How the Gut Microbiome Could Provide a New Tool to Treat Autism about:reader?url=https://www.smithsonianmag.com/science-nature/how-...

smithsonianmag.com

How the Gut Microbiome Could

Provide a New Tool to Treat Autism
Bob Roehr
9-11 minutes

At a young age, Ethan was diagnosed with moderate to severe

autism. By age seven, despite heroic efforts by family and
rehabilitation specialists, his vocabulary, diet and social interactions
were all extremely limited. He wasn't even potty trained.

Then one morning, just four weeks into a special clinical trial,
Ethan’s mother Dana awoke to him with a big smile on his face
saying, “Good morning mom.” The transformation was miraculous,
a side of her son she had never seen before, and she burst into
tears of joy.

It was a miracle of poop. Not quite the raw stuff out of the toilet but
rather processed gut microbial organisms from a highly screened
donor, which Ethan had been taking mixed in with his drinks as part
of the trial.

"There is a very high correlation between [gastrointestinal] severity

and autism severity—for language, for social interaction, for
behavior, all of the core symptoms of autism,” says Jim Adams, a
professor and autism researcher at Arizona State University. He
had seen the connection fist hand when his daughter was
diagnosed with ASD. “The question is, is this because of the pain

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and discomfort of the GI problems, or is it more than that?”

When Adams dug into the scientific literature, he found that

dysbiosis, or a disruption of the normal ecosystem of bacteria and
other organisms in the gut, can influence both ASD and GI
symptoms. Treatment with vancomycin, a powerful antibiotic that is
not absorbed in the bloodstream but stays in the gut, could bring
temporary relief. But an antibiotic can only be used for a short
period of time before bacteria begin to develop resistance to it.

More than a decade ago, a theory began to emerge of a gut-brain

connection, where a dysfunction in the gut could also affect brain
activity. “Seventy percent of our nerves that go into the central
nervous system go into our gut. Why is that?” asks Sarkis
Mazmanian, a medical researcher at the California Institute of
Technology. Mazmanian noted that in germ-free mice, with no
bacteria in their gut, “things like anxiety, locomotion, depression and
even brain development seem to be altered” compared with normal
animals.

Mazmanian and a team of researchers demonstrated this gut-brain

connection in a mouse model of autism in 2013. Three years later,
the team did the same for Parkinson's disease. And recently they
showed that transplanting feces from a person with autism into
germ-free mice would produce many symptoms of ASD in the
animals.

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After transplanting microbiome samples from people with ASD into germ-
free mice, the mice showed behavioral symptoms of autism. After further
microbiome treatment, the mice exhibited increased sociability. (Gil Sharon
et al. / Cell 2019.05.004)

A healthy gut ecosystem contains about a thousand different types

of bacteria, as well as archaea, fungi and viruses, though the
specific organisms and their numbers can vary from person to
person. In contrast, the variety of bacteria found in people with ASD
is about 25 percent lower than in healthy people. Their guts are
missing hundreds of different species of bacteria, often ones that
are important to fermentation and producing short chain fatty acids
that influence health.

Adams looked to pull together all the threads of these different lines
of research by conducting a study on the efficacy of fecal
transplants in kids with ASD. His team at ASU, the
Autism/Asperger’s Research Program, recruited an expert at
identifying bacteria in the gut, Rosa Krajmalnik-Brown, better

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known as Dr. Rosy. Little was known about fecal transplants in

children at the time the study was proposed, so the FDA first
required a small, preliminary safety study, limited to kids age seven
or older.

The study enrolled 18 children, ages 7 to 18, with a diagnosis of

ASD and significant GI problems. The regimen was exacting but
relatively kid friendly. First the antibiotic vancomycin was used to
knock down the number of microbes in their guts. Then the kids
received daily doses of purified microbes from the guts of healthy
donors, which were suspended in a liquid and mixed in with drinks,
along with an antacid to reduce stomach acids that can destroy the
microbes before they reach the intestines. The gut treatment
continued for ten weeks.

The ASU researchers didn't see much of a response at first. It is

likely that the initial dysbiosis had damaged some of the cells lining
the gut, as occurs in patients with irritable bowel syndrome (IBS),
and it took some time for those wounds to repair enough to support
colonization by the donor bacteria. But halfway through the
regimen, most participants showed increasing signs of
improvement.

Just two participants showed minimal response, about a 30 percent

improvement in their GI symptoms, and that didn't last for long after
the treatment was completed. But 16 kids had at least a 70 percent
improvement in their GI symptoms, and importantly, they showed
improvements in their behavioral symptoms of autism. That paper
was published in January 2017 and so impressed the Pentagon
that the Department of Defense agreed to fund a large study of
microbial transplants in adults with autism, which began enrolling
patients in early 2018.

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Adams was surprised to hear parents say that their kids continued
to show improvement in ASD-related behavior long after the study
was completed. The team decided to do a two-year follow-up to see
what was going on.

An independent professional evaluator using the Childhood Autism

Rating Scale (CARS) found that symptoms were 23 percent less
severe at the end of treatment than at the start; two years later that
had improved to 47 percent. Initially 83 percent of participants had
been rated on the severe end of the ASD scale, but after the two-
year follow up, that number had dropped to 17 percent, while 44
percent had improved to the point that they fell below the ASD
diagnostic cutoff.

Measurements using the parent-rated Social Responsiveness

Scale (SRS) assessment showed parallel improvements, according
to the follow-up paper published in April of this year. The gut
microbiome, it seems, could provide a new tool to treating ASD.

After the follow-up, participants still showed healthy microbiome

diversity, but the bacteria populations in their guts had shifted away
from resembling the donor to become more personalized. The
changes reflected the diets, environmental exposures, immune
systems and genetics unique to each individual.

“The analogy is when you have a company that has a great working
environment, good people want to come and work for that
company,” Krajmalnik-Brown says. “In the gut, if you have a good
environment then you have good microbes, and other good
microbes want to come and be there too.”

The team does not claim that all the improvements spring from the
gut bacteria treatment, however. While Adams believes that

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reestablishing a healthy gut microbiome benefits the gut-brain axis

that has gone askew in ASD, he also thinks that simply removing
the pain and distraction of a dysbiotic gut can help kids
concentrate, focus, and benefit from speech, behavioral and other
therapies offered by state and social services organizations.

“Unfortunately these GI symptoms generally have been ignored,

even when parents of children with autism have reported their
child's behavior improves when they treat those symptoms,” says
Paul Ashwood, a microbiologist studying ASD at the University of
California Davis. He acknowledges the limitations of Adams and
Krajmalnik-Brown’s study, such as small sample size and the
influence of outside factors, but says “the data is very interesting
and should be followed up.”

As with any new approach to treating a medical condition, initial

success raises more questions than it answers. Will the approach
benefit a broader group of ASD patients, including those who do
not suffer significant GI distress? Is vancomycin needed to knock
down the existing microbial ecosystem prior to an influx of healthy
gut bacteria? What is the best duration of the treatment? It will take
time and multiple studies to answer these questions, but Adams is
optimistic that a licensed microbial treatment for ASD will become
available in a few years.

In the meantime, the ASU team is preparing another trial for

children. Their collaborators have developed a pill form of the
microbial transplant that they believe will bypass the issue of
stomach acid and deliver a more consistent product to the gut. The
pill is already being used in other studies, and Adams believes the
change will deliver more consistent results than their first trial.

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For her part, Dana is delighted by the “fantastic progress” that

Ethan, now 12, continues to make. He has met all the goals set by
speech and occupational therapists and continues to work on social
and life skills, such as learning how to understand his own
emotions and those of others and articulating what he feels. If
medical researchers like the ASU team can continue to make
progress developing a microbiome treatment for ASD, many more
kids could benefit from the multifold value of a healthy gut.

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