Autism: Its Gut Stupid

Can green tea help brain function? The autism model.

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Exposure to toxins on top of genetic predisposition is thought to be one of the factors involved in instigating autistic behavior. Treating animals with drugs/toxins such as valproate produces autistic behavior in the animals and is used as a model to study effect of therapies with potential for benefit in autism.

Green tea is rich in polyphneols especially flavonoids. These chemicals have antioxidant and antiinflammatory properties. They can easily cross from blood in to the brain and help with electro-biochemical messaging between brain cells and prevent brain cell death.

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Autism-Green Tea Study

The study was conducted by Dr. Banji and colleagues and published in the journal Brain research.

• Autistic behavior in mice was induced by valproate (antiepileptic drug).
• Green tea extract was administered to the experimental group of mice.

Dose of Green Tea used in the study

Two doses of green tea extract were used in the study: low dose of  75mg/kg and high dose of300 mg/kg.

Results of Autism-Green Tea Study

• Geotaxis measures ability to navigate in inclined setting. Visual, sensory and touch senses and reflexes need to be coordinated for successful navigation. Valproate treatment caused an increase in re-orientation time in mice. Green tea administration resulted in significant improvement in geotaxis in these mice.
• Valproate treatment resulted in reduced mid-air righting (muscle coordination) as measured by mid-air righting. This decline was suppressed in green tea treated mice as compared to controls.
• Valproate treated mice showed greater muscular and movement clumsiness and this was attenuated by green tea therapy.
• While valproate increased the time to  paw lag on a hot plate as a measure of heat pain perception. High doses of green resulted in improvement of time to paw lag.
• Green tea resulted the reduction of valproate induced hyperactivity in animals.
• Open field test was conducted to measure the exploration activity in animals. Exploratory activity decline as a result of valproate in animals. This was improved by green tea therapy.
• Elevated maze test was done to examine effect on high anxiety levels and fear which is seen in autism.. Valproate treated mice pups spent less time in open arms of elevated plus maze. Green tea administration showed that the treatment helps suppress anxiety and fear on this test.
• Green tea treatment benefited the spatial learning and memory decline induced by valproate.
• The healthy electro-chemical messaging circuits in brain depend in part on purkinje cells. On autopsy, the brains of the valproate treated animals showed damage purkinje cell layer whereas this was found to be healthy in green tea treated mice.

Results in nutshell

Green tea protects against brain damage of autism and helps ameliorate many of the behavioral manifestations like muscle dis-coordination, fear, anxiety, hyperactivity and cognitive dysfunction.

Conclusions of Autism-Green Tea Study

Use of green tea is an effective treatment autistic behavior in experimentally induced autism in mice. The mechanism is believed to be strong anti-oxidant properties of the many constituents in green tea.

Dr. Minocha's comments

While it is always prudent to exercise caution in leaping from results in animals to their application in humans, there certainly is biological plausibility for beneficial effects of green tea on brain health. Green tea may be an easy, low risk nutritional component of holistic treatment of autism. As always talk to your doctor first.

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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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Butyrate is the healthy acid for gut, body and brain

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Gut bacteria can have both a beneficial as well as harmful effect on our brain through gut brain connections.

Fermentation of undigested carbohydrates by gut bacteria can produce certain biochemicals that enter body, affecting not just the body but also cross blood-brain barrier and exercise their functions in different parts of the brain.

These neuro-chemicals play a critical role in messaging circuits in the brain and beyond. Other bacterial chemicals are involved in affecting our immune system, and help generate more energy from the cells in the body.

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Potential benefits of pre- and probiotics

All of above indicates that manipulation of diet and gut bacteria by prebiotics/probiotics could bring about a healthier beneficial gut bacteria which in turn would lead to healthy brain.

What is butyrate?

Butyrate, a short chain fatty acid (SCFA), is one such byproduct of food-bacteria interactions in the colon. In fact most of the butyrate in gut is produced by bacterial fermentation of undigested carbohydrates although small amounts may be derived from the food consumed.

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 Effects of butyrate

• Energy source for intestinal cells
• Energy source for bacteria themselves
• Effect on various forms of brain including neuro-degenerative diseases and neuro-behavioral dysfunction

According to Drs. Leonel and Alvarez-Leite, one the most prominent roles of butyrate is blocking the enzymes that play a critical role in intestinal health:

• Affecting gene function by turning them on or off
• Affect immune system, both suppressing and/or activating as needed
• Blocking cancer process
• Helping gut wall barrier to prevent leaky gut
• Control of intestinal movements and control diarrhea

Is It Leaky Gut or Leaky Gut Syndrome?

Different diets/bacteria result in different amounts of butyrate production

The fermentation capacity of all the bacteria is not the same, some producing more butyrate than others.

For example, the fermentation by  Clostridium, Eubacterium, and Butyrivibrio type of bacteria are the richest source of butyrate in colon.

Foods to consume to get more butyrate

Helpful high fiber foods that are a rich source of butyrate  including:

• Whole grains
• Lentils
• Oat bran
• Bananas
• Onions
• Asparagus
• Cellulose
• Gum arabic

On the other hand starch-free wheat bran is a relatively poor source of butyrate.

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Our own body produces butyrate also

Butyrate is also produced by our own body, but that is a very small contribution to the total butyrate we use.

Butyrate directly from food

Cow’s milk is a rich source of butyrate in the form of tributrin. Tributtrin is broken into 3 times the butyrate by the digestive enzymes. Cow milk consumption should be taken in context that caseins in cow's milk may possibly adversely affect brain, although controversial in some quarters.

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How does butyrate affect brain?

It is amazing that a single chemical such as butyrate has affects numerous genes affecting numerous functions. Data indicates that it enhances function of genes that:

• Improve nerve cell adaptability
• Regeneration of nerve tissue
• Protecting nervous tissue against injury
• Enhancing the mitochondrial function in brain which can help to repair the damaged mitochondria in the brain.

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Increasing energy in brain: Alzheimer's analogy

Potential for increasing energy in brain is very exciting. For example, brain cells in Alzheimer’s show decrease in glucose consumption and reduced energy long before memory loss evident.

Henderson and colleagues examined the effect of ketogenic compound AC-1202, a medium chain triglyceride,  in patients with Alzheimer’s in a randomized placebo-controlled trial.

Results

• Patients consuming AP-1202 resulted in increased levels of butyrate
• Significant improvement in cognitive function by day 45 as compared to the placebo group
• Cognitive function returns to baseline within two weeks after stopping this dietary supplement
• The results are the best when the treatment starts early in the disease process.

The results of the study suggest that if enough of butyrate as a result of bacterial fermentation in the gut could reach the brain, it would serve as a great energy source for brain just as it does as a food for the colon. This would certainly counter the decreased glucose as a energy source  in brain in a variety of neuro-degenerative diseases.

Butyrate and neuro-degenerative diseases

Huntington disease

Ferrante and colleagues from the Bedford Veterans Affairs Medical Center, Bedford, MA have shown that use of butyrate in mice with Huntington’s disease:

• Protects against nerve toxicity
• Perks up body weight
• Improves muscle functioning
• Prolongs life

Is It Leaky Gut or Leaky Gut Syndrome?

Parkinson's disease

Dr. St Laurent from the Colby College, Waterville, ME that butyrate supplemented food salvaged chemical induced muscle functioning and prevented early death in Parkinson’s disease in animals.

Butyrate also suppresses inflammation in animals with Parkinson’s thus protecting the brain cells from damage.

Hearing

Butyrate protects against hearing loss caused by cancer chemotherapy.

Stroke

Multiple studies have documented that butyrate use limits the size of dead part of brain in stroke along with an improved behavioral function in animals.

Miscellaneous diseases based on animal models

• Alzheimer’s
• Traumatic brain injury
• Brain infections

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Clinical effects of butyrate

• Improve learning
• Improve memory

Diet, bacteria and brain: Butyrate is the connecting link

Typical American diet is much lower in fiber than is recommended. High fiber diet is believed to exert its beneficial effects in variety of diseases via its modification of microbiome, bacterial fermentation and production of short chain fatty acids especially butyrate.

Bacterial fermentation results in production of short chain fatty acids (SCFAs) including butyrate.  Most but not all of short chain fatty acids are consumed by gut wall as food, while some is absorbed to get into liver.

A small component of  gets into blood stream raising the blood butyrate levels with potential to enter our brain.

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Intestines and brain barrier in animals without gut bacteria

• Intestines of animals without any bacteria tend to be leaky gut as well as leaky blood brain barrier as compared to animals with healthy intestinal bacteria.
• This leakiness is accompanied with leaky tight junctions of the blood brain barrier and lower levels of tight junction proteins in different areas of the brain.

However, if these germ-free mice receive butyrate producing bacteria by mouth, the blood brain barrier is strengthened to healthy normal levels along with increased levels of tight junction proteins.

This illustrates the connection between gut bacteria, butyrate and the brain structure/function.

Is It Leaky Gut or Leaky Gut Syndrome?

Soluble fiber, butyarte, brain inflammation and sickness behavior

Sherry and colleagues from the University of Illinois, Champaign, IL studied the effect of prebiotic soluble fiber on toxin induced inflammation in brain.

Mice were administered toxin. One group received soluble fiber whereas the other was administered insoluble fiber in diet.

Results

• Mice fed soluble fiber suffered lower levels of sickness behavior as compared to the control group receiving insoluble fiber
• There was lower levels of inflammation in the brain

These investigators suggested that butyrate production via bacterial fermentation of the soluble fiber was responsible for the effects on the brain and the behavioral reaction of the animals.

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Role of Inflammation in Autism?

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GI dysfunction is known to occur in autism although its significance has been disputed.

 

Dr. de Theije and colleagues from the Utrecht University in The Netherlands wished to examine the structural and functional correlates of human observations that the GI dysfunction correlates with severity of autism symptoms. The findings were published in the Brain Behavioral Immunology 2013.

 

Methods of autism-gut study

Mouse model of autism was used. Autism was induced by injection of valproic acid to pregnant mice and the pups were then studied after 21 days after birth.

 

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 Results autism-gut study

• Changes in social behavior as well as gut and brain were found. However, many of these abnormalities were gender specific, with males being affected and not the females...
• There was a decrease in social behavior and interaction with unfamiliar pup in male pups. However, there was no effect in females did not display autistic behavior.
• There was increased inflammation in the brain irrespective of the gender.
• There was decrease in serotonin or 5HT levels in brains of male pups. Females were not studied since they did not have any autistic behavioral changes.
• There was increased gut inflammation and reduced number of cells in male pups. Females were not affected.
• There was decreased serotonin or 5HT in the gut of males whereas females were not affected.

Is It Leaky Gut or Leaky Gut Syndrome?

 

Conclusions of autism-gut study

Inflammation is seen in the gut as well as brain in the experimentally induced autism in mice. Findings are also consistent with the leaky gut hypothesis underlying autism.

 

Dr. Minocha’s comments

Results of this study bring to forefront the importance of gut being a critical element in causation of autism and the need to target gut as part of a comprehensive therapy for autism. 

 

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Role of Unhealthy Microbiome and Intestinal Infantile Colic

Traditionally, family psychodynamics, family bonding etc. have been implicated in pathogenesis of infantile colic. Use of modern molecular probes has shown that there is significant dysbiosis in these patients.

de Weerth and colleagues compared the microbial DNA of more than 200 samples from 12 infants with intestinal colic and 12 age-matched control infants. These investigators found that bacterial diversity increased only the healthy control babies and not in those with colic.

Samples were also less stable during the first few weeks in those with colic. Differences in bacterial patterns could be seen as early as week 1 or 2 of life.

The number of Proteobacteria is was more than 2 times higher in babies with colic as compared with control infants. The number of bifidobacteria and lactobacilli were significantly reduced in colic group.

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Dubois conducted an integrative review of literature and confirmed above findings. Specifically, the intestines in these patients exhibit greater numbers of Proteobacteria and significantly lower diversity of intestinal bacteria overall as compared to healthy subjects. 

Research also indicates that fewer the Actinobacteria Bifidobacterium and Firmicute Lactobacilli bacteria, the greater the crying and fussiness in babies. Such changes are significant because the imbalance is being created as a result of bacteria not normally abundant in the gut.

 

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Is It Leaky Gut or Leaky Gut Syndrome? 

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Is It Leaky Gut or Leaky Gut Syndrome?

Gluten is a well known toxin especially for patients with celiac disease. Gluten free diet is widely used for patients with functional bowel symptoms of irritable bowel syndrome. Many patients use it for variety of other disorders as well including but not limited to autism and obesity.

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Some of the bacteria of digestive system excreted in feces, most notably from the oral cavity have enzymes that can break down gluten. These enzymes if available commercially could offer a n attractive therapeutic target. Likewise use of these bacteria as probiotics may also help alleviate the disease.

Dr. Wei and colleagues from the School of Dental Medicine in Boston, Massachusetts, collected feces from 3 healthy subjects and then isolated the protein extract from them. The active strain of bacterial source of the enzyme was Pseudomonas aeruginosa.

Is It Leaky Gut or Leaky Gut Syndrome?

Gliadin breakdown activity was seen. An enzyme called pseudolysin was isolated. This enzyme was active at both acidic and neutral environment.

Pseudomonas aeruginosa is an opportunistic bacteria present normally in gut but can wreck havoc in immune-suppressed patients.

Conclusions

The results indicate that such an enzyme product could be used as an oral agent with the goal of breaking down gluten in the stomach before it even gets to the small intestine and cause damage. However, since such enzymes can have Harmful effects as well, more studies are warranted.

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Healthy sleep and nap for a healthy body and mind

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Is It Leaky Gut or Leaky Gut Syndrome?

Sleep: is it active or passive?

Sleep is not a passive phenomenon. It is just as essential as food and water for survival. It is critical for physical, mental and emotional health. Short as well as long sleep duration are associated with increased health risks. In fact, almost one third of our life is spent sleeping. Many experts argue sleep should be considered one of the vital signs.

How much sleep you need depends on your age and other health and lifestyle factors.

Recently, an expert panel of the National Sleep Foundation has made a reassessment of the state of the art sleep science and come up with updated made recommendations. The following recommendations have been published in the journal Sleep Health:

• Newborns: 14–17 hours a day (should not be less than 11 or more than 19 hours)
• Infants: 12–15 hours (should not be less than 10  or more than 18 hrs)
• Toddlers: 11–14 hours (should not be less than 9 or more than 16 hours)
• Preschoolers: 10–13 hours (should not be less than 8 hours or more than 14 hours)
• School-aged children: 9–11 hours (should not be less than 7 hours or more than 12 hours)
• Teenagers: 8–10 hours (should not be less than 7 hours or more than 11 hours)
• Young adults (up to age 25): 7–9 hours  (should not be less than 6 hours or more than 11 hours)
• Adults (26–64 years): 7–9 hours (should not be less than 6 hours or more than 10 hours)
• Older adults (65+): 7–8 hours (should not be less than 5 hours or more than 9 hours)

Dr. Minocha's comments

Healthy effects of sleep depend on sleep quality, sleep structure and time of day involved. It is frequently difficult to assess differences between time in bed and actual sleep time. As such, above data may be an over-assessment of actual sleep needs.  

 Is It Leaky Gut or Leaky Gut Syndrome?

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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.

Abnormal Gut Structure and Function in Autism

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Gastrointestinal illness is common in patients with autism and related disorders although some literature has disputed this.

 

Study

 

 Dr. Kim and colleagues from the School of Medicine and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Korea wished to study if there are structure abnormalities in the gut associated with autism. They reported their findings in the journal Toxicology Research.

Is It Leaky Gut or Leaky Gut Syndrome?

 Methods of autism-gut study

• The study was conducted in a rat animal model of autism. Use of valproic acid during pregnancy is a risk factor for in human autism. In fact, autism like behavior can be induced in rats exposed to valproate during fetal life.
• On embryonic day 12, pregnant rats were injected with valproic acid or control solution without valproic acid.
• The gut of the resulting rat babies was analyzed at age 4 weeks.

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Results autism-gut study

Multiple structure and functional abnormalities were found in valproic acid treated animals as compared to controls.

• The gut was slow. This is consistent with frequent finding of constipation in human autism.
• There was thinning of the stomach and terminal small intestinal wall consistent with the leaky gut hypothesis in autism.
• There were fewer absorptive cells in small intestine which is consistent with reports of digestive problems encountered in autism.

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Conclusions of autism-gut study

Rat model of autism is associated with structural and functional gastrointestinal changes consistent with clinical manifestations in humans.

 

Dr. Minocha’s comments

The results of this study lend further add to the scientific evidence of GI involvement in autism and the gut-brain axis. The fact that such changes can be seen in early life suggests that these are part of and not the result of autism disorder. Gut-focused therapy is of paramount importance in autism.

 

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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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Beverages, unnatural delivery, abdominal pain and other news

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Unnatural labor/delivery increases risk for autism.

Do soda beverages affect brain adversely and make kids violent?

Chronic abdominal pain can lead to anxiety in later life.

Read more on what treatments may work for chronic abdmonal pain in kids.

Striking rise in emergency room visits due to ADHD medications.

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Does vitamin D have role in autism?

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Hippocrates aptly stated, All disease begins in gut."

Vitamin D deficiency has been described as rising to epidemic proportions; however, not everyone agrees. Kikewise, recommendations for what is “normal leves” as well as indications for vitamin D supplementation are controversial.

Vitamin D status in health and disease

Vitamin D deficiency has been implicated in causation of multiple diverse diseases including neuro-psychiatric disorders like schizophrenia.

• Evidence supports a role of suboptimal vitamin D levels in depression.
• Autism shares many of the in-utero risk factors with schizophrenia.

Vitamin D and risk of autism

Recently several investigators have implicated vitamin D deficiency in increasing risk for autism [Cannell JJ 2010; Glasser 2009; Currenti 2010; Dealberto MJ 2011].

However evidence is circumstantial and studies examining direct cause-effect linkage are lacking.

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How vitamin D could affect autism risk and manifestations

1. Body does not wish to express all the genes present in the body all the time. Vitamin D plays an important role in gene regulation and its deficiency could initiate or expose the underlying genetic risk or induce genetic mutations.
2. Vitamin D plays an important role in DNA repair and its deficiency could impair reparative processes and increase risk for mutations.
3. Vitamin D has been shown to be neuroprotective. A deficient vitamin D state would increase the risk of brain injury during otherwise easier to manage acute problems during pregnancy like infections etc. or obstetric complications during delivery.
4. Vitamin D receptors are present in the central nervous system. Vitamin D deficiency would affect neurosignaling by its effects on neurotransmitters.
5. Vitamin D affects brain development via its neurotrophic effects. A deficiency would affect development of some or all parts of brain.
6. Calcitriol (the active vitamin D hormone) affects numerous neurotransmitters and neurotrophic factors, relevant for mental disorders.
7. Vitamin D enhances immune system and reduces viral infections. Vitamin D protects against Influenza which has been shown to damage brain. Putting these two together suggests that vitamin D may protect against infection and consequently reduce risk of harmful effects on brain.

Autism and vitamin D levels

Low levels of vitamin D have been documented in children with autism [Meguid 2010] as well as with other psychiatric problems including depression as compared to controls [Humble MB 2010]. A recent article in Mayo Clinic Proceedings (2011)documented correlation between  low vitamin D levels and depressive symptoms.

• In contrast, some studies have reported no difference in maternal vitamin D levels.
• The studies showing lack of relationship have been criticized for being too small to detect differences and for not examining prenatal levels or testing during pregnancy.

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Epidemiology of autism and vitamin D deficiency

Some data suggests vitamin D deficiency as a risk factor

• Parallel with increase in autism over the last few decades has been an increasing emphasis on protecting skin from sun’s ultraviolet rays thus reducing vitamin D synthesis and  causing increasing risk for vitamin D deficiency
• Children of mothers from outside Europe, America and Australia are at a greater risk for autism [Dealberto] and authors hypothesised  potentially lower vitamin D levels as potentially a causative factor.
• Others have argued that such ethnic/immigrant differences involve increased risk of allergic and autoimmune disorders and increased prevalence of autism may be immune dysfunction rather than vitamin D levels [Goines 2007].
• In contrast, another study comparing vitamin D levels found that the autism rates and vitamin D levels were similar in immigrant mother of kids with and without autism [Furnell 2010].
• There is no effect of paternal ethnicity.

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Nutritional epidemiology

• Exclusively breasts fed infants consume less thiamine, riboflavin, and vitamin D than the minimal daily requirements and have been shown to be at greater risk for autism as compared to mothers participating in nutritional programs.
• A controlled study found that autistic kids have lower intake of vitamin D, protein, calcium, and vitamin B12 as compared to controls.

Autism and skin color

• Higher risk in kids of dark skinned mothers may in part be explained by reduced vitamin D levels since darker skin requires greater sun exposure for vitamin D synthesis and the risk is exacerbated in moms who have migrated to colder, higher altitude areas.
• Effect of season of birth and effective latitude suggest role of maternal vitamin D in risk for autism. 

Dr. Minocha's comments on data and what to do?

In the absence of large randomized controlled trials, the issue remains open to debate.

The balance of data favors the hypothesis of involvement of vitamin D deficiency in pathogenesis of autism.

Given the limited data and widespread role of vitamin D in many organs including nervous system, it is prudent to maintain adequate levels of vitamin D.

• Note however, that what constitutes "normal" is mired in scientific debate.
• I recommend that all patients with low or low normal vitamin D levels receive vitamin D supplementation.
• Always talk to your doctor prior to taking such supplements.

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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.

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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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Effect of probiotics on brain dysfunction: Multiple sclerosis analogy

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Growing evidence indicates that there is an ongoing cross-talk between  intestinal bacteria and brain mediated in part by immune system. There is some evidence linking intestinal bacteria in pathogenesis of some disorders like autism including differences in type of gut bacteria and short term effect of antibiotics.

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Herein we will review the link between the intestinal bugs and another nervous system disorder, i.e. multiple sclerosis.

Animal model of multiple sclerosis

Certain type of mice, e.g. Relapsing-remitting (RR) mouse model spontaneously develop experimental autoimmune encephalomyelitis (EAE) which in analogous to human multiple sclerosis (MS). Thus these mice are genetically predisposed to the disease which I will refer to as EAE/MS

• However not all of these mice develop disease EAE/MS
• Interestingly, the risk for development of disease (35% to 90%) varies depending upon where they are located i.e.  institution where breeding center is located .

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Hypothesis underlying multiple sclerosis (MS)

• There are two schools of thoughts. The changes in central nervous system (CNS) are primary initiating events. Others suggest that disease is rooted in the immune system.
• Not unlike autism, diet has been implicated in pathogenesis of MS in order to explain the exponential rise of the prevalence in Japan attributed to Western Lifestyles.
• According to Ochoa-Raparaz and colleagues from the Dartmouth Medical School in Lebanon, NH, the reservoir for the immune cells involved in multiple sclerosis may lie within the Gut Associated Lymphoid Tissue (GALT).

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Gut bacteria Brain study

Berer and colleagues from the Department of Neuro-immunology, Max Planck Institute of Neurobiology, Germany conducted studies in RR mouse model to determine the role of gut bacteria in the developmental of experimental multiple sclerosis.

• Comparison of totally germ free animals (never exposed to bacteria) and specific pathogen free (SPF) animals showed that disease EAE/MS developed in SPF animals within 3 months, it did not develop in germ free animals.
• Since bacteria play a key role in immune development, absence of disease in germ free animals suggests that lack of immune activation by gut bacterial stimulation.
• When the germ free mice were colonized with conventional bacteria, the formerly germ free mice developed EAE/MS disease shortly thereafter further substantiating the critical role of gut bacteria in autoimmune disorders.
• The difference between the 2 similar animals but with or without gut bacteria  is not based upon capacity to produce anti-MOG antibodies upon immunization.
• A word about MOG: Myelin Oligodendrocyte Glycoprotein (MOG) is a protein which plays an important role in myelinization of nerves in CNS. It is critical as an adhesion molecule providing structural integrity to the myelin, a sheath that insulates the nerves. When damaged for example by antibodies, it causes demyelinating disorders like multiple sclerosis (MS).
• Administration of anti-MOG serum results in increased risk of MS relapse presumably because of antibody induced damage to the myelin sheath.
• In subjects at risk for developing multiple sclerosis, the presence of these antibodies increases the likelihood that the subjects develop the disease.
• Caution: Data thus far on MOG link studies do not necessarily establish cause-effect relationship.

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How may gut bacteria affect brain?

• The gut bacteria could interact with MOG-specific lymphocytes by probably mimicking MOG which is important for maintaining integrity of myelin sheath of nerves.
• This suggests that the disease process starts in the Gut Associated Lymphoid Tissue (GALT). A bacterial stimulus results in autoimmune lymphocytes which instigate the demyelinating encephalomyelitis.

Potential therapeutic strategies to treat multiple sclerosis and other neurological diseases like autism if Gut Bugs and Brain theory is confirmed

• Repopulation of gut bacteria
• Immunization against bacterial antigens
• Antibiotics targeted against specific pathogens
• Probiotics to alter gut bacteraia balance to modify immune system

Evidence for some of the above therapeutic options

• Treatment of RR animals with probiotics reduces MS like symptoms as well as inflamation.
• Treatment with probiotics reduces the severity of established EAE/MS in mice.
• Opposite is true as well. Administration of lipid derived from normal mouth bacteria (commensal) Porphyromonus gingivalis exacerbates EAE/MS in mice.

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Omega-3 Fatty Acids: Implications for autism

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• Patients with autism spectrum disorders tend to have greater prevalence of gastrointestinal disorders.
• Many autism patients have food aversion and are picky eaters.
• Most of the pharmacological treatments in vogue currently have strikingly little evidence to support their use.
• Many parents have undertaken complementary and alternative treatments (CAM) especially nutritional interventions.
• Omega-3 fatty acid (n-fatty acids) supplementation has been advocated by many experts.
• Omega-3 fatty acid supplements are part of 12-step autism treatment program.

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Essential fatty acids

• Polyunsaturated fatty acids (PUFAs)
• Play critical role in function of nervous system as well as immune system
• Not synthesized in human body.
• Hence need to be consumed in diet or as supplements.
• Some fatty acids are conditionally essential

Omega-3 versus Omega-6 fatty acids

Long chain omega -3 fatty acids

• Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) mainly from fish and sea food.
• Most of the DHA build up in the brain occurs during late pregnancy to the third trimester of pregnancy to the second year of life.
• Conversion from ALA to DHA is more efficient in the developing brain than in the well-developed brain.
• Exogenous sources as diet is an important source for maintaining adequate DHA levels in adult brain.

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Short chain omega-3 fatty acids

• Alphalinolenic acid (ALA) mainly derived from vegetarian sources such as flaxseed, grains, soya beans and olives
• ALA can be converted to EPA and DHA to a modest degree by the human body

Omega-6 fatty acids (example Linolenic acid (LA)

• Major sources include derived from vegetable oils and animal fat
• Target ratio of omega-3 versus omega-6 fatty acids has been suggested to be 1:1 to 4:1
• Modern diet frequently exceeds these ratios increasing potential for sickness.

Essential fatty acids and nervous system

• Play a critical role in brain functions and transmission across nerves
• Balance between various essential fatty acids is a major determinant in the maturation of brain function.
• Inadequate 3-PUFA during the perinatal period in animal models leasd to disordered learning, neurotransmission and visual processes
• Polyunsaturated fatty acids (PUFAs) can cross blood brain barrier and enter brain

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How Omega-3 fatty acids may be important in ASD

• Reduced omega-3 fatty acids with or without changges in omega-6 fatty acids (increased imbalance) has been linked to nervous system disorders like ADD, dyslexia and dyspraxia.
• Role in pathogenesis of depression and schizophrenia.
• Some studies suggest that omega-3 fatty acid supplementation is of benefit in cases of depression and Alzheimer’s disease

Is It Leaky Gut or Leaky Gut Syndrome?

Increasing Incidence of Autism and Traditional versus Modern diet

• Ancient diets contained higher amount of wild sea food and fats from grass fed animals
• Modern diet is deficient in omega-3 fatty acids
• Modern diet contains excess of omega-6 fatty acids
• Fat in modern diet is mainly derived from vegetable sources and rich in omega-6 fatty acids
• Modern food processes like hydrogenation used to extend shelf life result in decrease in omega-3 fatty acids thus increasing the imbalance

Omega-3 fatty acid deficits may be patient specific

• May have greater than average requirement especially in case of inefficient metabolic processes

Evidence for omega-3 supplementation in autism spectrum disorders

• Most data is uncontrolled studies/reports (Johnson 2003, Patrick 2005; Bell 2004)
• Two small randomized controlled trials (Amminger 2007 and Bent 2011) with conflicting results
• Amminger study from Medical University of Vienna, Vienna demonstrated that omega-3 fatty acids are superior to placebo for improving hyperactivity and stereotypy.
• Bent study from University of California, San Francisco, CA, showed no effect although authors offered a disclaimer that “small sample size does not exclude small to moderate beneficial effects".
• A metaanalysis (Montgomery and Williams 2011) combining the above two studies concluded that “effectiveness of omega-3 fatty acids for ASD cannot be determined” since there is “insufficient evidence” indicating that omega-3 fatty acids are effective in ASD. Authors recommended that high quality, large randomized controlled trials to resolve the issue.

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Dr. Minocha’s comments on implications of above

• Both the controlled trials enrolled too few subjects especially for a disorder as heterogeneous as autism.
• Only large randomized controlled trials can resolve the issue of potential benefits.
• Based on available clinical and preclinical data and our modern diet, it is my opinion that omega-3 fatty acid supplements have potential to be of benefit in at least a subset of patients with autism spectrum disorders.

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More treatment strategies at the 12-point treatment program for autism. 

PANDAS: Do you know about it?	Warning signs of autism
Overview of autism spectrum disorders	Unhealthy gut and digestion are at root of many chronic diseases
Desulfovibrio: The new bad actor on autism scene	Abnormal gluten gliadin antibodies in autism
Functioning brain MRI scan evidence probiotics affect brain changes	D-ribose reenergizes brain in autism,  ADHD
Autism is rising in developing countries too	Probiotics improve brain function, mood, memory
Intergenerational effects: Implications for chronic diseases like autism	Altered Fermentation of Undigested Food by Gut Bacteria in Autism: Clues to Treatment Strategies
Antibiotics in meat: A case for organic food	Does Influenza and Antibiotic Use During Pregnancy Increase  Autism
Does proximity to freeway traffic  increase risk of autism	Ketogenic diet and autism
Moms' Probiotic Use Reduces Eczema	Effect of Gut Bacteria on Ultimate Health Starts During Pregnancy

Is It Leaky Gut or Leaky Gut Syndrome?

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Gut dysfunction link to behavioral problems: The autism model

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Autism spectrum disorders (ASD) are a group of heterogenous disorders characterized by behavioral problems etc along with non-neurological co-morbidities.

Evidence suggests that there is increased prevalence of gastrointestinal symptoms (whether or organic or neurobehavioral) in autism. Based on gut-brain hypothesis, such symptoms could be the child's method of communicating his/her symptoms to the care-giver.

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Autism-GI study overview

• Dr. Maenner and colleagues from the Waisman Center and Department of Population Health Sciences at the University of Wisconsin-Madison conducted the study.
• The investigators wished to examine if the behavioral problems tend to occur more in patients with gastrointestinal (GI) problems.
• The results of the study were reported in the Journal of Autism Developmental  Disorders.

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Autism-GI study design

• An ADDM network methodology was used. Behavioral features were compared between autism patients with and without GI problems.
• Patients were classified as autism if they met the DSM IV-TR  (American Psychological Association 2000) criteria  for the disorders at any time prior to the age of 8 years.
• The demographic and clinical information including results of psychometric tests and concurrent medical problems were recorded
• Eight different behavioral manifestations that may reflect a gastrointestinal disturbance were analyzed and included sleep abnormalities, mood disturbances and temper tantrums.
• Six non-GI related behavioral features like fear, delayed motor milestones were also analyzed for comparison.

Results of Autism-Gut study

• 7.2% of ASD patients studied had documented GI problems. Constipation and encopresis were common
• Autism patients with GI problems were more likely to have cerebral palsy and seizure like activity as compared to those who did not.
• Occurrence of gastrointestinal (G)I problems positively correlated with behavioral problems such as sleep problems, mood, abnormal eating habits, oppositional and defiant/destructive behavior, tantrums and delayed motor milestones.
• There was no association of GI problems with stereotypic/repetitive and self-injurious behaviors.
• There was lack of association with most control behaviors studied except delayed milestones.

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Conclusions of Autism-Gut Study

• The association of GI problems with cerebral palsy, seizure like activity and delayed milestones suggests that a subset of patients suffers from multisystem disorder involving nervous, gastrointestinal and immune system.
• Behavioral problems thought to be an expression of GI problems are common in autism although not specific to those with GI problems.
• Example: sleep problems were seen in 11% of those with GI problems as compared to 4% in those without
• Prevalence of autism behaviors does not accurately identify autism patients requiring gastrointestinal evaluation.

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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.

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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?

FREE at Barnes & Noble: Doctor's Guide to Milk and Your Health: The Good, The Bad or The Slow Poison

Wall Street Journal Best Seller Dr. M's Seven-X Plan for Digestive Health

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Is It Leaky Gut or Leaky Gut Syndrome?

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Is It Leaky Gut or Leaky Gut Syndrome?

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Autism link to cancer gene

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Is It Leaky Gut or Leaky Gut Syndrome?

FREE at Barnes & Noble: Doctor's Guide to Milk and Your Health: The Good, The Bad or The Slow Poison

Wall Street Journal Best Seller Dr. M's Seven-X Plan for Digestive Health

A. Interesting report: Autism is linked to a cancer gene!

B. ADHD diagnosis in minorities. Is there a difference?

C. Can bad parenting styles cause ADHD?

D. Healthy recipe to try

E.  Did you know that food rituals are important and contribute to fun and enjoying food! 

Is It Leaky Gut or Leaky Gut Syndrome?

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Wall Street Journal Best Seller Dr. M's Seven-X Plan for Digestive Health

Health tips, yoga, pilates and other news

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FREE at Barnes & Noble: Doctor's Guide to Milk and Your Health: The Good, The Bad or The Slow Poison

Wall Street Journal Best Seller Dr. M's Seven-X Plan for Digestive Health

This article has about 20 tips to improve health. I may not agree with all of them, but they mostly make sense. Worth checking them out!

What is better: Yoga or pilates?

Cocoa healthy for brain? Helps some cases of dementia!

How having a breakfast has become a health controversy.

Identical twins will act as guinea pigs for NASA. Both are astronauts, one will go into orbit, while other stays here. The goal is to examine the effects on the human after a long term space flight. 

Can cell phones cause cancer? 

Is It Leaky Gut or Leaky Gut Syndrome?

Facebook Dr. Anil            Home page            AutismItsGutStupid

Wall Street Journal Best Seller Dr. M's Seven-X Plan for Digestive Health