Probiotics: Therapeutic Potential in Autism

Megan Brooks

December 12, 2013

Probiotics may have therapeutic potential in autism spectrum disorder (ASD), new research suggests.

A study conducted by investigators at the California Institute of Technology in Pasadena shows that treatment with the human gut microbe Bacteroides fragilis alleviates ASD-like behaviors and eases comorbid gastrointestinal (GI) symptoms in a mouse model of autism.

"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," study investigator Sarkis K. Mazmanian, PhD, said in a statement.

The findings were published online December 5 in Cell.

Growing Evidence

For the study, the investigators explored gut-microbiome-brain interactions in ASD using the maternal immune activation (MIA) mouse model of autism developed at Caltech.

"The MIA model," said Dr. Mazmanian, "is founded upon an environmental risk factor associated with human ASD and schizophrenia, namely, maternal infection or inflammation. Modeling this risk factor in both mice and monkeys yields animals that display the core symptoms of ASD and schizophrenia."

The researchers discovered that offspring of MIA mice had defects in intestinal integrity and alterations in the composition of the commensal microbiota similar to those reported in some individuals with ASD.

"To our knowledge, this is the first report of an animal model for autism with comorbid GI dysfunction," Elaine Hsiao, PhD, a senior research fellow at Caltech and first author on the study, said in a statement.

They also found that oral treatment of MIA offspring with B fragilis corrects gut permeability and alters microbial composition.

"Remarkably," B fragilis treatment also "ameliorates defects in communicative, sterotypic, anxiety-like and sensorimotor behaviors," they report.

"B fragilis is known to confer anti-inflammatory effects on the immune system, making it effective in treating symptoms of inflammatory bowel disease and multiple sclerosis in mice," said Dr. Mazmanian.

"In addition to this effect, our new work reveals a novel mechanism by which B fragilis treatment can confer beneficial effects on behavior, likely by shaping the resident microbiota and correcting intestinal permeability ― called 'leaky gut.' By correcting leaky gut, B fragilis may be reducing the levels of behavior-altering microbial metabolites that escape into the circulation," he added.

Evidence for gut-brain interactions is mounting. For example, as reported by Medscape Medical News, a recent study in autistic children found distinctly different levels of intestinal flora, which may increase their vulnerability to pathogenic bacteria and perhaps play a role in autism pathogenesis.

In the current study, Dr. Mazmanian and colleagues "propose the transformative concept that autism, and likely other behavioral conditions, are potentially diseases involving the gut that ultimately impact the immune, metabolic, and nervous systems and that microbiome-mediated therapies may be a safe and effective treatment for these neurodevelopmental disorders."

Hypothesis Generating

Commenting on the findings for Medscape Medical News, Armin Alaedini, PhD, from the Department of Medicine and the Institute of Human Nutrition, Columbia University Medical Center, New York City, who was not involved in the study, said the findings provide "important information to the expanding body of evidence implicating gut flora in the proper functioning of the brain and its potential involvement in neuropsychiatric disorders."

Dr. Alaedini noted that the demonstration of increased intestinal permeability and gut dysbiosis in a mouse model of autism and the amelioration of both intestinal permeability and behavioral abnormalities upon treatment with human commensal bacteria are "novel and intriguing."

He said the study is "particularly relevant to autism, because GI symptoms are thought to be a common feature in the disorder. The results might also help to explain some of the observed immune abnormalities in autism."

For example, the elevated antibody response to dietary gluten and its association with GI symptoms in children with autism, which was recently reported by his group and covered by Medscape Medical News, may be directly linked to increased intestinal permeability and changes in gut microbiota.

"Another interesting feature of the study is that it shows certain serum metabolites in affected mice, possibly increased because of GI barrier defects, to be directly responsible for some of the behavioral symptoms. Taken together, the data offer clues regarding a potential mechanism for how commensal gut bacteria might link GI symptoms, intestinal barrier function, and certain immune abnormalities with behavioral deficits in a subset of individuals with autism," Dr. Alaedini said.

Ted Dinan, MD, PhD, professor of psychiatry who is also from the Alimentary Pharmabiotic Centre at University College Cork in Ireland, said the study "both builds on what we already know while at the same time helping to integrate information obtained from various studies. It has set up a series of hypotheses which are testable in clinical populations. We need proper studies in patients evaluating barrier function, metabolomics, and the possible therapeutic benefits of probiotics such as B fragilis."

As reported by Medscape Medical News, Dr. Dinan's own research suggests that probiotics may offer an alternative treatment option for depression and other psychiatric disorders.

The study was supported through grants and fellowships from Caltech, Autism Speaks, the National Institutes of Health, and the National Science Foundation. The authors, Dr. Alaedini, and Dr. Dinan report no relevant financial relationships.

Cell. Published online December 5, 2013. Full article

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