Biomedical Update: Autism Research Review

Written by:  Sonya Doherty, N.D.

Research has identified a number of metabolic dysfunctions, underlying biochemical impairments and physiological abnormalities associated with autism spectrum disorder (ASD).  Leading investigators in the field of autism have a found both neuro inflammation and neuropathological alterations.  Additionally, elevated oxidative stress, impaired methylation and transulfation, depleted glutathione and lymphocytic nodular hyperplasia of the gastrointestinal tract and mitochondrial dysfunction as potential causative factors of, or contributing factors to ASD.  Genetic research has also identified a number of genes and gene mutations involved in ASD.

Missing, is something that ties all of these metabolic, biochemical and physiological issues together into a working model of ASD.  While each piece of the puzzle is important, to date, no single avenue of research has been able to explain the complex interplay between genetics, environment, biochemistry and physiology.  That may be about to change.  Research being done at the University of Western Ontario (UWO) by Dr. Derrick MacFabe,  has been awarded one of the top 50 scientific discoveries in Canada by the National Sciences and Engineering Research Council of Canada (NSERC).

Dr. MacFabe is an Assistant professor, director and principle investigator of the Kilee Patchell-Evans Autism Research Group at UWO.  His investigation into gut bacterial metabolites is changing the path of autism by bringing together ground breaking research from researchers around the world.  He describes it, while addressing attendees at Canada’s inaugural Autism One Conference in Toronto this past October, as “a start, an important way to bring research together”.

The group’s mandate is “to combine the expertise of various disciplines in looking at the many aspects of autism, specifically neurodevelopment, seizure, neurochemistry, obsessive compulsive disorder, anxiety disorders, social behaviour, cellular metabolism, neuro-immunology and infectious disease”.

Investigation by the group centers on prorionate (PPA), a short chain fatty acid produced by gut bacteria.  Of particular interest to MacFabe was the Clostridial species because of its early colonization of the digestive tract, ability to resist antibiotic treatment and ability to cause opportunistic infection in hospital and community settings.  The risk of autism is associated with pre and post natal infection is a Dr. MacFabe and his team postulated that the overuse of antiobiotics that has contributed to an increase in Clostridia infections could also be playing a role in the pathophysiology of autism.  Clostridial species are also being studied by another leading autism researcher, Sidney Finegold, who estimates there may be as many as 100 species of Clostridia in the digestive tract.  Clostrial species have also been found in higher numbers in children with ASD. One of the known risk factors for autism is pre and post natal infection.

Dr. MacFabe and his group found a number of important discoveries when a small amount of PPA was infused into the brains of rodents.  Previously typical rodents began exhibiting hyperactivity, complex movement and object fixation two minutes after receiving intraventricular infusion of PPA.  PPA has been shown to impact the basal ganglia which may explain why infusion demonstrated increased locomotor movement.  Investigators also reported subcortical spiking with movement, neuroplasticity and intermittent complex partial seizures.

Impact on socialization and behaviour was also evaluated in this novel gut-mediated autism model.  PPA, was again, infused in small amounts resulted in social impairment, repetitive behaviour, obsessive compulsive behaviour and object fixation.

Upon examination, the brains of PPA rodents showed many of the same metabolic, biochemical and physiological abnormalities identified by other investigators.  Astrogliosis, microglial activation and neuro inflammation in the PPA rodents mirrored the findings of Martha Herbert. M.D, Ph.D, and Carlos Pardo, M.D.   Endovascular involvement resulting in swelling of the vessels surrounding the blood brain barrier in the PPA model, may also shed light on previous research demonstrating reduced blood flow to the brain in ASD (Ohnishi et al. 2000), and increased susceptibility to environmental toxins postulated by many investigators studying the general metabolic theory of autism.

Dr. Pardo is an Assistant professor of neurology and pathology in the division of Neuroimmunology and Neuroinfectious Disorders at Johns Hopkins University School of Medicine.  In a 2004 study, published in the Annals of Neurology, the researchers demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes.

“This ongoing inflammatory process was present in different areas of the brain and produced by cells known as microglia and astroglia,” said Pardo.

Dr. Martha Herbert is an Assistant Professor of Neurology at Harvard Medical School, a Pediatric Neurologist at the Massachusetts General Hospital in Boston.  Dr. MacFabe states the results of the Kilee-Patchell Evans group are “identical to Martha Herbert’s research demonstrating reactive astrogliosis”.

An interesting finding in the research of MacFabe, Herbert and Pardo is the lack of neurotoxicity in the presence of significant neuro inflammation.

Dr. S. Jill James is the Director of the Metabolic Genomics Laboratory at Arkansas Children’s Hospital Research Institute (ACHRI). Dr. James’ research is focused metabolic and genetic factors that may contribute the causation of ASD.  In three key publications James and her team showed that 90% of children with ASD demonstrated impaired methylation, elevated oxidative stress and depletion of glutathione.  The link to Dr. MacFabe’s research is the ability of PPA to increase oxidative stress, shut off glutathione in the brain and induce multiple genes.  Some of these genes are implicated in learning, neurodevelopment, learning, aggression and anxiety. The rodents also had evidence of white matter damage precipitated by lipid peroxidation, edema and cholesterol abnormalities.  All have which have been demonstrated in human based research of aberrant biochemistry in ASD (Chauhan et al. 2004 and Tierney et al. 2006)

As the methylation cycle plays a crucial role in development, PPA induction gene induction may impair this cycle.  PPA metabolism is upregulated by B12 and biotin, each of which are important biochemical supports of methylation.  James’ finding of glutathione depletion coupled with the PPA model of shutting off glutathione suggests a mechanism of increased susceptibility of the autistic brain to environmental toxicity.

An area of significant interest in autism investigation is the role that mitochondrial dysfunction plays.  A recent Portugeuse study (Oliveira et al. 2005) screened 120 children and found mitochondrial respiratory chain disorder in 7.2 % of children.  Jill James’ research has identified mitochondrial glutathione depletion as a potential underlying metabolic causative factor in autism in her 2009 study.  According to John Pangborn, PhD, co-founder of Defeat Autism Now!, mitochondrial disorders lead to increase in PPA.

The new research surrounding mitochondrial dysfunction also fits into the bacterial gut-mediated autism model proposed by Dr. MacFabe because PPA causes mitochondrial uncoupling as evidenced by electron microscopy (McFabe et al. 2008 – In Press) and relative carnitine deficiency shown by elevated acylcarnitine.  Carnitine is essential for fatty acid metabolism because it acts as a shuttle into the mitochondrial matrix.  Carnitine is to fat metabolism what insulin is to sugar metabolism.

Dr. MacFabe has demonstrated that enteric short chain fatty acids like PPA can have a profound effect on neurodevelopment, neurons, inflammation, neuronal communication neuropathology, gut motility and barriers, brain electrical activity, immune function, lipid metabolism, oxidative stress, glutathione levels and gene induction, behaviour and socialization.  These effects are consistent with what is seen with autism.  This exciting new research supports the theory that autism is a neurobiological or whole body disorder giving hope for future treatment and prevention of ASD.

 

 

 

REFERENCES

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Finegold SM.  Therapy and Epidemiology of Autism: clostridial spores as key elements.  Med Hypotheses. 2008;70(3) :508-11.  Epub 2007 Sep 29.

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