Using a mouse model, US researchers have linked neurodevelopmental symptoms similar to those seen in autism spectrum disorder (ASD) patients to changes seen in the bacteria in the animals' guts.
ASD is diagnosed when individuals exhibit characteristic behaviours that include repetitive actions, decreased social interactions, and impaired communication. Many individuals with ASD ?also suffer from gastrointestinal (GI) issues, such as abdominal cramps and constipation.
Using the co-occurrence of brain and gut problems in ASD as their guide, researchers at the California Institute of Technology (Caltech) were investigating a potentially transformative new therapy for autism and other neurodevelopmental disorders. The research, which was published online in the December issue of the journal Cell, is the first to demonstrate that changes in the gut bacteria can influence autism-like behaviours in a mouse model. The gut microbiota - the community of bacteria that populate the human GI tract - previously has been shown to influence social and emotional behaviour.
"Traditional research has studied autism as a genetic disorder and a disorder of the brain, but our work shows that gut bacteria may contribute to ASD-like symptoms in ways that were previously unappreciated," said Sarkis K. Mazmanian, an author of the study and Professor of Biology at Caltech. "Gut physiology appears to have effects on what are currently presumed to be brain functions," he said.
Study method
To study this gut-microbiota-brain interaction, the researchers used a mouse model of autism previously developed at Caltech in the laboratory of Paul H. Patterson, the Anne P. and Benjamin F. Biagginin Professor of Biological Sciences. In humans, having a severe viral infection raises the risk that a pregnant woman will give birth to a child with autism. Patterson and his lab reproduced the effect in mice using a viral mimic that triggers an infection-like immune response in the mother and produces the core behavioural symptoms associated with autism in the offspring.
In the new study, Professor Mazmanian, Professor Patterson and their colleagues found that the "autistic" offspring of immune-activated pregnant mice also exhibited GI abnormalities. In particular, the GI tracts of autistic-like mice were "leaky", which means that they allowed material to pass through the intestinal wall and into the bloodstream. ?This characteristic, known as intestinal permeability, has been reported in some autistic individuals.
"To our knowledge, this is the first report of an animal model for autism with comorbid GI dysfunction," said Elaine Hsia, a senior research fellow at Caltech and first author on the study.
Mice treated with probiotics
To see whether these GI symptoms actually influenced the autism-like behaviours, the researchers treated the mice with Bacteroides fragilis (B. fragilis), a bacterium that has been used as an experimental probiotic therapy in animal models of GI disorders. ?The researchers said the leaky gut was corrected with this treatment.
In addition, observations of the treated mice showed that their behaviour had changed. In particular, they were more likely to communicate with other mice, had reduced anxiety, and were less likely to engage in a repetitive digging behaviour.
"The B. fragilis treatment alleviates GI problems in the mouse model and also improves some of the main behavioural symptoms," Ms Hsia said. "This suggests that GI problems could contribute to particular symptoms in neurodevelopmental disorders," she said.
With the help of clinical collaborators, the researchers are now planning a trial to test the probiotic treatment on the behavioural symptoms of human autism. The researchers said the trial should begin within the next year or two.
"This probiotic treatment is postnatal, which means that the mother has already experienced the immune challenge, and, as a result, the growing fetus have already started down a different developmental path," Professor Patterson said. "In this study, we can provide a treatment after the offspring have been born that can help improve certain behaviours. I think that's a powerful part of the story," he said.
The researchers stressed that much work was still needed to develop an effective and reliable probiotic therapy for human autism - in part because there are both genetic and environmental contributions to the disorder, and because the immune-challenged mother in the mouse model reproduces only the environmental component.
"Autism is such a heterogeneous disorder that the ratio between genetic and environmental contributions could be different in each individual," Professor Mazmanian said. "Even if B.fragilis ameliorates some of the symptoms associated with autism, I would be surprised if its a univeral therapy - it probably won't work for every single case," he said.
The Caltech team proposes that particular beneficial bugs are intimately involved in regulating the release of metabolic products (or metabolites) from the gut into the bloodstream. Indeed, the researchers found that in the leaky intestinal wall of the autistic-like mice, certain metabolites that were modulated by microbes could both easily enter the circulation and affect particular behaviours.
"I think our results may someday transform the way people view possible causes and potential treatments for autism," Professor Mazmanian said.
Along with Professor Patterson, Ms Hsiao, and Professor Mazmanian, additional Caltech coauthors on the paper, "Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders," are Sara McBride, Sophia Hsien, Gil Sharon, Julian A. Codelli, Janet Chow, and Sarah E. Reisman.
The work was supported by a Caltech Innovation Initiative grant, an Autism Speaks Weatherstone Fellowship, a National Institutes of Health/National Research Service Award Ruth L. Kirschstein Predoctoral Fellowship, a Human Frontiers Science Program Fellowship, a Department Of Defense Graduate Fellowship, a National Science Foundation Graduate Research Fellowship, an Autism Speaks Trailblazer Award, a Caltech Grubstake award, a Congressionally Directed Medical Research Award, a Weston Havens Foundation Award, several Callie McGrath Charitable Foundation awards, and the National Institute of Mental Health.
Australian experts respond
The results of the study have been welcomed by Australian experts, but suggest caution when considering diet therapies for ASD.
"These findings are of great interest and very relevant for the subgroup of people with ASD who also have gastrointestinal problems, a symptom that can be associated with ASD," said Dr Cheryl Dissanayake, Director of the Olga Tennison Autism Research Centre at La Trobe University.
"These complex neurodevelopmental disorders can be associated with many other conditions, and it's of particular interest that the anxiety-like behaviour was reduced in the treated mice," Professor Dissanayake said. "We are currently researching anxiety and sleep in fly and mouse models, which leads me to wonder what the sleep cycles were like in these experimental mice," she said.
Helen Leonard, Clinical Associate Professor and Head of Child Disability Research at the Telethon Institute for Child Health Research in Western Australia agreed that the research suggested a potential new direction for ASD treatment.
"Whether children with autism are more susceptible to gastro-intestinal problems has long been an area of interest with conflicting findings in the literature," Professor Leonard said.
She said more recently there had been emerging interest in the role of the microbiome in health and disease states and in particular its relationship with neurodevelopmental disorders.
"Using a mouse model the results in this article provide some evidence to suggest that the microbiome may indeed influence brain development and behaviour, and suggest that strategies that favourably influence the gut bacteria could play some role in neurodevelopmental disorders," Professor Leonard said. "At this stage there is a need for further research to further explore this possibility," she said.
Probiotics may be a potential treatment for autism
