Gut microbes from autistic children can alter behavior in mice. Mice colonized with gut microbes from some autistic children have been observed to display child-like behavior. The results provide the first evidence that gut microbes may contribute to autism symptoms.
Experts found evidence that microbes from autistic children produce unusually low levels of two small molecules. Delivering these molecules to a mouse model facilitates some of the mice's autism-like traits.
The results are based on stool samples from only 11 children with autism and 5 controls. But if confirmed, they could lead to a better understanding of the brain-gut connection in autism.
Sarkis Mazmanian, the lead researcher, says this opens the possibility that changes in the microbiome may contribute to symptoms. Therefore, if this correlation is confirmed, it opens up the potential for interventions.
It's been established that approximately 40% of children with autism have digestive problems, increasing the likelihood of developing an altered gut microbiome. A 2017 pilot study found that fecal transplants from neurotypical individuals alleviated gut problems and social difficulties in some autistic children, suggesting that microbes could help treat this disorder.
The new findings are consistent with studies showing that germ-free mice that received fecal transplants from people with depression, Parkinson's disease, or schizophrenia adopted the behavioral characteristics of their donors.
In the study, the researchers isolated microbes from the feces of five controls, three children with mild autism and eight with more severe traits. They transplanted each set of microbes into male and female “germ-free” mice, which lack a microbiome, when the mice were about 4 weeks old. Three weeks later, the researchers bred pairs of mice that had received transplants from the same child. They designed the study this way so they could analyze the effects of the microbial transplants on brain development and behavior. (Mouse pups typically inherit their gut microbes from their mothers.)
At 6 weeks of age, pups whose mothers received microbes from a child with mild autism traits behaved the same as those with microbes from controls. But mice whose mothers received microbes from a child with severe autism spent less time socializing, made fewer vocalizations, and displayed more repetitive behaviors than controls. The effect was more pronounced in male pups than in females.
The brains of offspring with microbes from autistic donors also show an unusual increase in genes involved in "alternative splicing," the process by which a cell generates different proteins from the same gene. They also show alternative splicing of 560 genes, including 11 with strong links to autism.
Mice with transplants from children with severe autism have less microbial diversity than those with transplants from controls, and tend to have unusual proportions of certain bacteria. These mice also have unusual levels of 27 small molecules in their guts. Two of these molecules are taurine and 5-aminovaleric acid, which activate receptors for the chemical messenger gamma-aminobutyric acid (GABA). Low levels of GABA are implicated in autism.
The team found that offspring treated with these molecules were more sociable and exhibited less repetitive behavior than controls. The treatments had a similar effect on social behavior, but not on repetitive behavior, in offspring with microbes from an autistic child.
Mazmanian's team is exploring which receptors mediate the effects of the two molecules in the brain. They are also testing other small molecules and microbes as treatments in mice.
References:
Sharon G. et al. Cell 177, 1-19 (2019) Abstract