universal definition, but there's got to be some separation between proof and evidence. When there's evidence admitted into a court case, it doesn't necessarily mean that someone is guilty. When there's a lot of evidence and still no proof, you can and should (and will) still make a probabilistic case that something did happen.
So I'd agree with and disagree with you. There's no evidence (that you know of) that Russell's Teapot is there, which is why you do not believe it is there. If somebody does believe it is there, but admits that they have no proof that it is there, it would be reasonable to ask what evidence makes them believe that it is there.
Where I obviously agree with is that "belief" can't mean just something you want to think for no particular reason. Or if it does, it's certainly not worth talking about.
What makes a hypothetical brain microbiome so hard to find? I would think that once you’re doing microscopy on brain slices that a biome would show you quite fast. But if you’re still optimistic after a negative search I assume there must be many reasons why a brain microbiome could exist but still be hard to detect.
I once saw a video about using a scanning tunneling microscope. I wanted to get a handle on how hard it was, so I scanned an area the size of 4 football fields and found a single dime. It takes a long time just to figure out what you are looking for. We have literally not even scratched the surface.
I would bet that your search was interesting, and that eventually you will find something.
Mikelson-Morely went looking for ether, and Einstein found relitivity.
Thank you for your work.
> I scanned an area the size of 4 football fields and found a single dime.
Despite only finding a single dime, that sounds fascinating. Can you say more?
Cool! Has anything similar been attempted in tumor tissue, given the many claims of microbes in tumors? Especially tumors not in contact with the exterior.
As far as I know, most of the tumor microbiome claims haven't held up very well. For example, the 2020 Nature paper "Microbiome analyses of blood and tissues suggest cancer diagnostic approach" was retracted this past year [1].
Given the ease of contamination of tissues (and databases), I tend to be pretty skeptical of tumor microbiome claims -- especially the wide-ranging claims of microbes being present in all tumors.
[1] https://www.nature.com/articles/s41586-024-07656-x
I know nothing about this, so I guess I'm asking "why can't we do this?": take some brain, throw it in a blender, and look for DNA the same way the ancient environmental DNA people do?
You can't find out this way. Removing brains exposes it to an outside environment where there are microbes. You can't tell if they arrived before or after you removed the material.
Related recent story about earth microbes colonizing what was hoped to be a pristine sample of astroid captured in space: https://www.space.com/ryugu-asteroid-sample-earth-life-colon...
Maybe the first point you make is also the argument for why our brain might have a microbiome, as our body is not in any way hermetically enclosed, and e.g. amoebas are able to infect our brains just by going through our nose.
Very hard to clean a blender!
More nitpickfully, one of the big things we care about is if the bacteria are living _harmlessly_ in the brain. i.e., site of microbes, and a lack of inflammation, will answer more than just "are there microbes around".
From what I understand Joe DeRisi's approach[0] comes relatively close to your "blender" idea!
[0]: I already mentioned Adam Savage's excellent podcast with him elsewhere in this dicussion but here's a direct link: https://m.youtube.com/watch?v=MzzD2F73iGU&t=2s&pp=2AECkAIB
You’d have to get that brain cleanly from the creature to the blender.
Since I don't have enough information on the topic... how would one distinguish a microbiome that was present while the organism was alive, from contamination after death?
That's a question more suited to a microbiologist or bacteriologist than to me, but my educated guess, at least in the electron microscopy case, is that you'll see the bacteria inside the depth of the slices, rather than sitting "atop" the slices. i.e., if you cut open an apple and find half a worm, the worm was in the apple. If you cut open an apple and then see a worm on top of the slice, it's possible it arrived post-cut.
Two months ago we had almost the same topic here on HN and I posted a question that no one seemed to be able to answer:
> I mentioned Adam Savage's "Scariest [Podcast] Episode Yet" in a different context the other day[0] in which I remember Joe DeRisi[1] saying something along the lines of brain & spinal fluid being "absolutely pristine" when it comes to the presence/absence of a microbiome (in healthy individuals) and that it'd be real problem if there were one.
> I'm just a layman but can anyone ELI5 how this can be squared with the OP, specifically with statements like
> > It turns out our grey matter is teeming with bacteria, viruses and fungi
Can anyone explain this?
[0] https://news.ycombinator.com/item?id=41765112
Probably the vast majority of studies are correct and a few misinterpret artefacts, and then a journalist uses an evocative word like "teeming" without knowing that what they're saying doesn't pass the sniff test. Same reason these papers languish for years and don't pass peer review in rigorous journals
I was very surprised that just last year, 2023, we discovered a whole ass thin membrane covering the brain we didn't know was there.
The thin membrane discovered, again, just last year, is called the Subarachnoid Lymphatic-like Membrane (SLYM), and apparently acts as a protective barrier separating "clean" and "dirty" cerebrospinal fluid among potentially other things.
We don't know a lot.
On this topic, you might be interested in this article and the related discussion regarding novel anatomy.
https://news.ycombinator.com/item?id=41517059
Just how much we still don’t know about the brain and its protective systems... It’s crazy to think that a major part of the brain’s anatomy was essentially hiding in plain sight for all these years.
If this were to be the case in humans, I wonder what effect antibiotics would be having on behaviour.
How much of the thinking/feeling would be due to this microbiome? Is this how people develop mental illnesses? Such an interesting topic! I hope it gets the funding it needs!
and conversely whether probiotics for the brain might exist.
Countdown until the nutrition influencers start pushing them.
Pretty sure all parts of our bodies are riddled with viruses and fungi, and maybe bacteria too if we look hard enough.
They'll just be in low concentrations so they're hard to detect.
Aren’t viruses much harder to detect than bacteria? Viruses are generally smaller and are completely inert without a host cell. Bacteria, besides be larger, also have their own metabolic processes and distinct structures you can do things like grow them in a laboratory culture until the colony is much obvious.
Your comment makes it sound like bacteria are harder to detect but if we’re already identifying viruses, locating bacteria seems easier.
(Though some viruses are bigger than the smallest bacteria, like Mycoplasma at 200nm, viruses are generally smaller)
Both are hard to detect if there are only hundreds of them amongst trillions of human cells.
At that point, 'just look with a good microscope' becomes infeasible, and you end up needing biological tricks like DNA amplification.
That rather speaks against it being a microbiome - it could just be incidental contamination the body is in the process of cleaning up. To be a microbiome I would expect to a diverse, well-adapted quorum of species that find some type of symbioses.
Absent that evidence, well biology is probability - something is always happening somewhere just by chance and statistics, but it doesn't make it a feature.
And it makes me wonder how much we’re still missing or overlooking in the microbial landscape of our own bodies.
Look up "Cosmic Death Fungus", there is some (but only some..) truth there.
Dr Salinas is awesome. She did an interview on "The Children's Hours" about lung fish that was so interesting. Her fish research is leading to a ton of human immunology understanding.
Aren’t there some kinds of amoeba that can cross the BBB and take up residence in the brain? And fungal infections? (Or am I just thinking of horror movie plots?)
It’s rare, but viruses, bacteria, fungi, amoeba, worms and other parasites can get into the brain and cause meningitis.
Amoeba can get in via the nose from contaminated water.
https://en.wikipedia.org/wiki/Naegleriasis
You really don’t want that happening because they’ll literally eat your brain.
The one I know of is terrifying and usually lethal. It gets in through the nose/cribriform plate https://en.wikipedia.org/wiki/Naegleria_fowleri
There has been some research on this, establishing the presence of microbiome in the brain:
https://www.biorxiv.org/content/10.1101/2023.02.06.527297v1
Why hasn't it passed peer review yet? Maybe because they only used techniques prone to artefacts. IMO if a brain microbiome exists in healthy people it would have been seen already, with all the microscopy and sequencing done
Not sure if this article provides enough definitive info - happened to see it yesterday.
https://www.newscientist.com/article/mg26335104-500-the-brai...
The whole microbiome thing is way overblown. It's like studying a great city by looking at rats in the sewer. And yeah, maybe some people have rats in their houses too. That's doesn't really tell you much about the city.
> Is possible that the bacteria were swallowed by the white cells
Then this would hardly count as brain "microbiome".
Do wolves have a macrobiome of deer inside wolves guts?.
Sooo our brain might not be sterile (frighteningly). And we might see a shift in how we approach even mental health in the future.
If this were also true for humans, what would the implications be?
that a bacteria decided to "lemme make this dude ask a question on HN". On a serious note, it's already answered in the article - it means that our behavior is not only influenced by the gut bacteria (already proven), but the brain ones too.
Well finally I have a new excuse to ask dumb questions here...
But what I mean is, what are the downstream consequences of this knowledge? Does it change how we can reason about health, cognition, etc?
unknown. they barely suspect this, to your question is another leap in science for future generations of researchers
Wow. If true, that would be fascinating.
We know that non-brain microbiomes can influence behavior. What might something in brain tissue itself do?
Influence behavior.
You can look at toxoplasmosis as an example, synthesizes dopamine and is somehow able to selectively modulate attraction to predators.
Somehow the brain microbiome is only able to influence the gut.
My gut tells me that the gut influences behavior.
I recall reading about this 1 or 2 years ago! But I don't remember details. Has there perhaps been tentative evidence?
What would this say about taking antibiotics? Would the blood-brain barrier keep them out?
no. they are molecules, and they are let in by the barrier.
It depends. Some antibiotics pass the BBB easier than others. Some are used especially when passage through the BBB is desired.
Gut microbes affect brain too
I’m skeptical but there’s plenty of intracellular bacterial pathogens. Perhaps there’s an intracellular commensal bacteria/symbiote.
I think if it was extracellular we would see it more often in CSF - which is collected quite a bit in healthcare. Regular histology/pathology slices and staining would detect as well.
I could imagine an intracellular commensal bacteria that is small and virtually indistinguishable from an organelle like a mitochondria or lysosome that may exist.
Mitochondria were already bacteria at one point. Could there be another endosymbiont?
Mitochondria have circular DNA and phage like polymerase. Perhaps our secret symbiont can be found through DNA studies.
Examples of intracellular bacterial pathogens include: Brucella abortus Listeria spp. Chlamydia spp. Rickettsia spp. Ehrlichia spp. Anaplasma spp. Coxiella spp. Mycobacterium tuberculosis Salmonella spp.
left-handed and right-handed bacteria determining political beliefs
That would explain a lot of things that seem completely baffling.
Consider a worm attacking the judgment and inhibition center.
Most people will read this headline as a question. I read it like a proposition for bio weapon lab research. Post covid.
Parasites can live there. I think, Toxoplasma gondii and malaria and a brain eating ameba exists. If you planted a bean in the brain of a beagle, it would grow too. Though I hope we don't ever do that.
Some do and it has a huge impact on human behavior.
In case it helps others: to find out what the above comment’s “huge impact on human behavior” is supposed to refer to, you’ll need to dig into references/footnotes #23, #25, #27, #28 and #29 on the linked Wikipedia entry.
Short answer: yes.
https://www.theguardian.com/lifeandstyle/2024/dec/01/the-bra...
Let's not jump to conclusions. That guardian article is about a pre-print study that used frozen brain samples from a single tissue bank, and RNA sequencing was done on a single machine.
There's a lot of controversy around this[1], because contamination is possible and it's known that the blood brain barrier weakens with age. The sample are all from older individuals.
[1] https://www.news-medical.net/health/Is-there-a-brain-microbi...
Contamination is possible, but it's hard to explain the results that way. Definitely needs replication, of course.
I don't see the point of the samples all being from older individuals. Even if it exclusively occurs in older individuals (unlikely), it would still mean that the blood-brain barrier is not 100% effective (which we already know to be true).
From the article:
> When microbes have been found in the human brain, they are associated with active infections or typically linked to a breakdown in the barrier due to diseases such as Alzheimer’s.
I think the question is whether there is a brain microbiome in healthy people, which seems to still be an open question.
I mean, we know about all kinds of microbes that can be in the brains of "unhealthy" people, and we've known that for ages (taxoplasmosis and CJD come to mind).
The association in the article isn't a case of "we didn't find it in healthy people", but "we found it in more in unhealthy people".
From the article: "It found that, while there was a remarkable diversity of species in the control brains, there were often overgrowths of certain bugs in Alzheimer’s brains."
That doesn't seem to be that clear cut.
Evidence is scarce and the article is talking about brains with active illnesses. It could be that there isn't any microbiome normally but if the safety mechanisms fail and bacteria colonize the brain, that would cause the illnesses described.
> Evidence is scarce and the article is talking about brains with active illnesses.
They compared them to control brains, which also had microbes.
> It could be that there isn't any microbiome normally but if the safety mechanisms fail and bacteria colonize the brain, that would cause the illnesses described.
That would describe a scenario where the blood-brain barrier isn't 100% effective, no? If it's not 100% effective (which we know to be true), it is also seems unlikely that 100% of the things that cross the blood-brain barrier cause something that we currently consider a disease. Heck, in healthy individuals, latent taxoplasmosis' effects are often so minimial I don't think we'd call it a disease (otherwise 30%+ of the world has the disease).
Biology and binary do not play nice.
Indeed.