More Support for Gut-Brain Link in Autism

Megan Brooks

January 30, 2017

A new study provides more evidence of a gut-brain relationship in autism spectrum disorder (ASD).

In intestinal epithelial tissue from patients with ASD, researchers observed reduced expression of barrier-forming cellular components and higher expression of molecules that increase intestinal permeability. In postmortem brain tissue from patients with ASD, they observed altered expression of genes associated with blood-brain barrier (BBB) integrity and function in association with neuroinflammation.

"Our study is the first to explore mechanistically the molecular signature of defects in the gut epithelial barrier and the BBB in ASD," Maria Rosaria Fiorentino, PhD, of Harvard Medical School and the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital East in Charlestown, told Medscape Medical News.

"Our findings suggest there is a molecular mechanism linking the gut and brain that involves both the intestine and the BBB in the pathophysiology of ASD. Elucidating the molecular basis of gut and BBB impairment in ASD will be the first step toward the design of more targeted and effective therapies. If we can prevent alterations of the function of these barriers, we may be able to treat the GI symptoms and/or autism core symptoms in the ASD population," she added.

The study was published online in Molecular Autism.

Leaky Gut and Brain?

The research team analyzed gene and protein expression profiles in postmortem cerebral cortex and cerebellum tissue from eight individuals with ASD, 10 with schizophrenia, and 15 control persons. They also analyzed duodenal biopsy specimens from ASD patients and control persons.

"This study is part of a project aimed at testing our working hypothesis about the pathophysiology of ASD, which proposes that the combination of gut microbial dysbiosis, increased gut permeability, and the passage of nonself antigens and/or activated immune complexes through an impaired BBB interferes directly with the function of the central nervous system of ASD," Dr Fiorentino explained.

The study authors observed altered expression of several genes associated with BBB integrity and function in ASD brain tissue relative to healthy brain tissue. Of note, say the researchers, they observed increased expression of the inflammatory marker matrix-metalloproteinase-9 (MMP-9) in ASD brain tissue, which "supports our hypothesis of an impaired BBB, most likely associated with neuroinflammation. Several pieces of evidence indicate that MMP-9 secretion induces BBB disruption and this is an important step in the development of inflammatory diseases of the nervous system," write the authors.

They also observed high expression of proinflammatory translocator protein (TSPO) in ASD brain tissue. Prior studies have shown increased TSPO expression in association with brain injury and neuroinflammation, "making TSPO a reliable marker of brain inflammation," they note.

The researchers also assessed expression of the four claudins (CLDN-1, -3, -5, and -12) that are thought to be incorporated in the BBB. They found that two were significantly more expressed in the ASD brain than in the healthy brain.

CLDN-5, the major and more abundant cell adhesion molecule of tight junctions in brain endothelial cells, was expressed 5.1 and 3.6 times more in the cortex and cerebellum of ASD patients, respectively, relative to control persons. CLDN-12 was expressed about 7.7 and 3.6 times more in the ASD cortex and cerebellum, respectively, than in the cortex and cerebellum of the control group.

In the intestine, 75% of the ASD samples analyzed had reduced expression of three barrier-forming tight junction components – CLDN-1, occludin (OCLN), and tricellulin (TRIC); 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to samples from control persons.

These observations suggest an impaired gut barrier and "serve as a proof of concept to support the hypothesis of a gut-brain axis dysfunction in a subgroup of ASD patients," Dr Fiorentino and her colleagues say.

For the most part, there were no major changes in the genes analyzed in the cohort with schizophrenia relative to control persons.

A limitation of the study is the fact that, because of the investigators used postmorten samples, no information was available on potential confounding factors for each person, such as exposure to medications, health conditions, and cause of death, the researchers say. Another limitation is that few samples were analyzed, owing to limited availability. This might have had an effect on the statistical significance of some of the results.

More in-depth molecular studies are needed to further investigate the observations in this study, they conclude.

"Intriguing" Findings, Interpret Cautiously

David Beversdorf, MD, of the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri in Columbia, has studied gastrointestinal problems in ASD but was not involved in the current study.

He told Medscape Medical News that, to his knowledge, this is the first study of gene expression of markers of BBB integrity in ASD that also investigated related factors in gut mucosa, with "significant alterations" observed in ASD in both tissues.

"However, as the authors correctly discuss in the paper, this does not represent an answer to the questions raised regarding the controversial 'leaky gut' hypothesis. There are other lines of evidence that have not been as supportive of this hypothesis, and while intriguing, there could be a number of other factors in play," Dr Beversdorf said.

As an example, he said, MMP-9, one of the BBB factors examined in brain tissue (levels of which are elevated in persons with ASD) is involved in a "tremendous array of other functions.

"Furthermore, glial cells, for which TSPO is a marker of activity, play a remarkable range of roles that are only beginning to be understood. These were among the most strongly ASD-specific markers observed in this study for the brain tissue," he noted.

In addition, Dr Beversdorf said the "considerable degree of variability among the ASD samples is noteworthy and may have important implications."

Summing up, he said, "Much more work needs to be done to examine the gut-brain relationship in ASD, and evidence is mounting regarding its importance, while also establishing what role might be played by the microbiome. However, consideration of the clinical implications would need to wait until after a more complete understanding of these interrelationships is established."

No funding for the study has been declared. The authors have disclosed no relevant financial relationships.

Mol Autism. Published online November 29, 2016. Full text

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