Summary: Researchers transplanted fecal microbiota from children with autism spectrum disorder (ASD) and from neurotypical children into germ-free mice. Mice colonized with microbiota from the ASD group developed behaviors resembling core features of autism, while mice receiving microbiota from typically developing donors did not. The ASD-colonized mice also showed altered brain gene expression and changed metabolite profiles, including reduced levels of 5-aminovaleric acid (5AV) and taurine. These findings support a role for gut microbes and their neuroactive metabolites in modulating behavior and strengthen evidence for a gut–brain axis connection in ASD pathology.
Source: CalTech
Autism spectrum disorder (ASD) affects about one in 59 people in the United States and causes challenges in social communication and repetitive behaviors. The condition arises from a complex mix of genetic and environmental influences, and currently there are no approved cures. New experiments in mice by Caltech researchers show that the gut microbiota can directly influence autism-like behaviors, pointing to microbial metabolites as important regulators of brain function and behavior.
The study was led by the laboratory of Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute Investigator. The peer-reviewed report was published in the journal Cell on May 30. “Prior studies have documented differences in gut bacterial composition between individuals with ASD and neurotypical controls,” Mazmanian explains. “But those observational studies could not determine whether microbiome changes are a consequence of ASD or whether they contribute to behavioral symptoms.”
“Our results demonstrate that the gut microbiota alone is sufficient to promote autism-like behaviors in mice,” says Gil Sharon, senior postdoctoral scholar in the Mazmanian lab and the study’s first author. “This does not mean that gut microbes cause autism in humans, but it does indicate a causal role for microbial communities in shaping behavior in this experimental model. More research is required to clarify the relevance to human ASD.”
The human gut is home to a diverse community of microorganisms—the microbiota—whose combined genetic material forms the microbiome. These microbes help digest food, modulate metabolism, and shape immune development while living in a symbiotic relationship with the host.
To test whether human gut microbiota could influence behavior, the team used germ-free mice, which are raised without any microbes. Researchers transplanted fecal microbiota from children diagnosed with ASD into one group of germ-free mice and microbiota from typically developing (TD) children into another group. After colonization, the mice were evaluated for social and repetitive behaviors, vocalization, brain gene expression, and metabolic changes in tissues and circulation.
Mice that received ASD-derived microbiota exhibited measurable autism-like behaviors: they spent less time interacting socially with other mice, produced fewer social vocalizations, and showed increased repetitive behaviors. By contrast, mice colonized with microbiota from TD donors did not display these behavioral changes. These behavioral outcomes mirror core diagnostic features of ASD in humans and demonstrate that microbial communities can influence social and repetitive behaviors in mice.
Beyond behavior, the researchers found differences in brain gene expression and in the animals’ metabolomes. Several metabolites produced or influenced by gut bacteria differed between groups. Notably, the ASD-microbiota mice had lower levels of 5-aminovaleric acid (5AV) and taurine—two metabolites that interact with GABAergic signaling, the brain’s primary inhibitory system. Because ASD has been linked to imbalance between neural excitation and inhibition, the reduction of inhibitory-modulating metabolites suggested a mechanism by which gut microbes could affect neural circuits.
“We were surprised to see how profound the effects were,” says Sharon.
To test whether restoring candidate metabolites could rescue behavioral deficits, the team treated an independent ASD mouse model (BTBR mice, which naturally display autism-like traits) with 5AV or taurine. Treated BTBR mice showed improved social behavior and reduced repetitive actions. Electrophysiological studies further showed that 5AV reduced neuronal excitability, supporting the idea that microbial metabolites can modulate neural activity and behavior.
“Mouse models capture specific features of ASD but cannot reproduce the full complexity of the human disorder,” Mazmanian notes. “Still, these results highlight the gut microbiota as a modifiable factor that can influence neural circuits associated with social and repetitive behaviors. They point toward new therapeutic possibilities—such as targeted metabolites or microbiome-based interventions—that act on the gut to impact the brain.”
Contributing Caltech authors include Gil Sharon, Nikki Jamie Cruz, Bo Wang, Michael Sweredoski, Annie Moradian, Carlos Lois, and Sarkis Mazmanian. Additional collaborators are from the University of Toledo, UCLA, Pacific Northwest National Laboratory, UC San Diego, USC, the University of Washington, Tel Aviv University, the Santa Fe Institute, and Arizona State University.
Funding: The research was supported by multiple sources including Pacific Northwest National Laboratory, Autism Speaks Meixner Postdoctoral Fellowship in Translation Research, Human Frontiers Science Program, SFARI Bridge to Independence Award, San Diego Diversity Fellowship, National Biomedical Computation Resource, the National Institutes of Health, the Autism Research Institute, the Emch Foundation, the Brenen Hornstein Autism Research and Education Foundation, private donors, the Simons Foundation, and the Heritage Medical Research Institute.
Source:
CalTech
Media Contacts:
Lori Dajose – CalTech
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The image is credited to Caltech.
Original Research: Open access. Title: “Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice.” Sarkis Mazmanian et al., Cell. DOI: 10.1016/j.cell.2019.05.004
Abstract
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Highlights
• Mice colonized with human ASD microbiomes display ASD-like behaviors while those colonized with TD microbiomes do not.
• ASD and TD microbiota drive distinct metabolome profiles in recipient mice.
• Brains of mice harboring ASD microbiota show altered alternative splicing of ASD-relevant genes.
• Administration of 5-aminovaleric acid (5AV) or taurine to an ASD mouse model improved social and repetitive behaviors.
Summary
Autism spectrum disorder involves changes in social communication and stereotyped behaviors. Alongside genetic risk factors, the gut microbiome differs between individuals with ASD and neurotypical controls. By transplanting human gut microbiota into germ-free mice, researchers show that ASD-derived microbiomes are sufficient to induce hallmark autistic behaviors and to alter brain gene expression. Microbiome and metabolome analyses identify candidate bacterial taxa and neuroactive metabolites—particularly 5AV and taurine—that can modulate neuronal excitability and behavior. Treatment of an ASD mouse model with these metabolites reduced behavioral abnormalities, supporting a model in which gut microbes regulate behavior through production of neuroactive compounds and highlighting gut–brain connections in ASD pathophysiology.