New animal research offers insights into the effects of the microbiome on social deficits in ASD

A new study provides additional clues about the role the gut microbiome may play in autism spectrum disorders (ASD).

In earlier research (see ARRI 2019, Volume 1), Mauro Costa-Mattioli and colleagues found that in several different mouse models of ASD, administering a specific strain of gut microbes called Lactobacillus reuteri ameliorated social deficits. The researchers found that the microbe reversed social deficits in all models tested—whether the autism was environmentally caused, genetically caused, or idiopathic (meaning that the cause was unknown).

The researchers also found that the effects of L. reuteri did not result from changes to the composition of the gut microbiome, which was altered in all of the models tested. Instead, they discovered that L. reuteri promotes social behavior via the vagus nerve, a nerve that bidirectionally connects the gut and the brain and the oxytocin-dopamine reward system. When this nerve was severed or when the researchers blocked oxytocin uptake, L. reuteri could no longer restore social behavior in ASD model mice.

In the new study, the researchers (including first author Shelly Buffington) worked with mice lacking a gene called Cntnap2, which is loosely associated with autism. The mice had abnormal microbiomes and exhibited hyperactivity and autistic-like deficits. However, the researchers found that when they housed regular mice and Cntnap2 knockout mice together after weaning, the gut microbiomes and social behaviors of the knockout mice normalized (although the mice remained hyperactive). Once again, the researchers found that L. reuteri alone was sufficient to restore normal social behavior in the knockout mice.

The researchers also discovered that tetrahydrobiopterin, which is used in the biosynthesis of dopamine, was deficient in isolated knockout mice but was restored by L. reuteri. Administration of tetrahydrobiopterin alone proved to be sufficient to re-store social behavior in the knockout mice. Finally, the researchers found evidence\ that both L. reuteri and tetrahydrobiopterin improve social reward-mediated synaptic transmission in these mice.

The researchers conclude, “[G]iven the current brain-centric view of genetic neurological disorders, we believe that our results widen our understanding of how a genetic mutation leads to behavioral abnormalities. In addition, they suggest that both brain and gut microbiota may need to be targeted to fully and effectively reverse the core symptoms associated with some neurological disorders.”

Buffington adds, “Our work strengthens an emerging concept of a new frontier for the development of safe and effective therapeutics that target the gut microbiome with selective probiotic strains of bacteria or bacteria-inspired pharmaceuticals.” Costa-Mattioli notes that L. reuteri is already being tested in Italy as a treatment for children with autism, and he plans to conduct a trial himself.

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“Dissecting the contribution of host genetics and the microbiome in complex behaviors,” Shelly A. Buffington, Sean W. Dooling, Martina Sgritta, Cecilia Noecker, Oscar D. Murillo, Daniel F. Felice, Peter J. Turnbaugh, and Mauro Costa-Mattioli, Cell Press, Volume 184, Issue 7, P1740-P1756, April 1, 2021. Address: Mauro Costa-Mattioli, Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, costamat@bcm.edu.

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“Microbes may hold the key for treating neurological disorders,” news release, Baylor College of Medicine, March 10, 2021.

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“Bugs R Us: Restoring sociability with microbiota in autism,” Camilla Bellone and Christian Lüscher, Cell Press, April 20, 2021 (free online). Address: Camilla Bellone, camilla.bellone@unige.ch.

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“Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder,” Martina Sgritta, Sean W. Dooling, Shelly A. Buffington, Eric N. Momin, Michael B. Francis, Robert A. Britton, and Mauro Costa-Mattioli, Cell, December 3, 2018 (online). Address: Mauro Costa-Mattioli, costa-mat@bcm.edu.

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“The power of the microbiome: A microbe-based treatment reverses social deficits in mouse models of autism,” From the Labs, Baylor College of Medicine, December 13, 2018.

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“Can autism be treated with a simple microbial-based therapy?”, ScienceBlog.com, December 21, 2018.

This article originally appeared in Autism Research Review International, Vol. 35, No. 2, 2021