Scientists have long been searching for the causes of autism spectrum disorder (ASD), and the number of diagnoses has risen dramatically in the past decade (although comparisons are difficult to make since diagnostic criteria have changed during that time). As of 2018, around one in 59 eight-year-old kids are affected by the neurodevelopmental disorder, which is a complex disease. It impacts different people in different ways. ASD can impair social communication and interaction, cause repetitive behaviors, and delays or difficulties with speaking. A complicated interplay of genetic and environmental factors is thought to underlie ASD.
Researchers at Caltech have now used a mouse model of autism to learn more about how the gut microbiome is related to the disorder. The vast community of microorganisms that we carry in our gut has been shown to be closely connected to our health and well-being, and can even affect the brain. Previous work by other researchers has connected autism to the gut microbiome. Reporting in Cell, the Caltech scientists have found that the microbes in the gut can encourage the symptoms of ASD, but it’s still not clear whether they are causative.
"In recent years, numerous studies have revealed differences in the bacterial composition of the gut microbiome between individuals with ASD and neurotypical subjects," said study leader Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute (HMRI) Investigator. "However, while this previous research identifies potentially important associations, it is unable to resolve whether observed microbiome changes are a consequence of having ASD or if they contribute to symptoms."
"Our study shows that the gut microbiota is sufficient to promote autism-like behaviors in mice. However, these findings do not indicate that the gut microbes cause autism," noted the study’s first author and postdoctoral researcher Gil Sharon. "Additional studies are needed to address the impact of gut bacteria in humans."
Germ-free mice lack microbes and have been used to learn more about the physiological impact of different strains of gut bacteria. In this study, the researchers transferred gut microbes harvested from kids with ASD, or healthy individuals, into germ-free mice. Mice colonized with gut microbes derived from ASD individuals became less social, less vocal, and displayed repetitive behaviors, which are autism-like symptoms. The gene expression in the brains of these mice and the metabolites they produced also changed. There were two specific metabolites, 5-aminovaleric acid (5AV) and taurine, which can both inhibit GABA receptors, that were lower in the ASD-gut microbe-carrying mice.
"We were surprised to see how profound the effects were," said Sharon.
In additional work, the scientists turned to a mouse called BTBR that naturally shows autism-like characteristics. When these mice were treated with 5AV or taurine, their autism-like tendencies were decreased. An assessment of these mouse brains indicated that 5AV was decreasing neural excitability.
"There are many factors that make autism more complicated in humans than in mice. In mice, we can model the symptoms of the disorder but not reproduce it," said Mazmanian. "However, this research provides clues into the role that the gut microbiota plays in neural changes that are associated with ASD. It suggests that ASD symptoms may one day be remedied with bacterial metabolites or a probiotic drug. Further, it opens the possibility that ASD, and perhaps other classical neurologic conditions, may be treated by therapies that target the gut rather than the brain, a seemingly more tractable approach."