To quote a segment from the series of tweets by the author, Kevin Mitchell (a neurogeneticist from Trinity College, Dublin) :
"1. A supposed mechanism in search of a phenomenon... (What is the microbiome supposed to explain here?)
2. No actual mechanism.
3. No actual findings. Just lots of exploratory blips, unconstrained by prior hypotheses, uncorrected for multiple tests, and unreplicated.
4. Massive hype.
Just because the genetics of complex disorders is complex and just because the neuroscience of the highest functions of the human mind is complex, doesn't mean we need to go looking for new kinds of biology to explain them"
Be careful who you believe. This grumpy genetic determinist is clearly out of touch with an entire field of emerging research about the gut-brain axis.
Apparently this guy you're quoting is also skeptical of epigenetic inheritance. (http://www.germlineexposures.org/blog/no-convincing-evidence...)
Why should I listen to him again?
He's hung up on finding a singular "actual mechanism" in a complex, nonlinear system? I know almost nothing about this guy but I suspect he's another a drug company biologist, desperately holding onto shattered dreams of genetic determinism.
Rather, I think he is challenging the notion that epigenetic inheritance is the driver of / underlies behaviour change in mammals.
I disagree with your assertion that he is skeptical of epigenetic inheritance. I think he's skeptical that epigenetic inheritance can drive multi-generational neuro / psychiatric behaviour change, which is a far more nuanced position to take.
For instance, had you made the effort of actually checking his blog,  is a response to the article you linked / cited:
To quote him:
"So, in case I have come across as merely unpleasantly grumpy, let me spell out my general grounds for being skeptical of the claims of TGEI in mammals."
And further, in the context of behaviours and neuro disorders, and their inheritance in humans.
That's what he is commenting about. Not epigenetic inheritance in general. In as much as you didn't actually check his writings and painted his position with such a broad brush and value judgements, then yes. I would agree this was shameless and an ad-hominem attack indeed.
Now, I don't know this guy. But his arguments, especially the lots of different ways in which biologists mis-interpret and mis-apply statistics rings true. His arguments are cogent, and his analysis reasonable and conservative. Which, in science (the conservative interpretation) is an excellent thing, IMO. So yes, I do choose to consider his opinion carefully.
I think, in all this hype and buzz-wordy social media noise that appears to be driving everything including research and politics, it's important to identify and defend the voices that are saying, slow down, let's not read too much into these things yet; let's not get carried away.
Jill Escher, whose article you linked to, is a lawyer by training. This guy is a neuro-biologist and a professor at Trinity College, Dublin. Who do you think has more credibility here?
This suggests to me that you didn't even look the people you were citing up, or who you were criticising. Surely, you can do better?
[Edit: added excerpt and replaced "crap" with "noise"]
This is as good as it's probably going to get from here on out.
My bet is it’s the former, not the later.
So if you transport the message, you get a universal reaction.
You pretty much nailed all those studies. Those type of hard to characterize, very complex, and poorly understood diseases, are the only candidates that you will see a “microbiome can cause/cure it” type of paper.
At the end of the day, they see a mouse, bearing a set of mutations that is not even close to mimic the disease population, adopt some new behaviors, and then they miraculously cured everything.
On top of that, VC have started to invest massively in that field, even starting their own company. On one side, I hope this will bring some much needed robustness to the current lack of rigor. On the flip side, since the biotech VC model is to IPO whithin 5 years, I doubt they will do better.
If the original research were in a twitter thread rather than a publication, it would be unreasonable to consider it seriously.
Then they reversed causality for some wild theories.
And these low-reputation journals are poorly discriminating. Status here has a reason.
After decades of looking for brain abnormalities and finding none it really is time to look elsewhere.
This Mitchell guy is in denial.
After just reading up on the possible causes of schizophrenia it seems many more discoveries have been made which has only resulted in more confusion and we're basically nowhere near having a clue.
One of the most important points that rarely come up in these discussions is that schizophrenia is not one illness but a bunch of different ones grouped together that we haven't figured out how to differentiate. You can find several patients that share very few symptoms.
I remember meeting someone at an alumni networking event who worked with mentally ill people, including schizophrenics. He explained to me that a lot of his patients had extreme sleep apnea, and their CPAPs were turned up much higher than a typical sleep apnea patient.
His theory was that some of his patients were mentally ill due to their sleep disorder.
He went to multiple doctors to verify the cause, but wasn't getting anywhere - didn't seem to really be either thing, but exhibited similar symptoms. He was eventually diagnosed by a super competent neurologist with extreme sleep deprivation due to sleep apnea.
When tested it was determined that his sleep apnea was waking him nearly once a minute, but he wasn't becoming fully conscious and therefore wasn't aware he was constantly waking up. He was never entering deep sleep at all. It was more like moving out of dozing into almost-awake and then back again rapidly all night long. He knew he was tired, but had no memory of really restless sleep.
He started using a CPAP and the symptoms started declining immediately. He was back to himself within a couple of weeks. It was really astonishing - I had never heard of anything like this - and of course it was an enormous relief for everyone in my family.
It was more that I really often saw a flicker of motion in the corner of my vision or thought I heard someone mumble or say something that I didn't quite catch. These hallucinations were easy enough to rationalize away - maybe the people near me just took a breath weirdly and I thought it was a word, or a bird flew nearby or something.
I didn't realise any of the above were symptoms until I I noticed they weren't happening to me any more a few years after I had started treatment and hadn't happened in quite some time.
I can easily see myself ending up like your grandfather after a few more years of living with severe sleep deprivation. Ironically I got treatment when seeking help for insomnia (because it took me a ridiculous time to fall asleep and could basically only do it when I was completely exhausted)
Couldn’t he easily test that by having the patients reduce the intensity?
Unusually high CPAP intensity indicates unusually severe sleep apnea, suggesting a connection between sleep disorders and mental disorders.
Reflecting on the impact sleep has on my mental health, that makes intuitive sense.
I was rather scared at the time, as my CPAP was almost up to the level of the patients. (I got surgery shortly afterwards.)
But I will admit this: There was one time, prior to my CPAP, where I had trouble knowing if a memory came from a dream or real life. Makes me wonder if some mental disorders are just about having difficulty differentiating between dream state and awake.
I think we’re still maybe a step or two beyond the theory of humours in how much we understand the brain and what effects it and how it effects us. We’ll look back at how we’re treating a lot of those symptoms today as barbaric in a few decades, I think.
I feel like all the comments are ignoring this part of the blog post
And we can test them on a whole range of behaviours, without correction for multiple tests, without a hypothesis of which should show an effect, and again without a replication sample
In this case, the ones getting a SCZ fecal transplant showed greater activity, but less anxiety and less "depressive" behaviours. Why? Who cares? You can spin these kinds of findings any way you want. We all love a good story."
Please read the cited thread.
/disclaimer: I am not a neurologist / neurobiologist. My training was in genetics & molecular biology, and I've since moved out of active research / life sciences. But bad statistics and gross over-interpretation bothers me immensely; folks read such breathless reports & then start doing all kinds of harmful stuff because it's been proven! But it's not. It may be a hypothesis (and this report may not even qualify as that). And cruel as it is, we still don't understand nearly enough about so many things in biology to be able to address these disorders.
But it is a problem. Lots of people publishing just to publish (a consequence of how academia is laid out), and then sensationalist media who doesn't understand what's actually being said, or why to be skeptical (or maybe they do, and just don't care) , takes over and runs with it.
VC and SV entrepreneurship is pretty much the same game. That’s why you have the “Uber for X” syndrome. Sometimes it sticks, sometimes it doesn’t. We are all human search functions reporting back to the hive mind.
Now I don’t actually think the gut microbiome is just an automatic p-hacker - most studies are measuring pretty standard aggregate measurements of “diversity”, not just finding one class of the billions of bacteria that happens to correlate, so I’d agree with the OP that the question is more one of causality. And since a fecal transplant from an ill mouse caused signs of illness in an otherwise healthy mouse, then there’s reason to follow up.
Sure, sometimes you have a hypothesis and you go searching for a way to measure something.
Other times, you find a new way of looking at things, or you come across some new fascinating data. This helps you generate hypotheses for which you need to design new studies, not least of which is to ensure that the new measuring tool is measuring what you think it is.
I definitely agree with the sentiment that the product of research such as this shouldn't be policy or a change in world view. It should be hypothesis generation and new testing.
You have to start with a hypothesis and then come up with the measures and expected outcomes based on it. Then you design the experiment to determine if the hypothesis is false.
Which, while its an effective way to do science when we don't know what we don't know, has to be interpreted with lots of caveats & caution, and should only be considered to be the 1st step in a long, deliberate investigative process. And that doesn't seem to be the case, particularly in how pop-sci articles communicate the results.
You consider the fecal transplants to be mere correlation?
If a study shows A and B are correlated, it could be any of:
1. A causes B.
2. B causes A.
3. They are both caused by a third factor C.
4. Random chance.
5. Bad experimental design. Science is hard.
7. Probably other things I can't think of right now.
As far as I know, the gut microbiome is most directly affected by what you eat. Do schizophrenics have different eating habits than non-schizophrenics?
Anyhow, it's perfectly reasonable that people suffering Schizoaffective disorders might have different interactions with common foods that are considered tolerable by "most people".
On the flip side, there are people out there with super gut, that feel happy no matter what life throws at them. Just a dose of optimism to lighten up the mood.
That's not how science works. If something is proven and reproducible via the scientific method, it must work(used to make verifiable predictions) whether you accept it or not.
Let's never forget https://en.wikipedia.org/wiki/Diederik_Stapel . His M.O. was to fabricate results that would be easy for his peers to accept.
And if we take into account all the dangerous pseudo-scientific hype around the gut(leaky gut, cleansings, etc) we should be twice as careful.
But clearly, diet, the gut microbiome, the immune system, at the very least, are linked, and linked tightly. So it would not be surprising at all, that there's a microbiome component. But we don't know what it is; how it affects the underlying disorder, and how to approach it for treatment as of now.
And as you alluded to with "genetic risk factor"; its well possible that though there is a component of the microbiome involved in the disease; it may not be significant enough to act as a vector for treatment. Or that it is just a comorbidity. We just don't know!
Why not? That would be a fast way to find out if it works.
That doesn't work (the treating depression part), but suddenly, this person becomes more susceptible to obesity / develops diabetes.
These things must not be rushed into!
I don't think the authors are drawing a casual effect here; in effect, this is scientific anecdata: hey, we tried this and this happened. We think you should know.
I think it's great they published the result, even if the n=1.
Assuming this is due to the fecal transplant, it just goes to show, we are messing with a major functional system in the body. And we should tread very very carefully. Scary..
It's plausible that to some degree these changes could be reversed to some degree long term of they're the result of a tonic stress from the gut biome, and it's also possible that acute schizophrenic episodes could be ameliorated if it turns out they're triggered by the gut, but it's highly unlikely that replacing the gut biome of a schizophrenic person would give you a neurotypical person.
The other thing about schizophrenia is that people usually develop the disorder in their late teens or early 20s with an acute episode. If there is indeed a link to gut bacteria, and if you could identify pre-symptomatic, high-risk individuals, I would imagine this could create a very compelling vector for preventative treatment.
It's nice to see they're being a bit cautious.
These sane, rational folk should surely flock to that opportunity!
Dr. Stanislav Grof's essay "Mind, Nature and Consciousness" provides a very lucid introduction to this theory (http://www.stanislavgrof.com/wp-content/uploads/pdf/Gregory_...):
"The basic idea of Gregory Bateson's theory of schizophrenia is that this disorder basically represents a breakdown of metacommunication [messages about messages, indicating how the communication should be understood, i.e. a wink to indicate that this is a joke, /s for sarcasm, etc]. Psychogenetically, this problem can than be traced to a specific disturbance in the communication between the mother and the future schizophrenic which involves what he called a "double bind.”
The basic characteristics of this situation are the following:
1. The child is in a relationship of vital dependency, where it is critical to identify correctly the communication from the mother.
2. He or she is receiving from the mother messages which are contradictory, since the qualifying metacommunication denies the verbal content or is otherwise incompatible with it.
3. The child does not have the opportunity to ask questions to clarify the communication.
4. The child cannot leave the field. Under these circumstances, he or she is forced to distort his or her perception of the outer world and of the inner feelings, and is incapable to develop meta-communicational skills.
Gregory's favorite example was a situation in which a mother, annoyed by a child who is active and noisy, tries to get rid of him by saying: "Darling, it is very late and you must be terribly tired; mommy will put you to bed. You know I mean well for you." The message misrepresents the truth about the matter. It says "you are tired and need to sleep" instead of "I really need some space for myself." Messages and situations of this type force the child to deny or disregard his or her inner clues and accept what the mother is saying.
Metacommunication is extremely important in human communication and individuals who do not master it tend to have great interpersonal difficulties. Metacommunicationally inept persons who are incapable to read subtle signals, understand jokes, and decode hidden meanings become easily victims and scapegoats of their peers. There has been much discussion, whether this mechanism is sufficient to explain serious psychopathology encountered in schizophrenic patients. Gregory Bateson himself believed that much of schizophrenic symptomatology can be understood as a total breakdown of metacommunication."
I mean, if this theory was true, you would expect to find schizophrenic families--after all, they all had the same mother. It also doesn't line up with the timing of onset at all.
"I mean, if this theory was true, you would expect to find schizophrenic families--after all, they all had the same mother."
First of all, maladaptive social behavior of the kind that is labeled as "schizophrenia" (or other so-called mental illnesses e.g. "bipolar", "depression") does tend to cluster in families. This is why doctors screen for things like "family history of depression."
Secondly, there are major differences in siblings' roles and how they are treated, despite having the same mother. The birth order concept is the most obvious version of this. There is another concept of the "identified patient" which explains how in some cases one family member plays the role of the "sick one" as a way to maintain stability of the family unit as a whole.
"It also doesn't line up with the timing of onset at all."
I don't see how this theory conflicts with whatever timing of onset you are referring to. Perhaps you can clarify or provide citations for what appears to be a very strongly held opinion.
Yes but not necessarily at the sibling level, which is what you'd expect if this was a problem caused by bad mothers.
Also, you would predict that siblings should be highly correlated regardless of their genes if it was "mothering" but instead what you find is this (from the study you cited):
Monozygotic Twins 44.3
Offspring two schizophrenic parents 36.6
Dizygotic Twins 12.1
Offspring one schizophrenic parent 9.4
So a half-sibling raised with the same parenting is barely correlated on schizophrenia, but a twin has a 44 percent correlation. That puts the schizophrenogenic mother theory 100% off the reservation in my book. Reasoning past that damning fact is just wishful thinking.
> I don't see how this theory conflicts with whatever
The average age of onset is 18 in men and 25 in women. If this disordered thinking style is created in say 6 year olds, it seems odd that it takes 12-20 years to cause a problem.
Anyhow theories are a dime a dozen, and the burden of proof is on those proposing the theory to prove it, and that has failed rather spectacularly in this case.
Separated twins show high concordance for schizophrenia (why would this be if it is due to parenting?)
The important bit: It was concluded that genetic factors are important in the transmission of schizophrenia, whereas there was no evidence for environmental influences in the rearing family.
> Bateson's double bind theory was never followed up by research into whether family systems imposing systematic double binds might be a cause of schizophrenia. This complex theory has been only partly tested, and there are gaps in the current psychological and experimental evidence required to establish causation [citation?]. The current understanding of schizophrenia emphasizes the robust scientific evidence for a genetic predisposition to the disorder, with psychosocial stressors, including dysfunctional family interaction patterns, as secondary causative factors in some instances.
(Which makes me wonder: if the predisposition is genetic, why don't we have schizophrenic families? After all, they have the same genes!)
We currently have a very robust physiological understanding of the disorder, and the symptomatology is linked to observable structural changes in the brains of Schizophrenic individuals.
As with many psychological disorders, there appears to be a stress component: i.e. individuals may be more or less predisposed to the disorder, and therefore some individuals will only ever experience symptoms if triggered by a high level of stress, while for others it's unavoidable.
So in some cases, yes it's possible that a problematic family life was the stressor that pushed them over the edge to develop full-blown Schizophrenia, but that person might have equally been effected by being mugged at gunpoint, or going through prolonged sleep deprivation during basic training in the military.
The causal mechanism is almost certainly an interaction with Cortisol or other stress hormones, or some other well understood biological pathway. It's outdated pseudoscience at this point to take seriously the idea that Schizophrenia is the result of mixed messages during childhood.
While I agree overall with your point, I think your wording emphasizes a common but mistaken view that psychological experience can't induce physiological changes in the brain. This is obviously false.
For lack of a better analogy, there’s a degree to which different disorders are the result of a software problem or a hardware problem, and all the evidence points to Schitzophrenia as being firmly toward that hardware end of the spectrum.
Microbiota could influence psychology and thus physiology, or it could directly affect physiology and thus psychology. The fact fecal transplants triggered schizophrenic behaviours in mice shows there's some direct connection here that needs explanation.
On maybe it's neither and also both. Personally I think Physiology vs Psychology is the wrong terminology to use: Psychology's domain is the mind which is a somewhat abstract concept, and usually refers to things in terms of thoughts and emotions. Our "psychology" is an emergent property of our physiology, but to me it seems like the wrong abstraction to use as a reference point when speaking about the pathology of something like Schizophrenia.
Rather, what I think we're more concretely talking about is the division between nervous system structure (physiology), and activity (which includes, but is broader than psychology).
To me, saying the physiology affects the physiology implies the wrong interpretation: i.e. it would be inaccurate to say that the gut bacteria made rat feel certain emotions or have certain thoughts, and those led to long term structural damage. However, it might very well be the case that the gut biome causes a neural activity pattern which leads to long-term pathological adaptations in nervous system structure.
If I had to guess, there's probably not a one-way causal relationship, but these systems likely feed back on each-other in a way which results in the symptomatology we describe as Schizophrenia.
What are schizophrenic behviours in mice?
In HN you will find a very hostile audience towards the idea that an _inner world_ exists at all. This is unfortunate, when I denied my inner world I lived only half of what I experienced, and I insisted that all my problems could be resolved with pills and external stimulus. This leads to a barren emotional life and a distinct sensation of being stuck in the same place, which eventually leads to depression.
If you have an opinion or idea that isn't reproducible, verifiable or testable and the only thing you can do is "accept" it based on how good it sounds to your ears then it doesn't belong in science.
So please, leave that stuff out of science, it's our last barricade.
if so, you'd be quite vulnerable the next time someone offers you a double bind.
All of your remaining assumptions are wrong, so no reason to even bother.
ps; probiotic yogurt makes me very happy
Sorry to hear about the Borderline. Just remember that mental health diagnoses are less rigid than traditional medical diagnoses. You've heard of mind over matter; mind over mind is even more effective.
Rice bran, oat bran, psyllium husk, ground linseed, and slippery elm powder.
Typically equal proportions, but it varies depending on how much of what I’ve got left when it goes in to the mixing bowl.
I also regularly buy not continuously take a priobiotic and / or Greek style unsweetened yogurt.
Lots of Vitamin D. I also need to supplement essential fatty acids or my skin tears at the edges of my nails.
Plus running and lifting heavy things. Also dogs. My dogs are well trained, they know our routines, and they make me laugh out load a lot!
Also, check out partially hydrolyzed guar gum which has some promise for IBS. It is a prebiotic fiber (feeds your beneficial bacteria) and also like psyllium husk does not produce a lot of gas which is bad for IBS.
Hope you feel better! :)
First try doing OMAD and see how u react . Basically fast for 23 hours and eat for one hour . If u think you can handle doing that for a week. do it a few days straight
Interview w/ a doctor focused on the links between gut, autoimmune, and mental health.
You might look up the term somatopsychic (assuming you don't already know it) and start thinking of mental health issues as probably at least partly rooted in physical health issues.
I have read that IBS is implicated in fibromyalgia, including shoulder pain, but I am interested in the reverse causal direction: can a painful shoulder injury cause IBS?
If nerves and the gut are tightly connected, it seems plausible that pain receptors would also be implicated in both directions. (Of course, going back to the link to the central nervous system, your brain doesn't have pain receptors, but it is connected to every nerve in your body.)
...I'll blame Cartesian though and the idea of free will for this.
I think you're right. So much so that my doctor actually suggested prescribing SSRIs for the IBS, even in a patient (such as myself) having no signs of clinical depression. I didn't take the prescription, so I couldn't say if it would have helped in my case, but I went home and read a study that SSRIs have been shown to alleviate IBS. Pretty interesting.
Since the problem has only mostly subsided, I'd be thankful for any ideas about just what was going on.
Osmosis is a less efficient means than direct blood supply, so joints probably tend to accumulate wastes firsts if they aren't all being removed from the body for some reason. Anecdotally, cartilage and nervous system tissues are the last things to heal. Everything else has to improve first.
Also, some infections, like strep, are known to settle in the joints. The shoulder is one of the larger joints and has a fair amount of cartilage and similar tissues.
So, you injure a major joint and old infection hiding out in the joint gets released into the blood stream. This impacts the entire body.
But the gut is where you find 70 to 80 percent of immune cells in the body. My hypothesis is that it is because food is the single largest threat we deal with on a daily basis.
So you have what amounts to an internal toxic spill and it stresses the gut because that's the largest concentration of cleanup crews. Dealing with this crisis taxes the entire immune system, but you are most aware of impact on the gut because that's where the vast majority of your immune function is found.
I am skeptical about the value of blood tests. It seems to me that by the time a blood test shows a problem, things have to be pretty bad. I think reliance on blood tests probably misses a lot.
/More speculative postulating
Hmm, well that part about calcium is quite interesting, at least in my case. I say this because right around the time I started getting leg cramps, my joints started popping like crazy.
My working hypothesis was always that the tight muscles were pulling on the joints, causing them to pop more easily. But maybe now I was actually being slightly deprived of calcium? I say slightly because the calcium blood levels were normal.
As a bonus, I am insulted a lot less ;)
A person with asthma or a broken leg is usually not told to just breathe or just go for a walk.
Tone is hard to read on the internet. Personally I read that comment as reassuring rather than invalidating. (Of course it wasn't directed at me). I get anxiety quite regularly and have battled depression since age 10 after experiencing something very traumatic. When someone manages to successfully reassure me, I'll take it. It can help break me out of my digging.
There's also genetic relations with schizophrenia. I've always wondered if these had to do with nature or nurture. Often studies simply say they check a person's mental health background. Is it really genetic? Perhaps it could also be what gets taught and passed down to us or the home we live in.
Perhaps the mental illnesses that our society experiences is nothing more than poorly regulated drinking water, mold in the walls, a bad diet, Mom's spaghetti, or spices that don't agree with us.
I find this research very interesting. The bacteria change could be a side effect of something but since the bacteria is atypical, it leads to a very interesting question: How did it get there?
What foods carry this bacteria? Does this bacteria kill other healthy bacteria? Does it serve a purpose?
I'm not a biology specialist, but I would love to know if nutrition is related.
But actually it does seem to be the case that the ability to put on fat is in some ways protective against diabetes. In other words, people that easily store calories as fat don't have the metabolic problems associated with diabetes, since their body is able to effectively store any extra calories they take in. Diabetes develops in individuals who are not effective at converting excess sugar in their blood stream into fat, so instead they suffer metabolic damage. That's not to say that they don't put on fat, but if you see someone who has an enormous amount of excess fat, they are likely to have a much higher threshold before they develop the disease.
Finished your sentence.
But as a preventative measure it could be interesting. If this theory is correct, there could be people out there who never developed schizophrenia because they did a course of Cipro at the right time and nuked their dysfunctional gut biome. We would have no way of knowing.
Yes. There are lots of articles (based on studies) on this. For example:
Here's a case of Levofloxacin inducing acute psychosis. For someone at risk of developing chronic psychosis, acute psychosis can trigger an avalanche.
There are other cases in which this has happened, and it's to the point where the FDA has administered a warning:
Schizotypal disorders are dynamic and non-deterministic. So I agree with your skepticism around the word "cause". But in this case, I think it would be unwise for someone with a history of schizotypal symptoms to use fluoroquinolones.
Trust the science, but don’t trust the science reporting.
This study pointed out 90+ days of taking minocycline/doxycycline during adolescence "had a significantly reduced risk of a subsequent psychotic disorder diagnosis than did those receiving other antibiotics." - from their 10-years sample of electronic records.
I had a suspicion that as you say "schizophrenia" might be an umbrella term for many distinct diseases with similar symptoms.
So yes, your questions are perfectly adequate, though for me personally that finding is exciting, as I can potentially apply supercomputing on that problem.