Contra Skolnick On Schizophrenia Microbes

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Stephen Skolnick is a gut microbiome expert blogging at Eat Shit And Prosper. His most recent post argues that contra the psychiatric consensus, schizophrenia isn’t genetic at all - it’s caused by a gut microbe. He argues:

1. Scientists think schizophrenia is genetic because it obviously runs in families

2. But the twin concordance rates are pretty low - if your identical twin has schizophrenia, there’s only about a 30%-40% chance that you get it too. Is that really what we would expect from a genetic disease?

3. Also, scientists have looked for schizophrenia genes, and can only find about 1-2% as many as they were expecting.

4. So maybe we should ask how a disease can run in families without being genetic. Gut microbiota provide an answer: most people “catch” their gut microbiome from their parents.

5. Studies find that schizophrenics have very high levels of a gut bacterium called Ruminococcus gnavus.

6. This bacterium secretes psychoactive chemicals. Constant exposure to these chemicals might be the cause of schizophrenia.

I disagree with all of this. Going in order:

1: Scientists think schizophrenia is genetic because it obviously runs in families

This is not why scientists think schizophrenia is genetic, but we’ll get back to this later.

2: But the twin concordance rates are pretty low - if your identical twin has schizophrenia, there’s only about a 30%-40% chance that you get it too. Is that really what we would expect from a mostly genetic disease?

This is exactly the concordance rate you should expect from a polygenic condition where 80% of the variance is explained by genes. I discuss this example in Some Unintuitive Properties Of Polygenic Disorders and run a discount simulation that assumes an 80% genetic disorder with 1% prevalence and demonstrates that you can get a very low twin concordance rate. Here is a paper that does the full formal simulation and finds a rate consistent with observed values.

3: Also, scientists have looked for schizophrenia genes, and can only find about 1-2% as many as they were expecting.

This is the “missing heritability” problem, common to all polygenic traits. See my Missing Heritability: Much More Than You Wanted To Know. The leading explanation is that our current genetic screening methods aren’t good enough to pick up rare variants; an alternative explanation proffered by some geneticists is that there are lots of invisible gene x environment interactions.

In either case, schizophrenia doesn’t have much more “missing heritability” than anything else, and it would be surprising if every single trait - from height to educational attainment - was determined by gut microbes.

4: So maybe we should ask how a disease can run in families without being genetic. Gut microbiota provide an answer: most people “catch” their gut microbiome from their parents.

This doesn’t work.

Going back to the first claim: scientists don’t think schizophrenia is genetic just because it runs in families. They think it’s genetic because they’ve done twin studies and find that identical twins share a schizophrenia diagnosis more often than fraternal twins. Skolnick describes microbiological inheritance as:

See, many of the bacteria in your gut right now are strains that you picked up from your parents, back when you were still crawling around on the ground and putting everything in your mouth, picking your nose and eating it, and so on. If you think you didn’t do this as a kid, ask your parents. They remember. Those bacteria have stayed with you most of your life, eating the food you eat, reproducing faster than you can shit them out. If you have kids, you will pass those same heirloom strains on to them. Heritable. Biological. But not genetic.

This doesn’t describe a process which could be expected to differ between identical and fraternal twins!

Skolnick could add an epicycle: maybe identical twins have more similar microbiomes because their identical genes caused identical gastrointestinal ecologies. But then schizophrenia is determined by genes again (albeit indirectly) and it should show up as genetic in GWASes (ie they should pick up the genes for having a certain type of gastrointestinal ecology suitable to schizophrenia-causing bacteria, and identify them as schizophrenia genes). There might be some complexities around gene x environment interactions, but it wouldn’t look like the simple pattern of missing heritability that Skolnick uses as his star evidence that schizophrenia is “not genetic”.

This is just one example of how microbiological inheritance doesn’t exactly track genetic inheritance - and whenever we see a difference, schizophrenia tracks the genetic rather than the environmental pattern. So for example, spouses have more similar microbiomes than siblings, but schizophrenia doesn’t transfer from spouse to spouse. Adoptive children presumably crawl on the ground and put things in their mouth just as much as biological children, but there is no adoptive-parent-to-adoptive-child schizophrenia correlation (and if Skolnick tries to get around this by saying the bacteria are transferred during the birthing process, I’ll answer that schizophrenia is often inherited through the paternal line).

Finally, this study finds that family environment only explains 13% of variation between individuals’ microbiomes during adulthood - and remember that family tendency for schizophrenia can persist across two or more generations.

5: Studies find that schizophrenics have very high levels of a gut bacterium called Ruminococcus gnavus.

The study that Skolnick cites to establish this is Vasileva, Yang, and Baker, Association Of The Gut Microbiome With Treatment Resistance In Schizophrenia.

All the schizophrenics investigated in VYB were on antipsychotic medication. Previous studies have already shown that antipsychotic medication disrupts the gut microbiome. VYB couldn’t investigate whether the disruptions were caused by medication in their own sample, because they had no unmedicated controls, but they checked whether more medication = more disruption, and it did. They concluded that the most likely cause of the microbiome disruption was the medication:

The findings indicate that individuals with treatment-resistant schizophrenia have significantly different microbiome composition compared to control individuals without psychiatric diagnoses and individuals with treatment-responsive schizophrenia, which is most likely driven by clozapine.

Even though this is right in the abstract and torpedoes Skolnick’s theory that the increased microbe population causes the schizophrenia, he doesn’t mention any of this in his post!

If some other study finds unusual gut microbiota even in untreated schizophrenia, will this support Skolnick’s theory? Not really. Schizophrenics differ from the general population on a wide variety of health outcomes - for example, they die about 15 - 20 years earlier, often of heart problems. Why? Probably some combination of medication side effects, poor health decisions, and maybe a direct effect of the disease itself - the same neurodevelopmental issues that affect cognition also affecting some autonomic process that regulates the heart. In any case, there are many reasons to expect schizophrenics’ guts to be abnormal, and plenty of evidence that this is in fact true.

(also, during residency, I met a schizophrenic patient who, whenever he wasn’t restrained, would eat as much glass as he could until he got internal bleeding and had to go to the emergency room. I don’t know what kind of microbiome disruption this causes, but I bet there aren’t many non-schizophrenics who have it.)

This page says that R. gnavus is also increased in inflammatory bowel disease, irritable bowel syndrome, colon cancer, skin allergies, liver disease, etc, but that "association with diseases does not necessarily mean that R. gnavus is a cause of these diseases, it may just indicate that these conditions may be more favourable to R. gnavus expansion in the gut compared to other bacteria."

6: This bacterium secretes psychoactive chemicals. Constant exposure to these chemicals might be the cause of schizophrenia.

Schizophrenia doesn’t resemble exposure to psychoactive chemicals.

Just to give one example, schizophrenics are normal (or only slightly weird) until around age 18-30, then become psychotic over the course of a few months. According to the consensus theory of schizophrenia, this is because schizophrenia is a neurodevelopmental disorder that interferes with adolescent synaptic pruning. How does a microbiological theory explain this progression?

In fact, it doesn’t really make sense to posit a single cause for schizophrenia at all. For example, we know that children infected with rubella virus in utero have 20x the usual schizophrenia risk. But we also know that many schizophrenics had no prenatal exposure to rubella or anything else. Other risk factors include urban environment, winter birth, prenatal stress, and maybe cat exposure (really!) To me, these - combined with genetics - make the most sense in the context of schizophrenia being a failure (for any reason or combination of reasons) in a complicated neurodevelopmental cascade we still don’t fully understand.

People have been looking for magic bullet explanations of schizophrenia for a hundred years. It’s time to admit there aren’t any. Or if there are, they’ll have to do better than this.