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Autism spectrum disorder (ASD) involves a group of neurodevelopmental conditions characterized by impairments in social interactions and behavior. It is also accompanied by gastrointestinal dysfunction. According to World Health Organization, one child in 160 worldwide has ASD, which tends to persist into adolescence and adulthood.

Beyond genes, environmental factors have been suggested to play a role in the onset of ASD. For example, the gut microbiota differs between children with ASD—especially those with recurrent gastrointestinal problems—and typically developing controls. However, these previous associations do not tell us whether a gut bacteria imbalance is responsible for autism symptoms or is a consequence of having the condition.

A new study, led by Dr. Sarkis K. Mazmanian from the California Institute of Technology (Pasadena, USA), provides the first evidence of gut bacteria’s direct contribution to autism-like behaviors in mice.

In order to explore gut microbiota’s role in autism-like behavior, the researchers transferred gut microorganisms from male children with ASD (mild-ASD and ASD donors) and children without ASD into germ-free wild type mice via fecal transplantation. Mice colonized with the same gut microbiomes were mated and their offspring mice were behavior-tested (6 to 9 weeks of age) and sampled (feces, serum and brains). The mice that inherited the gut microbiome from children with ASD showed autism-like behaviors, including spending less time interacting with other mice, increased repetitive behaviors, and decreased locomotion.

Different gut microbiota profiles in ASD and control donors were maintained in recipient mice and their offspring. Specifically, Bacteroides and Parabacteroides were decreased in the offspring ASD mice, whereas Lachnospiraceae was increased. Besides this, these bacterial taxa showed correlations with repetitive and social behaviors in male mice. These findings support the contribution of specific gut bacteria to autism-like symptoms.

In addition to the observed behavioral differences, the researchers dissected the mouse brains and found that ASD-colonized mice showed differences in the way 52 autism-related genes are processed before being translated into proteins (called alternative splicing) in the brain.

Furthermore, 37 metabolites in the colonic contents and 21 serum metabolites in offspring ASD mice were differentially abundant, compared with offspring colonized from the gut microbiota of children without autism. The content of the mouse gut colonized by the gut microbiome from children with autism had a reduced level of 5-aminovaleric acid (5AV) and taurine metabolites, which are agonists of inhibitory GABA receptors. These results show that taurine and 5AV production in offspring ASD mice is deficient. This concurs with the theory that explains autism as an imbalance between excitatory and inhibitory signals in the brain.

Levels of other metabolites such as 3-aminoisobutyric acid and soy-derived isoflavones genistein and daidzein increased. In contrast, the gut microbiota from offspring controls preferentially metabolized proline, taurine, glutamate and glutamine dietary amino acids.

Sharon and colleagues also found that oral administration of 5AV or taurine to mice that naturally exhibit autism-like behaviors, during the prenatal and weaning periods, increased social interactions and led to less repetitive behaviors, which were accompanied by decreased neural excitability in brain samples. The role of microbial metabolites-based interventions (or ‘post-biotic’ interventions) has been previously shown in another context for ameliorating excessive secondary weight gain.

Based on the link between gut microbiome and autism-like behaviors, in a previous open-label clinical trial, researchers from Arizona State University (USA) observed a significant improvement in gastrointestinal symptoms and autism-related symptoms after administration of a 10-week microbiota transfer therapy that combined oral vancomycin treatment, a bowel cleanse, a stomach-acid suppressant, and a fecal microbiota transplant from healthy donors. Both gastrointestinal and behavioral ASD symptoms remained improved 8 weeks after treatment ended, together with a shift in the gut microbiota to resemble that of the neurotypical control children.

A follow-up study with the same 18 ASD-diagnosed children, two years after treatment was completed, provides evidence that microbiota transfer therapy could be a potentially effective and safe way of improving autism symptoms and related gastrointestinal symptoms. Such improvements were accompanied by an increase in bacterial diversity and relative abundances of Bifidobacteria and Prevotella when compared with the baseline.

Altogether, these findings do not prove that gut bacteria can cause autism, but they do support the direct contribution of the host gut microbiome in shaping repetitive and social behavioral abnormalities related to autism in mice. The administration of specific metabolites was able to improve autism-like behaviors in mice and, together with the benefits of microbiota transfer therapy in improving both autism and gastrointestinal symptoms, suggest that targeting the gut ecosystem might be a potential way of keeping some hallmark features of autism at bay.

References:

Sharon G, Jamie Cruz N, Kang DW, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell. 2019; 177:1600-18. doi: 10.1016/j.cell.2019.05.004.