Can you use the gut microbiome to diagnose autism? I think not

Last week, the New York Times published a story claiming that we might be able to use the gut microbiome to diagnose autism. The Times story was based on a just-published scientific paper that claimed the same thing.

This report set off all my skeptical alarm bells. My initial reaction was “oh no, more bad science around autism.” For one thing, as most scientists studying autism are aware, the modern anti-vaccine movement started with a scientific paper, back in 1998, that claimed, falsely, that childhood vaccines caused autism. That paper in The Lancet was later shown to be fraudulent and was eventually retracted, but not before a huge amount of damage was done. Its lead author, Andrew Wakefield, went on to become a hero to the anti-vaccine movement, and he continues to promote anti-vaccine misinformation to this day.

The new paper (from the journal Nature Microbiology) is not making outrageous claims like that, nor was the New York Times. However, anyone claiming autism is caused by microbes in the gut should know that the notorious Lancet study was based on a hypothesis about a “leaky gut,” a hypothesis that was discredited long ago. (I don’t want to give it any credibility, but that hypothesis held that virus particles in some vaccines somehow “leaked” from the gut and made their way to the brain. It was nonsense at the time and still is.) That’s one reason why the suggestion that microbes in the gut might cause autism (or even be used to diagnose it) raises so many alarm bells.

I’ve now looked at the study, and frankly I don’t believe a word of it. Let me be clear, though: I’m not trying to prove scientifically that the study is wrong, which would require many months of effort and a much more detail than I can put into a column anyway. Fortunately, though, there’s an earlier study that did that job for me, which I’ll get to below.

However, the science behind this study is closely related to my own work, so I feel pretty comfortable offering my opinion. So what did the authors do?

Well, as the new study explains, they collected poop (”faecal samples”) from 1,627 children, some of whom had been diagnosed with autism and some who hadn’t, and they sequenced DNA from the poop. Then they looked for bacteria, viruses, and other microbes in the DNA sequence data.

That’s right: the “gut microbiome,” is really just a polite term for bacteria that live in the intestines and the colon, some of which come out in poop. Of course, some bacteria in poop might come from the food that a person ate, but mostly these are so-called gut bacteria.

I’ve been involved in many studies like this myself, so I’ve seen that these experiments yield hundreds of different species from every sample. The data sets are very complex, and a widespread problem in the field is that these data are often misinterpreted. In the Nature Microbiology paper, the authors took these very complex data sets and fed them to a machine learning program, and voila! The AI program was able to do a pretty good job (far from perfect, I should note) identifying the autistic children, based on the melange of microbes in their poop.

Right. I don’t believe any of this, as I wrote above. Why not? Well, first of all, machine learning programs are really good at telling apart two sets of subjects (such as children with and without autism) if you give them enough data. It sometimes turns out that the learning programs are keying in on irrelevant features that the scientists didn’t intend.

For example, this 2021 paper looked at over 400 studies that used machine learning to predict Covid-19, all of which had claimed some success, and found that all of the studies were essentially useless “due to methodological flaws and/or underlying biases.” Of course, the gut microbiome study wasn’t one of those, and some machine learning experiments do work, but we should be very skeptical.

Another reason for skepticism is that the new paper doesn’t even try to tell us what the machine learning models actually learned–it just treats the programs as a “black box” that we should trust.

Perhaps the biggest flaw in the study of autism and children’s gut microbiota is this: children with autism tend to be finicky eaters, and their parents try all sorts of diets in the hope that they can at least alleviate the symptoms of autism with food. There are countless websites–many of them scams, unfortunately–claiming that special diets can help these children. Why is this important? Because a special diet will alter your gut microbiome, sometimes quite significantly.

Thus even if the machine learning models in the new study are correct, the causality almost certainly goes the other way: children with autism might have a different microbiome because they’re eating different foods. Thus it’s autism that indirectly affects the microbiome. Unfortunately, both the New York Times and the scientific paper suggested the opposite.

Now on to that earlier scientific paper I mentioned above. It turns out 3 years ago, a group of researchers in Australia published a major study in the journal Cell that addressed precisely the problem I just pointed out. In that study, the scientists collected and sequenced poop from 247 children both with and without autism. They found “negligible direct associations between ASD [autism spectrum disorder] and the gut microbiome.“

On the contrary, the authors warned: “microbiome differences in ASD may reflect dietary preferences ... and we caution against claims that the microbiome has a driving role in ASD.”

In other words, three years ago a study in a major scientific journal found that there was no connection between autism and the contents of the gut microbiome. They went on to warn that if you see differences in the gut microbiome in autistic kids, those are caused by their diet, so don’t go claiming that the microbiome causes autism. The authors of the newer study, and the reporters at the New York Times, apparently decided otherwise.

So no, the gut microbiome can’t be used to diagnose autism.

A randomized controlled trial of parachutes had a surprising outcome. Anti-vaxxers, take note.

One of my themes in this column over the years has been that you need to be skeptical of many of the claims out there about science and medicine. A healthy dose of skepticism can be a good thing, especially when someone is telling you something that seems surprising.

On the other hand, anti-science forces often pretend that they too are just being skeptical, or “just asking questions,” when what they’re doing is actually science denialism. Denialism is what someone is doing when the science is basically settled, but they refuse to accept it.

Let’s consider perhaps the clearest example of denialism, and the one that causes the most harm to public health: vaccine denialism. The anti-vaccine movement, which has grown alarmingly fast during the Covid-19 pandemic, insists that vaccines don’t save lives, and even more they insist that vaccines cause neurological damage. The latter claim is a favorite of Robert F. Kennedy Jr., as he’s proclaimed in multiple books and articles, and of his VP running mate Nicole Shanahan as well.

The claim that vaccines cause autism was first promoted in a bogus 1998 article in The Lancet by Andrew Wakefield. That article was later shown to be fraudulent, and the journal retracted it, but not before it spawned the modern anti-vaccine movement and made Wakefield one of their heroes. I’ve written many columns on this topic, and others have written far more, but the movement persists.

Scientists and doctors have pointed out, over and over again, that vaccines have saved millions of lives, and are one of the greatest medical advances in the history of civilization. The rapid development of the Covid-19 vaccine was a triumph, and it undoubtedly saved tens of millions more lives.

In defending their denialism, anti-vaxxers frequently ask this question: “where are the randomized controlled trials for vaccines?” They imply that scientists haven’t run such trials because they (the scientists) know that vaccines don’t really work.

That’s nonsense, of course. Scientists have conducted hundreds of studies, involving millions of people, showing how vaccines prevent disease and death.

But we don’t have any randomized controlled trials for childhood vaccines, and we never will, for an obvious reason: it would be deeply unethical. Let me explain.

A randomized control trial (an RCT) works like this: first, you identify a large group of people whom you want to treat, say by giving them vaccines. Then you divide them at random into two groups: the treatment group, who get the vaccine, and the control group, who get nothing. To prevent bias, you might also “blind” the subjects and experimenters so that no one knows who’s getting treated. For example, you could use shots filled with saline solution for the control group, so they think they’re getting a vaccine.

Once you’ve administered the treatment, you follow everyone for some period of time and see who does better. If the treatment group does better, then we say that the treatment worked.

Obviously, we cannot run an RCT for childhood vaccines, because withholding vaccines from children could grievously harm or even kill them. Instead, we can use data collected over time from millions of children, some of them vaccinated and some not, and measure vaccines’ effects from that. It’s not perfect, but these observational data show overwhelming evidence that vaccines for diseases including measles, mumps, rubella, polio, and smallpox are incredibly effective.

Yet anti-vaccine activists continue to call for RCTs, and they pretend that scientists who point out what I just wrote are not to be trusted.

Now to those parachutes in the title of this piece. We know that parachutes work, right? And yet where are the randomized controlled trials? Maybe we shouldn’t use parachutes until some scientists conduct that study? Hmm.

Well, if you’re thinking of skydiving and wondering about this question, you’re in luck! Because a few years ago, a group of scientists at Harvard, UCLA, and the University of Michigan ran an RCT on parachutes! And they published it, too, in the highly regarded British Medical Journal, now called BMJ.

I’m sure you’re curious about how they did this study, and how it turned out. Well, I’m going to tell you.

It was a small study: they approached 92 aircraft passengers and enrolled just 23 people. They randomized them into two groups, with 12 people wearing parachutes and 11 jumping with just an empty backpack.

What happened? Amazingly, there was no difference! Also amazingly, no one died! How could that be?

Well, reading the details of this (ahem) well-executed study, one learns that “randomized participants ... could have been at lower risk of death or major trauma because they jumped from an average altitude of 0.6 m on aircraft moving at an average of 0 km/h.”

In other words, participants did jump from a plane, but they were jumping from less than a meter off the ground and the plane wasn’t moving. A figure from the study illustrates the experiment:

So as you see, this particular RCT of parachute use didn’t prove anything. Even so, the authors note, tongue in cheek, that “Beliefs grounded in biological plausibility and expert opinion have been proven wrong by subsequent rigorous randomized evaluations. The PARACHUTE trial represents one more such historic moment.”

In case you’re wondering how on earth the BMJ would publish a study like this, I can explain that the date of publication was Christmas 2018. The BMJ has a long tradition of publishing satirical but seemingly serious articles on Christmas, and this was a particularly good one.

On the other hand, though, my larger (and serious) point is that the public shouldn’t lose trust in science. Even when science gets things wrong–and it does–it’s still the best toolkit we have for figuring out whether or not something works, or is true. The recently popular cultural trope that truth is malleable, and that each person can choose their own “facts,” is dangerous. When it comes to scientific facts, that’s just wrong.

Parachutes work, and not using them would be exceedingly risky. Vaccines aren’t quite as guaranteed as parachutes, but they come pretty close.