Autism may have link to chemicals made by gut microbes

Mice with altered intestines were less social and more anxious

Leaky intestines and an abnormal mix of gut microbes may contribute to autism symptoms, a study of mice suggests.

A skewed mixture of intestinal microbes results in high levels of certain chemicals, including one similar to a compound found in the urine of some children with autism, researchers report in the Dec. 19 Cell.  Mice with autism-like behaviors also have leaky intestines, which allow the chemicals to build up in the animals’ blood, the team found.

Giving the mice beneficial bacteria reduced gut leakiness and improved some abnormal behaviors, suggesting that some children with autism might benefit from probiotic treatments.

The study “really connects the dots on some scattered observations about kids with autism spectrum disorders,” says Alessio Fasano, a gut biologist at Massachusetts General Hospital in Boston. While previous studies have also linked changes in intestinal microbes to autism, none has offered a plausible mechanism for how gut bacteria might contribute to the disorder, he says. The new work may explain a possible cause of autism in a fraction of children, Fasano says. But, he cautions, “this is not going to be the solution for everybody.”

Many people believe that children with autism are prone to digestive problems, but that connection has been hotly debated. This study is likely to provoke more controversy, says Caltech microbiologist Sarkis Mazmanian, who teamed up with Caltech neuroscientist Paul Patterson to lead the work.

The researchers knew that pregnant women who develop severe infections have a greater-than-normal risk of having children with autism. So Patterson, Mazmanian and colleagues stimulated the immune systems of pregnant mice to mimic severe infections. Those mice had offspring with characteristics of autism, such as problems socializing, including a tendency to squeak less when hanging out with other mice. They were also more anxious, startled more readily at noises and repeated behaviors such as burying a marble again and again.

Mice born to immune-stimulated moms also had leaky intestines, the researchers found. These mice had an altered mix of gut microbes, carrying more bacteria called Lachnospiraceae and related microbes than normally behaving mice did.

The autistic-like mice had high levels of some bacterially produced chemicals in their blood. One of those chemicals, called 4-ethylphenylsulfate, was 46 times as abundant in the mice with autism symptoms as in normal mice. Injecting the chemical into the blood of normal mice led to anxious behavior. Previous studies had found a similar molecule, known as p-cresol or 4-methylphenol, in high levels in the urine of some children with autism.

When the researchers gave a helpful bacterium called Bacteroides fragilis to autistic-like mice, many of their symptoms improved, although the mice were still less social than normal mice. The bacterial treatment also helped seal the mice’s leaky guts and reduced blood levels of the autism-linked chemicals.

Though the study is “fascinating and important,” says microbiologist Brent Williams of Columbia University, much more research is needed to establish whether people with autism have similar microbe-related problems.

Mazmanian echoes Williams’ concerns. “We know the limitations of our study,” he says. “At best we’re looking at what may be applicable to a subset of children.” 

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