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Thursday, September 17, 2015

The Gut-Brain Axis, Part 4 – Autism

From BrainBlogger

By Sara Adaes, Ph.D. (c)
September 14, 2015

Many genetic factors have been linked to autism spectrum disorder (ASD), but these only apply to a minor fraction of patients. Other factors that have been pointed out as possible causes of autism include early exposure to viruses and drugs, autoimmunity, and more recently, abnormal gastrointestinal (GI) microbiota composition.

The causes of autism are mostly unclear and immersed in controversy. The only consensus in the medical and scientific community is that autism is associated with a disorder in brain function and development. ASD is diagnosed based on the presence and the severity of stereotypic behavior and deficits in language and social interaction.

In Part 3 of the brain-gut axis series, it was briefly mentioned how ASD seems to have a strong connection to the gut. GI symptoms are observed in around 70% of ASD patients, ranging from simple digestive complications to food allergies or sensitivities, and including abnormal digestion, nutrient absorption, and intestinal permeability. As a consequence of these reported digestive symptoms, specialized diets have been devised as a potential therapy for ASD, with some promising results.

So, although ASD is mostly defined by the behavioral impairments it entails, the GI symptoms are rather meaningful. But what evidence is there of a link between the brain-gut-microbiota axis and autism? Let’s see.

Altered Microbiota in ASD Patients

Even though the underlying mechanisms are unknown, it is possible that an abnormal gut ecosystem may be involved in the etiology of ASD. Recent research focused on the gut microbiota of autistic patients has shown that GI symptoms are commonly observed at the onset of ASD and often persist thereafter. There is a subset of ASD patients who display what is referred to as “dysbiosis”–an imbalance in the microbial population in the gut.

This seems particularly evident in children with late-onset autism and there are several reasons to consider that gut bacteria may be involved in its etiology. One such indication comes from the observation that ASD if often diagnosed following antibiotic therapy, for example, to treat ear infections. Antibiotics are not selective for the bad microbes–they can also significantly alter the gut’s natural ecosystem and its interactions with our metabolism.

The antibiotic vancomycin, for example, when administered in high doses, over a long period of time, can even disrupt the intestinal flora to a point where it promotes colonization by pathogens. This is in line with data showing a higher number of species of Clostridia in both gastric and intestinal specimens from children with autism.

This higher prevalence of Clostridia infections has also been hypothesized to be a reason for the increase in families with multiple cases of autism–an environmental contamination with Clostridia spores could be the cause.

Another link between the gut microbiota and late-onset ASD involves a molecule named indolyl-3-acryloylglycine (IAG). IAG is produced by the intestinal flora and is a normal constituent of urine. When present in abnormally high levels in the urine, IAG is regarded as a sign of gut dysbiosis. And there have been a few studies showing increased levels of IAG in late-onset ASD patients.

But these are mostly hypothetical scenarios since the available studies are still insufficiently robust. Still, these are only just a few examples of numerous microbiota changes in ASD patients that have already been reported.

Can GI Symptoms Be a Consequence of Altered Brain-to-Gut Signaling?

Since anxiety is highly prevalent in ASD children, it is possible that these anxiety and stress traits may be the link to visceral hypersensitivity and GI disorders. An interesting observation is that ASD and functional GI disorders share brain imaging abnormalities in sensory and emotional regulation regions.

So, although other mechanisms may contribute to the total set of symptoms, some of these may result from changes in the sensory and emotional processing by the central nervous system. GI dysfunctions may be a consequence of brain-driven changes affecting the enteric nervous system.

But the GI symptoms can also be a consequence of local changes in the enteric nervous system, not necessarily driven by the brain. These can easily alter GI motility, secretion, and permeability. Or it can actually be a combination of these factors.

Can the Gut Microbiota Contribute to the Onset of ASD?

It has been speculated that these microbiota-related factors mentioned above may be at least partially responsible for ASD onset.

A favorable argument is the reported benefit ASD patients obtain from specifically designed diets. These diets may be beneficial not only by having direct health effects on the brain, but also by modulating the gut microbiota. Still, hard scientific evidence supporting a consistent effect on ASD symptoms is still lacking.

But it may be just a matter of time – animal research studies have shown that alterations in the gut microbiota can lead to changes in serum molecules that play an important role in the manifestation of autism-like behaviors and altered GI function.

In an animal model that has been used to study ASD, pregnant mice are injected with a viral mimetic to produce offspring with stereotypic autistic-like behaviors. First off, it’s important to mention that this model shows that, at least in rodents, a mother-to-offspring transmission of molecules associated with a maternal infection can induce the production of neuroactive factors and trigger the development of ASD symptoms in the offspring.

In addition, these molecules can induce specific GI changes-the offspring showed altered expression of intestinal barrier integrity genes and functional deficits in intestinal permeability, as well as marked differences in the composition of gut bacteria.

As seen in Part 2 of the brain-gut axis series, gut microbial products have the ability to influence metabolic, immunologic, and behavioral patterns in mice and humans. And they appear to play a role in the development of autism-like behavior-the behavioral changes induced in this animal model of ASD were rapidly reversed by ingestion of probiotics.

As also mentioned in part 3 of the brain-gut axis series, Bacteroides fragilis is another bacterial species found in smaller quantities in some children with autism. In this study, the administration of B. fragilis from humans to mice with autism-like symptoms led to an improvement in their behaviors, displaying less repetitive behavior, less anxiety signs, and being more communicative with other mice.

Thus, even though there is growing evidence of important links between the gut-brain axis and ASD, mainly arising from animal research, many questions remain unanswered. There are some ASD behavioral traits that, for some reason, are not as easily reversed by probiotic treatment, for example. 
Also, the mechanisms by which these probiotics affect behavior remain to be elucidated.

Animal models can be good predictors of a human outcome, but many end up failing when results are translated into clinical research. We must keep in mind that autism spectrum disorder refers to a set of heterogeneous neurodevelopmental disorders; it has multiple causes and progression patterns, variable degrees of symptomatic severity and several associated co-morbid disorders.

Although the gut-brain axis and the gut microbiota may not be the definitive answer to all the problems associated with ASD, they may very well be key players in at least a subset of autistic patients and, therefore, an important therapeutic target for those subjects. And even if the gut microbiota does not directly induce the development of ASD, it is still likely to significantly contribute to the overall disease burden in affected children. And that’s reason enough to act on it.


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Sara Adaes, Ph.D. student, has been a researcher in neuroscience for a decade. She studied biochemistry and did her first research studies in neuropharmacology. She has since been investigating the neurobiological mechanisms of pain and is finishing her Ph.D. at the Faculty of Medicine of the University of Porto, in Portugal. Follow her on Twitter @saradaes

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