Gut Microbe Links to Autism Revealed

31 May 2019. Lab mice with bacteria transplanted from human intestines show signs that autism behaviors may result from the state of their gut microbes. Findings of a team from California Institute of Technology in Pasadena and other institutions are reported in yesterday’s issue of the journal Cell.

Researchers from the microbiology lab of Sarkis Mazmanian at Cal Tech are seeking evidence that autism spectrum disorder could be caused in part by gut bacteria. Mazmanian’s lab studies connections between microbes in the gut and a range of human diseases including neurological disorders. He is also the founder of the 3-year old biotechnology company Axial Biotherapeutics in Waltham, Massachusetts that licenses the lab’s research on pathways from the gut to the brain to develop treatments for neurological conditions.

Autism spectrum disorder is a collection of neurodevelopmental conditions marked by communication difficulties and impaired social interaction, as well as repetitive and stereotyped patterns of behavior. Some 1 in 59 children in the U.S. have autism spectrum disorder, or ASD, according to Centers for Disease Control and Prevention, with males 4 times more likely to have the disorder than females. Classic autism is considered the most severe form of the syndrome.

“In recent years, numerous studies have revealed differences in the bacterial composition of the gut microbiome between individuals with ASD and neurotypical subjects,” says Mazmanian in a Cal Tech statement. “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.”

To find more definitive links, the researchers transplanted gut microbes from children with autism spectrum disorder into lab mice grown in an environment free of microorganisms. For comparison, similar germ-free mice were transplanted with microbes from children who exhibit more typical neurological development. Results show mice with gut microbes from children on the autism spectrum displayed more autism-like behaviors — less social interaction and vocalization, for example — than mice transplanted with bacteria from children with typical development.

The team found other differences in the two groups of mice. Mice with gut microbes from autism spectrum children exhibited genes in brain cells are more likely to express spliced or multiple proteins, particularly those related to autism spectrum disorder. In addition, mice with bacteria from autism spectrum children show lower levels of certain metabolites, digestive chemical byproducts, 5-aminopentanoic acid and taurine, an amino acid found in the brain and other parts of the body.

These two metabolites are also associated with proteins in the brain called gamma-aminobutyric acid or GABA A receptors that regulate brain activity. The researchers guessed that lower levels of 5-aminopentanoic acid and taurine may be linked to autism spectrum disorder, and tested this hunch in another strain of lab mice that naturally express autism-like behaviors. The team gave this new set of mice doses of the two metabolites and found the test mice exhibited fewer autism-like behaviors. Post-morten brain examinations confirmed less neural excitability among mice given 5-aminopentanoic acid.

Mazmanian cautions that “There are many factors that make autism more complicated in humans than in mice,” adding, “we can model the symptoms of the disorder but not reproduce it.” He notes that the study “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.”

Axial Biotherapeutics was founded in 2016 to discover treatments for neurological disorders through pathways originating in the gut. As reported by Science & Enterprise in June 2018, Axial and and the Parkinson’s Institute and Clinical Center in Sunnyvale, California started a joint project to find treatments for Parkinson’s disease targeting bacteria in the gut.

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