Dr. Mauro Costa-Mattioli, professor and Cullen Foundation Endowed Chair in neuroscience and director of the Memory and Brain Research Center at Baylor College of Medicine, Texas, discovered with his team that different abnormal behaviours are interdependently regulated by the host's genes and microbiome.
The findings, published in the journal Cell, reveal that in mouse models with neurodevelopmental disorders, hyperactivity is controlled by the host's genetics, whereas social behaviour deficits are mediated by the gut microbiome.
What's more, they found that treatment with a specific microbe that promotes the production of compounds in the biopterin family in the gut or treatment with a metabolically active biopterin molecule improved the social behaviour, but not motor activity.
Costa-Mattioli says: "In my wildest dreams, I could have never imagined that microbes in the gut could modulate behavior and brain function. To think now that microbial-based strategies may be a viable way to treat neurological dysfunction, is still wild, but very exciting."
The work by Costa-Mattioli's group offers a different way of thinking about neurological disorders in which both human and microbial genes interact with each other and contribute to the condition.
Co-first author Dr. Shelly Buffington, a former postdoctoral fellow in the Costa-Mattioli lab and now an assistant professor at the University of Texas Medical Branch, says: "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."
Their findings also suggest that effective treatments would likely need to be directed at both the brain and the gut to fully address all symptoms. Additionally, they open the possibility that other complex conditions, such as cancer, diabetes, viral infection or other neurological disorders may have a microbiome component.
"It's very difficult to study these complex interactions in humans, so in this study, we worked with a mouse model for neurodevelopmental disorders in which the animals lacked both copies of the Cntnap2 gene (Cntnap2-/- mice)," said co-first author Sean Dooling, a Ph.D. candidate in molecular and human genetics in the Costa-Mattioli lab. "These mice presented with social deficits and hyperactivity, similar to those observed in autism spectrum disorders (ASD). In addition, these mice, like many people with ASD, also had changes in the bacteria that make up their microbiome compared to the mice without the genetic change."
Further experiments showed that modulating the gut microbiome improved the social behaviour in the mutant mice, but did not alter their hyperactivity, indicating that the changes in the microbiome selectively contribute to the animals' social behaviour.
"We were able to separate the contribution of the microbiome and that of the animal's genetic mutation on the behavioral changes," Dooling said. "This shows that the gut microbiome shouldn't be ignored as an important variable in studying health and disease."
The researchers dug deeper into the mechanism underlying the microbiome's effect on the animal's social deficits. Based on their previous work, the investigators treated the mice with the probiotic microbe, L. reuteri.
"We found that L. reuteri also can restore normal social behavior but cannot correct the hyperactivity in Cntnap2-/- mice," said Buffington
What's more, the investigators found that when they administered a metabolite or compound that's increased in the host's gut by L. reuteri, that the animals' social deficits were improved.
"This provides us with at least two possible ways to modulate the brain from the gut, with the bacteria or the bacteria-induced metabolite," said Buffington.
Buffington. S. A., et al
"Dissecting the contribution of host genetics and the microbiome in complex behaviors"