Autism is a complex disease, and no one knows what triggers it. With diagnosis rates climbing every year, scientists are scrambling to understand the disorder. One mystery is why many children on the autism spectrum also have gastrointestinal ailments. Recent research shows not only that autism is associated with distress in the gut, but that there might be a causal link between the two.
Microbiologist Elaine Hsiao’s research focuses on unraveling a new mystery: How might single-celled denizens of the gastrointestinal tract affect whether the brain goes awry in autism? Her team sets off the immune system in pregnant mice, which causes autism-like symptoms in their offspring. These “autistic” mice are anxious, anti-social and obsessed with repetitive behaviors, three classic symptoms of autism.
Like many autistic children, autistic mice also have a leaky gut lining. Hsiao theorizes that certain waste products diffuse out of the gut, get into the bloodstream, and affect the brain—leading to the abnormal behaviors. When her team treated those mice with a probiotic containing the bacterium Bacteroides fragilis, some—but not all—of the symptoms disappeared.
Hsiao’s latest results made a splash in the media—and they might lead to promising new treatments for autism. The 28-year-old senior research fellow at the California Institute of Technology landed on the influential “30-under-30” list in Forbes in 2013. But Hsiao remains modest and says there is much more work to be done. In her talk at the 2014 meeting of the American Association for the Advancement of Science in Chicago, she stressed that the microbiome is only one piece of the puzzle in the quest to understand and cure autism. Afterward, she sat with SciCom’s Cynthia McKelvey to discuss guts, bugs, and brains.
Is it really true that there are more bacteria in the gut than human cells in the entire body?
That's the cliché: We're made up of ten times more microbes than our own eukaryotic cells. The gut is the richest source of microbes, but there’s also the skin microbiome, oral microbiome, and all different exposed surfaces are colonized by microbes.
What drew you to this field of research?
I started in Paul Patterson's lab [at Caltech] because I was interested in immune contributions to neurodevelopmental disorders. We stumbled upon the microbiome as a way to modulate immunity.
How did you stumble onto that?
We were looking at immune changes in these mice. With evidence that we could correct some behavioral problems through affecting the immune system, we identified certain microbes that we could use to affect the immune system and hopefully affect behavior.
How was the autistic disease model for mice discovered?
That stems from work by Paul Patterson. Older studies showed that infecting a pregnant mouse with influenza could increase the risk that her offspring would show schizophrenia-like symptoms. We came to understand that it wasn't a particular pathogen that was responsible. At the same time, there were data accumulating showing that maternal infection was a risk factor in autism. So we developed a mouse model to see if it has the autism-like symptoms, and it does.
"People shouldn't always jump to the gut. There are a lot of neurological problems in autism as well."
How do you explain the interplay between gut bacteria and brain dysfunction?
Scientists have known that there’s a relationship between the gut and the brain for a long time. But recently this has expanded to include gut bacteria. There are a lot of different ways that bacteria could affect brain function. One way is by affecting the immune system, and then the immune system interacts with the brain. Another is by affecting nerves that extend directly from the gut to the brain. And then lastly, my research: The waste products from the bacteria themselves can affect the brain or behavior as well.
How do those metabolites affect behavior? Do they enter the brain?
We don't yet know if they actually enter the brain. We know that they're elevated or altered in the blood of autistic mice. But do they enter the brain? And if they do, what exactly are they doing there? If they don't enter the brain, where is the interaction? What is it doing that's affecting neural function?
How would you test for that?
We could start by seeing if certain metabolites are elevated in the brain as well, or if they’re only elevated in the blood. Even if we don't see a difference, the bigger experiment would be to track the metabolites by labeling them with a fluorescent tag and seeing if they actually enter the brain.
Do you think the gut microbiome might be related to what other researchers have discovered about autism?
It could be, but people shouldn't always jump to the gut. There are a lot of neurological problems in autism as well. It’s just exciting that microbes can have an effect on the brain, too. That's not to say that all autism is caused by microbial imbalances or can be cured with probiotics. But maybe to a certain subset of patients, the gut microbiome would be relevant.
What would you say to parents who might see your research as a beacon of hope for a cure?
All the work that we've done with the probiotic therapy is in mice. We haven't translated our findings to humans yet. We’re starting up some clinical trials to test our theory in humans. But we need to conduct several studies conducted before proceeding, including experiments addressing safety and toxicity.
For parents with a child who does have gastrointestinal problems and autism, I would urge them to consult their clinicians. Then they can see whether treating some of the G.I. problems can also improve the behavior of their children. Some parents have asked me about certain probiotics that are available on the market, too. Right now there's just not strong scientific evidence that probiotics help children with autism.
Is the bacteria you found to affect autistic behavior in mice, B. fragilis, available in a probiotic?
B. fragilis is not available right now.
Will it become available soon?
Maybe further down the line, after clinical testing, it could be available over the counter.
Fecal transplants help correct some G.I. issues. Will you be trying that therapy with the autistic mice?
We're interested in doing that. We're also interested in doing the opposite experiment: taking the gut bacteria from an autistic mouse and putting it into normal mice to see if we can cause any of the symptoms of autism.
What other bacteria might you look into in the future?
We haven't been focusing on specific microbes. We've been taking the opposite approach: looking at particular functions related to the nervous system, and then backtracking to try to see which bacteria play a role in brain function.
But you did center on B. fragilis, so how did you get to that?
That was just by luck of the draw. We were looking at immunity and at the same time, all of these reports that B. fragilis affects immunity.
Might dietary “cleanses” affect the natural human microbiome?
Research suggests that dietary changes can lead to persistent changes in the microbiota. Exactly how it will change is not yet understood.
What about antibiotics?
There is some evidence of antibiotic effects on autism-related symptoms, ranging from dramatically beneficial to no impact at all.
Is there any connection between pregnant women getting flu shots and the vaccine controversy around autism?
Maternal immune activation is a risk factor for autism. That's not to say that anyone who gets pregnant and has any infection is definitely going to have an autistic child. It's important to realize that it's a risk factor that, combined with a lot of other conditions—like genetic susceptibility or environmental exposures—could produce an autistic child. Getting a flu shot does cause a slight immune activation, but there's no evidence that a flu shot while pregnant will cause the child to have autism. Do you want to get the flu and risk a huge immune activation? Or do you just want to get your small flu shot and prevent that? We definitely recommend pregnant women get their flu shots.
What do you hope to do in the future?
I now have my own laboratory. We're studying the idea that commensal microbes [harmless gut bacteria] can modulate neurotransmitters and neuropeptides [molecules that brain cells use to communicate with one another]. We're interested in defining the mechanisms required for this effect. We're also interested in identifying the specific microbes or communities that are responsible for each neurological function. Lastly, we'd be interested in seeing if we can apply these findings to disease models.
Will you continue to work with autism, or are you going to branch out to other diseases?
Autism is definitely an interest, but I'm not confined to it. We're looking at a general bottom-up approach: how microbes can affect neurotransmitters and neuropeptides. Whatever diseases are related to that effect are of interest to my lab.
Lastly, how does it feel to be one of the “30 under 30” in Forbes?
It feels really exciting! But there's a lot to come. I'm really glad to be recognized for what has been done, but I really hope to do a lot more.
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© 2014 Cynthia McKelvey
Cynthia's online community of stories lives here: cynthiamckelvey.com
