Autism: Its Gut Stupid

Not all gluten, wheat or grains are the same

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Gluten is not a singular entity. It is comprised of numerous proteins coming from grains, and these have variable properties.

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Looking at different grains in context of gluten

Wheat, barley and rye are intimately closely linked grains. Oats are distant cousins.

• Wheat gluten as well as the other gluten-like proteins hordeins in barley and secalins from rye bear many similarities structurally and in potential for gluten toxicity.
• Avenins derived from distant cousins oats are much less similar and create low toxicity.
• The gluten-like proteins in rice, corn, sorghum and tef are absolutely different from wheat gluten and are devoid of toxicity for humans.

All wheat is not the same

Wheat is not a monolithic entity.

• Thousands of varieties of wheat have been grown over the course of history. They have come up as a result of evolution, selective breeding and modern hybridization techniques.
• The most commonly used wheat for food are tetraploid durum wheats used mostly for pasta) and the hexaploid wheats used for breads.
• In fact, the term "durum" has now become part of common lexicon among people buying wheat flour for their cooking.  These are also the two types that contain the most gluten proteins.

Is It Leaky Gut or Leaky Gut Syndrome?

Why high gluten wheats are preferred by food industry?

• High nutritional value
• Higher the gluten content, the better the dough quality for baking.

What is gluten really?

Gluten is a multifaceted mixture of proteins seen in the seeds from wheat, barley and rye. These proteins are a source of food for the germinating seeds.

• Basically gluten comprises of two types of proteins: the gliadins and the glutenins. While many gliadin genes are seen in wheat, the genes for glutenins.are relatively uncommon.
• It is the glutenins that have most advantageous baking properties like elasticity and are critical for high quality dough widely used in food chain.
• The gliadins on the other hand are the proteins with the most toxic potential.

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Protein complex in rye versus barley

Rye contains both gliadin-like as well as glutenin-like proteins; The gliadin like proteins in rye are called secalins. Barley on the other hand has no glutenins but has gliadin-like proteins known as hordeins.

The oat exception

Because of distant cousin status, oat proteins are mostly gluten-like avenins which are dissimilar to gluten. Oat also has very few avenin genes, and as such oats contain kuch less avenins than the wheat.

• Thus oats consumption only creates a limited gluten exposure to the body and can be safely consumed by most unless contaminated by other grains.

Gluten and digestive juices in gut

• Gluten is highly resistant to breakdown by digestive juices in human gut.
• Gluten is rich in glutamine and proline aminoacids. It is the high proline content that makes it resistant to digestion in the gut.

Glutenins versus gliadins

While most of the gluten toxicity has been blamed on gliadins, it now appears that glutenins also have toxic potential in provoking immune system, albiet to smaller extent.

 Is It Leaky Gut or Leaky Gut Syndrome?

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Treatment of Seizures with Brain Dysfunction: Autism model

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Seizure disorder is frequently seen in patients with autism.

Study

Recently an international expert panel led by Dr. Frye from the Arkansas Children’s Hospital Research Institute, Little Rock, AR conducted a systematic review of medical literature on the effectiveness of various therapies for seizure disorder in autism.

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Study concerns

They lamented at “the striking lack of clinical trials performed to support the use of these treatments”.

Study results

They drew the following conclusions from the limited literature available. The grade of evidence for effectiveness in autism with seizures is provided on a scale of A to D.

Most effective drugs for epilepsy in autism in general
Valproate (C)
Lamotrigine (C)
Levetiracetam (C)

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Non-drug treatments (limited evidence)

• Ketogenic (C)
• Modified Atkins diet (C)
• Surgery, mostly multiple subpial transections (C)
• Neurofeedback treatment (C)

Auism associated with mitochondrial disorders and dysfunction (limited evidence)

• L-carnitine
• Multivitamins
• N-acetyl-l-cysteine 

Autism associated with tuberous sclerosis complex

• Vigabatrin (C)
• Abnormal folate in brain (limited evidence)
• Folinic acid (C)

Novel treatments (limited evidence)

• Magnesium with pyridoxine (D)
• Omega-3 fatty acids
• Gluten-free casein-free diet (C)
• Low-frequency repetitive transcranial magnetic simulation

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Novel treatments (supported by basic science)

• Zinc
• L-carnosine

Dr. Minocha’s comments
Overall the literature is limited at best. Patient characteristics of autistic symptoms plus seizures would guide the treatment with medications and non-traditional therapies as a valuable adjunct. More studies are sorely needed to identify effective treatment of seizures in patients with autism.

Role of antioxidant polyunsaturated fatty acids in autism

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Polyunsaturated fatty acids like arachidonic acid (ARA) and docosahexaenoic acid (DHA) are believed to play a critical role in growth and development of brain including the signal messaging system in the brain. Docosahexaenoic Acid supplementation is frequently used to treat kids with autism.

Dr. Voigt and colleagues recently conducted a randomized placebo controlled trial in 48 kids. Half of them received 200 mg DHA every day while the rest received placebo.

Clinical Global Impressions-Improvement (CGI-I) scales was used.

At the end of 6 months, although the DHA group showed a 431% increase in DHA levels, the investigators found that DHA did not have beneficial impact on core behavior of autistic kids as compared to those on placebo.

However, Voigt and colleagues conceded that the negative results may have been as a result of inadequate size of subjects studied and that just might be the case. The results were published in the Journal of Pediatrics Gastroenterology & Nutrition (Dec 2013).

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Let us look at another recent study published in Journal of Clinical Psychopharmacology (April 2012).

Yui and co-investigators examined the effect of large doses of arachidonic acid (ARA) added to DHA in  in 13 autistic subjects over 16 weeks. Autism behavior was studied using Social Responsiveness Scale and the Aberrant Behavior Checklist-Community. They also examined the antioxidant levels to determine the mechanism of action.

Results of the Yui study demonstrated that addition of high doses of ARA to DHA results in improvement in communication and social withdrawal.  These effects were accompanied by an improved levels of antioxidant markers like transferrin levels.

Dr. Minocha’s comments: Both studies are limited by the sample size. In addition, each antioxidant has specific actions at specific pathways of oxidative stress. In addition the requirements of antioxidants in subjects with neurobehavioral dysfunction like autism and hence a combination of polyunsaturated fatty acids plus other elements like zinc etc may be needed to accomplish the right effect.

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Carnosine & Carnitine for Brain Health in Autism

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While not an absolute substitute for human studies, animal models are a scientifically accepted method of studying disease processes and treatments.

Background

Altered intestinal bacteria especially Clostridium difficile have been those implicated. One of the mechanisms postulated is that an overgrowth of certain bacteria including C. difficile produces greater amounts of propionic acid as well as bacterial lipopolysaccharides (LPS) toxin. 

Indeed propionic acid is known to produce autism like manifestations  in rats.  Antibiotic use increases the risk of an overgrowth of C. difficile and has been implicated in pathogenesis of autism.

Is It Leaky Gut or Leaky Gut Syndrome?

Autism study objective

Dr. Ansary and colleagues wished to examine the neurotoxic effects of antibiotic induced dysbiosis as well as oral administration of propionic acid in hamsters and the protection against damage by carnosine and carnitine.

Autism study methods

54 hamsters were studied in different groups of experimental and controls. Neurotoxicity was induced by oral use of clindamycin or propionic acid. Further treatment groups included animals receiving carnosine 10mg/kg/d or carnitine 50 mg/kg/day for one week. At the end of experimental period, animals were sacrificed and the brain tissue examined.

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Autism study results

• Clindamycin caused altered intestinal bacteria with overgrowth of pathogenic bacteria including Clostridia type.
• Both propionic acid and clindamycin treated animals shows DNA damage in the brain. DNA damage was greater in the propionic acid treated animals than clindamycin suggesting that propionic acid may effciently cross blood brain barrier.
• It also suggests that  dysbiosis causes damage via production of propionic acid. The difference in damage due to clindamycin and propionic acid  likely relates to higher propionate delivered when given directly in contrast to that produced by abnormal pathogenic bacterial overgrowth.
• Both carnosine and carnitine provided protection against DNA damage in brains in both animal models suggesting their potential therapeutic role in brain dysfunction like autism.
• Caveat: Animal studies only suggest possibilities which may or may not translate into applicability to humans.

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Dr. Minocha's comments on study implications

• Dysbiosis and antibiotics use play role in causing and/or sustaining brain dysfunction.
• Propionic acid may be one factor that links diet and gut bacteria in causing brain disorders.
• The fact that oral administration can affect brain damage suggests the importance of diet.  Diet high in antioxidants may help.
• Antioxidants supplements may help in some especially those with unhealthy and picky eating habits.

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High Homocysteine, Low Vitamin Levels in Autism Across Cultures

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Abnormalities of metabolism involving vitamin B12 and folic acid have been implicated as one of the causative factors for autism spectrum disorders.

Testing of potentially toxic  homocysteine levels is commonly used by neurologists and psychiatrists as part of work-up of a variety of brain disorders and cognitive dysfunction including dementia. Such testing is especially undertaken when vitamin B12 levels are within "normal" range.

Is It Leaky Gut or Leaky Gut Syndrome?

Multiple Western studies have demonstrated high levels of homocysteine in autism spectrum disorders. While autism is more common in th West, a similar correlation in Eastern societies also would lend support to hypothesis that folate-B12-homocyteine metabolism reactions may play a key role in environmental factors in autism.

Background on Homocysteine and B12, Folic acid: Dietary amino acid methionine is converted to homocysteine in body. This potentially  toxic homocysteine may be converted to cystien or even back to methionine by enzymes involving vitamin B12 and folic acid.

• A potential deficiency of these vitamins can cause an abnormal levels of homocysteine in the body.
• Some data suggests that supplemention with vitamins lowers homocysteine levels
• There are reportsthat kids with autism respond to the vitamin supplements

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Potential causes of low vitamin B6, B12 and folic acid levels in body:

• Dietary deficiency
• Selective food choices
• Gastrointestinal dysfunction including mal-digestion and malabsorption of nutrients. Digestive enzyme supplements have been beneficial in some studies. 

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Autism Homocysteine B12 Study Overview: Dr. Ali and colleaagues from the Sultan Qaboos University in Oman and NorthEastern University in Boston, MA conducted a case control study comparing fasting homocysteine, folic acid and vitamin B12 levels in 40 kids with autism and 40 healthy controls.

Autism Homocysteine B12 Study: The investigators compared homocysteine, folic acid and vitamin B12 levels in autism kids and age-gender matched controls. Diagnosis of autism was made based on the American Psychiatric Association (DSMIV) criteria. Clinical DSM IV criteria was confirmed using Childhood Autism Rating Scale (CARS).

Results of Autism Homocysteine B12 Folic Acid Study:

• Homocysteine levels were significantly higher (more than twice the average 20.1 v 9.6) in kids with autism as compared to healthy controls.
• Mean vitamin B12 levels were significantly lower in autism as compared to controls (191 v 289 pg/ml)
• Average folic acid levels were several fold lower in autism as compared to controls (1.8 v 6.1  mcg/L )

Conclusions of Autism Homocysteine B12 Folic Acid Study:

• Elevated homocysteine is biomarker and may used for early testing for autism
• Elevated homocysteine may be involved as a causative factor and/or involved in progression of the disease.

Is It Leaky Gut or Leaky Gut Syndrome?

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Tricyclic Antidepressants Treatment for Autism: How good is the evidence?

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Clinicians frequently use drugs affecting brain function in order to manage the manifestations of autism. Here is further evidence how many of the medications prescribed for autism spectrum disorders (ASD) have little evidence to back their use.  This post pertains to the use of tricyclic antidepressants (TCAs), a class of antidepressants with potential for significant side-effects.

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How do tricyclic antidepressants work in autism

Tricyclic antidepressants increase the neurotransmitters like norepinephrine and serotonin in the our brain. Use of TCAs for autism is based on their effects mediated via serotonin.

Tricyclic antidepressants for autism

While the use of tricyclic antidepressants in autism is common, how sure are we that they are actually effective, or it merely a placebo effect with side-effects? How do side-effects square with the strength of evidence for their efficacy in autism?

TCA-Autism Spectrum Disorders Study

Dr. Hurwitz and colleagues from the Department of Community Pediatrics, Liverpool Hospital, in Liverpool BC, NSW, Australia, conducted a meta-analysis and systemetic review of efficacy of TCAs in patients with autism.

The results of the study titled, "Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents. " were published in the Cochrane Database Syst Rev. March 2012.

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Objectives of TCA Autism study

The investigators wished to examine if TCA treatment in autism improves:

• Social interaction and communication
• Stereotypic and repetitive behaviours
• Comorbid states, such as depression and anxiety

In addition, authors evaluated the potential for adverse effects of TCAs

Is It Leaky Gut or Leaky Gut Syndrome?

Methodology of TCA-Autism Study 

The investigators searched the medical literature using a variety of databases for studies related to autism spectrum disorders including Cochrane Central Register of Controlled rials, MEDLINE, EMBASE, PsycINFO and  CINAHL along with Dissertation Abstracts International via Dissertation Express, and the metaRegister of Controlled Trials.

• Only randomised controlled trials on use of tricyclic antidepressants as compared to placebo, in children and adolescents with autism spectrum disorders were included in data for analysis.

Results of TCA-Autism study

Despite the rigorous search outlined above, the investigators were able to find only three studies that met the inclusion criteria. Two of the studies used clomipramine and while one studied  tianeptine.

• All the trials comprised of few subjects (12 and 32 subjects).
• Meta-analysis was not possible because of heterogeneity in studies
• Only one of the three studies found any evidence for possible short term effectiveness of tianeptine
• The results of observation of clinicians versus parents/teachers were contradictory. While parents/teachers reported benefit from tianeptine, the clinicians did not.
• Tianeptine use was associated with significant side-effects like drowsiness and reduced activity levels in these individuals while being treated with tianeptine.
• Similarly theresults of two studies on use of  clomipramine were conflicting.

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Dr. Minocha's comments

• Be aware of the limited and conflicting evidence on efficacy of TCAs in autism.
• Be aware of that TCAs have potential for significant side-effects
• More studies are needed before tricyclic antidepressants can be prescribed with confidence for treatment of individuals with ASD.

Note: Results of studies pertaining to SSRI class of antidepressants are no more comforting. Williams et al in 2010 concluded that there is lack of evidence of efficacy of SSRIs in children. However, there is limited evidence favoring use of SSRIs in adults from small studies.

Is It Leaky Gut or Leaky Gut Syndrome?

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Is It Leaky Gut or Leaky Gut Syndrome?

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