Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

There are many comorbidities associated with autism.  I have long held the view that these comorbidities hold the key to understanding each particular case of autism.  In many cases this may be far more useful than genetic testing, which only seems to help in a minority of cases.

“Ringed esophagus” aka “Corrugated esophagus”


This then allows you to put people into sub-groups that may well respond to the same therapy.  This may all sound like common sense, but apparently is not.

Eosinophilic esophagitis (EoE) is a relatively new diagnosis and it is applies to a certain type of reflux/GERD/GORD that might be associated with a difficulty in swallowing and may not respond well to the standard stomach acid lowering therapies.

It is likely that most people with Eosinophilic esophagitis have never been correctly diagnosed. Many people have taken several years to get the correct diagnosis.

It is known that Eosinophilic esophagitis is much more common in autism than the general population. One study showed that EoE is four time more likely to be diagnosed in someone with autism. I suspect many people with autism never have their GI problems fully diagnosed.

We now have to add some new science to this blog

Granulocytes

There is a great deal already in this blog about mast cells.  Many readers have children who have allergies, mast cell activation, or even mastocytosis.  Mast cells are the ones (but not the only ones) that release histamine.

Mast cells are just one type of a class of cells called Granulocytes, that are produced in your bone marrow.

Granulocytes are a category of white blood cells characterized by the presence of granules, which release their contents when they degranulate.

The four types of granulocytes are:- 

·        mast cells

These have been well covered in the past. These are what cause problems for people with pollen allergy.

·        eosinophils

Eosinophils play a crucial part in the killing of parasites because their granules contain a unique, toxic basic protein and cationic protein. Eosinophils regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils), they are involved in the destruction of tumor cells, and they promote the repair of damaged tissue. Interleukin-5 interacts with eosinophils and causes them to grow and differentiate; IL-5 is produced by basophils.

Note that some people with autism find that the TSO helminth parasites modify their immune system and improve their autism. This may relate to what is contained in the granules of eosinophils.  

·        basophils 

Basophils are similar to mast cells, in that they contain prestored histamine within their granules. Unlike mast cells they circulate in your blood . Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting.

There is research underway to try to develop basophil stabilizers.

·        neutrophils

Neutrophils are normally found in the bloodstream. During the beginning phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.

Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection.

An obvious question would be, if you know you have a problem with mast cells are you likely to have an issue with the other types of granulocytes?

One role of eosinophils is to regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils).

The subject is highly complex and again not fully understood, but it is clear that granulocytes are all interrelated and so a problem with one may well be associated with a problem with others.

In the case of Eosinophilic esophagitis (EoE), both eosinophils and mast cell are directly involved.

Basophils, like mast cells, release histamine among other things when they degranulate.

Mast cells usually do not circulate in the blood stream, but instead are located in connective tissue.  Circulating granulocytes, like basophils can be recruited out of the blood into a tissue when needed.

So in addition to mast cell stabilizers perhaps, we might benefit from basophil and eosinophil stabilizers.

Surprisingly, the antihistamine cetirizine has Eosinophil-stabilizing properties, as does the asthma drug Montelukast. Both drugs are widely used in children.

Another substance, curine, also inhibits eosinophil influx and activation and is seen as a potential new treatment for asthma.  Interestingly the drug curine, is an alkaloid, that blocks L-type Ca²⁺ channels.

Regular readers may recall that I proposed the L-type calcium channel blocker Verapamil to control my son’s mast cell degranulation. Mast cells degranulate in a very complex fashion that involves the flow of Ca²⁺.

This may or may not be a coincidence. 

Fullerene nanomaterials are being developed as both mast cell and peripheral blood basophil stabilizers.

L-type calcium channels and GI disorders in Autism

There are many types of GI disorder in autism, however I suggest that a large group can be categorized as being broadly Granulocyte Disorders, which may well all respond to L-type calcium channel blockers, to some extent.

Indeed this may be a better solution than the widely used cromolyn sodium.

Perhaps people with autism, and their family members have certain calcium channels that are either overexpressed, or do not close fast enough, leading to a higher level of intracellular calcium.  This of course ties back in with Professor Gargus and his theories about IP3R and the calcium store inside the “endoplasmic reticulum”.

This all gets extremely complex.

My rather simple suggestion would be that if you have autism and any GI problem from the esophagus downwards, a three day trial of verapamil just might change your life.  As is almost always the case, there are some people who do not tolerate verapamil.

Interleukin 5

Interleukin 5 (IL-5) is an inflammatory cytokine produced by type-2 T helper cells  (Th2), mast cells, basophils and eosinophils.

IL-5 interacts with eosinophils and causes them to grow and differentiate.

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, where a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.

You might expect high levels of IL-5 in people with Eosinophilic esophagitis (EoE)

Anti–IL-5 (mepolizumab) therapy for eosinophilic esophagitis 

Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3⁺ blood cells) in patients with EE and improved clinical outcomes.

Not surprisingly the same anti-IL-5 therapy has been approved to treat severe asthma.

NICE recommends first-of-its kind asthma treatment mepolizumab  

Patients are given mepolizumab by injection every four weeks. It costs £840 per dose.

Mepolizumab for autism?

It is very expensive, so I doubt many people will think of Mepolizumab for autism.  If you have EoE, or severe asthma, you may be able to access this IL-5 therapy, my guess is that it would also reduce the severity of any comorbid autism.

Back to Eosinophilic Esophagitis

I was writing a while ago about food allergy in my book and came across the opinion that food allergy is no more common in autism than in typical people, but what is more common is Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of digestive system (gastrointestinal) illness.  In many cases it likely remains undiagnosed. If it continues, after a few years swallowing becomes difficult, in part because a “ringed esophagus” develops that impedes the passage of food.

As seems to be often the case there are plenty of contradictions in the diagnosis and treatment, as you will find as you read on.

The symptoms are broadly what would normally be diagnosed as reflux/GERD/GORD. This is very often found in people with autism and I expect in their relatives.

It is relevant to autism because it will be yet another comorbidity that when treated should improve autism, but it is also another marker of a particular sub-group of autism.

There are numerous other GI conditions comorbid with autism - colitis, IBD, IBS etc.  In the end I imagine that the molecular basis of some of these diagnoses is actually the same, so you will find the same therapies may be effective.

It looks like that one common factor is the mast cell and, just as in pollen allergy and asthma, stabilizing mast cells yields great benefit. Stabilizing mast cells is complex but involves the flow of calcium ions, Ca²⁺.  By modifying the flow of Ca²⁺ you can prevent mast cells degranulating.  This was one of my earlier discoveries, but there is now research showing the L type calcium channels “open” mast cells.  Keeping these channels closed is actually quite simple.

It would seem logical that the same approach could be therapeutic to other conditions that are, at least in part, mediated by mast cells.

According to the Mayo Clinic these are symptoms of eosinophilic-esophagitis

Adults:

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         Chest pain that is often centrally located and does not respond to antacids

·         Persistent heartburn

·         Upper abdominal pain

·         No response to gastroesophageal reflux disease (GERD) medication

·         Backflow of undigested food (regurgitation)

Children:

·         Difficulty feeding

·         Vomiting

·         Abdominal pain

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         No response to GERD medication

·         Failure to thrive (poor growth, malnutrition and weight loss)

The diagnosis of EoE is typically made on the combination of symptoms and findings of diagnostic testing.


Prior to the development of the EE Diagnostic Panel, EoE could only be diagnosed if gastroesophageal reflux did not respond to a six-week trial of twice-a-day high-dose proton-pump inhibitors (PPIs) or if a negative ambulatory pH study ruled out gastroesophageal reflux disease (GERD).

Treatment strategies include dietary modification to exclude food allergens, medical therapy, and mechanical dilatation of the esophagus.

The current recommendation for first line treatment is PPI in lieu of diet as a significant portion of EOE cases respond to this, and it is a low risk, low cost treatment.

The second and third line therapies are an elimination diet of either the 6 or 4 most common triggers, or topical corticosteroids, including both fluticasone, and topical viscous budesonide.

Elimination diets would be followed by re-introduction of foods under supervision if the first diet is successful. Allergy evaluation has not been found to be an effective means to determine what foods to eliminate.

  

Eosinophilic esophagitis in adults: An update

MAST CELL STABILIZERS

In a small case series, Cromolyn sodium failed to show any clinical or histologic improvement in EoE patients

LEUKOTRIENE INHIBITORS

Montelukast is an eosinophil stabilizing agent. It improved clinical symptoms in EoE but there was no histological improvement

PROGNOSIS

As mentioned earlier, EoE is a chronic inflammatory disease of the esophagus. The inflammation leads to remodeling, fibrosis and stricture. Fortunately, no case of esophageal malignancy has been reported in EoE. Patients are generally diagnosed after several years of their symptoms. Although symptomatic improvement occurs after treatment, recurrence is common after discontinuation of treatment. So maintenance therapy is needed to prevent recurrences. At the present time there is no head to head study to suggest the best maintenance treatment. Continuation of swallowed corticosteroid and/or dietary therapy should be done in all EoE patients particularly in those with history of food impaction, dysphagia, esophageal stricture, and in those with rapid symptomatic and histologic relapse following initial treatment

Eosinophilic esophagitis and Mast Cells

Eosinophilic esophagitis is called Eosinophilic because it is mediated by Eosinophils, however it has been established that mast cells also play a role. 

Involvement of mast cells in eosinophilic esophagitis

Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Herein we have identified local mastocytosis and mast cell degranulation in the esophagus of EE patients; identified an esophageal mast cell associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome with CPA3 mRNA levels serving as the best mast cell surrogate marker; and provide evidence for the involvement of KIT ligand in the pathogenesis of EE.

One possible explanation for eosinophilic esophagitis:

Expanding the paradigm of eosinophilic esophagitis: mast cells and IL-9

A potential immunological mechanism involved in the pathogenesis of EoE. An uncontrolled TH2 immune response initiated by an allergic insult results in the transition of the esophagus from a normal (NL) to EoE phenotype through enhanced IL-13 production that induces highly elevated CCL26 (eotaxin-3) expression by esophageal epithelium. Dysregulated TH2 immune response and enhanced CCL26 secretion together promote the infiltration of CD4⁺TH2 cells, eosinophils, and mast cells, and potentially, type-2 innate lymphoid cells (ILC2) and CD4⁺TH9 cells; into the esophagus. TGF-β and IL-4 produced by the activated mast cells and CD4⁺TH2 cells may induce eosinophils, ILC2, and/or CD4⁺TH9 cells to produce IL-9, which in turn, promotes esophageal mastocytosis that contributes to the development of EoE pathophysiology.

Possible Eosinophil stabilizers

An Open Label Add-On Trial of Cetirizine for Neuromyelitis Optica (P4.003)

CONCLUSIONS Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been well-tolerated in our patient population, with incoming data about efficacy expected over the coming months

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

·        Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum.

·        Curine inhibits eosinophil influx and activation and airway hyper-responsiveness.

·        Curine mechanisms involve inhibition of Ca²⁺ influx, and IL-13 and eotaxin secretion.

·        No significant toxicity was observed in mice orally treated with curine for 7 days.

·         Curine has the potential for the development of anti-asthmatic drugs.

  

Conclusion

Non conventional therapies for eosinophilic esophagitis might include:-

·        Cetirizine

·        Verapamil

·        Montelukast

·        Curine

The very expensive therapy is Mepolizumab.

If you have one type granulocyte causing a disorder, is seems almost inevitable that the other types of granulocyte are also involved.

Treating granulocyte disorders should improve autism and left untreated they may mask the effect of otherwise useful autism therapies. 

One reader did previously suggest a bone marrow transplant for autism. A rather radical solution, but if someone with autism was given donor bone marrow as part of another therapy, you might well see their autism improve.

More Melatonin!

  Older people, those with autism, those with reflux, IBS/IBD and other GI problems generally have low levels of melatonin.  Poor sleep is but one consequence.

I have previously written about the potential for melatonin in autism and I do not just mean to improve sleeping disorders.  Melatonin does a great deal more than that.

Melatonin for Kids with Autism, and indeed their Parents

MitoE, MitoQ and Melatonin as possible therapies for Mitochondrial Dysfunction in Autism. Or Dimebon (Latrepirdine) from Russia?

Most substances I write about in this blog are either prescription drugs or quite expensive supplements.

Other than in a small number of countries like the United Kingdom, melatonin is widely available as a cheap supplement, but that does not mean it is not a drug.

In humans melatonin is produced in two different places and it appears in two orders of magnitude.  Traditionally melatonin is considered to be a hormone produced by the pineal gland in the brain, but far more melatonin is actually produced in your intestines, where it has completely different functions.

Many people have low levels of melatonin, for example people with autism/schizophrenia/bipolar, older people and people with intestinal problems ranging from reflux/GERD/GORD to ulcerative colitis.

We know that melatonin is a potent antioxidant, but there are numerous other antioxidants.  Damaging oxidants vary both by type, but also by their location and so if you are clever you would match your antioxidant(s) very specifically to the oxidant(s).  

So if you have elevated risk of prostate cancer, take lycopene, it accumulates in fatty tissue and the prostate is surrounded by a fatty deposit called periprostatic adipose tissue (PPAT).  It is not agreed whether lycopene can cross the blood brain barrier in humans; it does for sure in rats.  

It seems that in people with type 2 diabetes there is oxidative stress in the mitochondria of the beta cells in their pancreas.  Beta cells make insulin and in type 2 diabetes there is often a gradual loss in beta cells resulting in type 1 diabetes.  Numerous cancer studies have shown the potential of different antioxidants in different cancers, NAC in breast cancer, Sulforaphane is esophageal cancer etc.  It seems to be agreed that antioxidants are most helpful in disease prevention, rather than cure.  

  

We know that melatonin is potent at combatting oxidants in the mitochondria, so logically people with mitochondrial dysfunction might well benefit from melatonin.  It is vastly cheaper than the antioxidant drugs that target the mitochondria (MitoE, MitoQ etc).

An interesting recent study has linked low levels of melatonin in the parents of those with autism.

Low parental melatonin levels increases autism spectrum disorder risk in children

  

Background: Low melatonin levels are a frequent finding in autism spectrum disorder (ASD) patients. Melatonin is also important for normal neurodevelopment and embryonic growth. As a free radical scavenger and antioxidant melatonin is highly effective in protecting DNA from oxidative damage. Melatonin deficiency, possibly due to low CYP1A2 activity, could be a major factor, and well a common heritable variation. ASD is already present at birth. As the fetus does not produce melatonin, low maternal melatonin levels should be involved. Methods: We measured 6-sulfatoxymelatonin in urine of mothers of a child with ASD that attended our sleep clinic for people with an intellectual disability (ID), and asked for parental coffee consumption habits, as these are known to be related to CYP1A2 activity. Results: 6-Sulfatoxymelatonin levels were significantly lower in mothers than in controls (p = 0.005), as well as evening coffee consumption (p = 0.034). In mothers with a second child with ASD and/or ID, 6-sulfatoxymelatonin levels were lower compared to mothers with one child with ASD (p = 0.084), 

Conclusions: Low parental melatonin levels, likely caused by low CYP1A2 activity, seem to be a major contributor to ASD and possibly ID etiology.

I think you would also find, more generally, high levels of oxidative stress in parents of those with autism, and more importantly oxidative stress during pregnancy would have negative effects.  I think autism produces stress and stress helps produce autism.

  

The Potential Role of Melatonin on Mental Disorders: Insights from Physiology and Pharmacology 

Potency of pre–post treatment of coenzyme Q10 and melatoninsupplement in ameliorating the impaired fatty acid profile in rodent model ofautism

  

Melatonin as a stabilizerof mitochondrial function: role in diseases and aging

  

"It is now almost 60 years since the discovery of melatonin and new physiological functions of the indole continuously appear in the most recent studies worldwide. Besides the pineal gland, the existence and value of other sources of synthesis force us to rethink the established premises about the biological role of this molecule, such as the well-known regulation of circadian and reproductive cycles (Hardeland et al., 2008). In the last few years, other properties of melatonin such as antioxidant power, immunoregulatory capacity, and oncostatic action have enriched our knowledge about the pleiotropic nature of the hormone.

The role of melatonin in mitochondrial homeostasis has gained strength in the scientific community. Experimental evidence emphasizes its importance as a stabilizer of organular bioenergetics, which could be related to the             prevention of development of aging and several diseases.

  

Role of melatonin on mitochondrial dysfunction and diseases

The idea that mitochondrial dysfunction is implicated in the etiology of various diseases has been strengthened after several years of research. Initially, studies of mitochondrial diseases have focused on mitochondrial respiratory-chain diseases associated with mutations of mtDNA. However, more recent evidence shows that oxidative damage is responsible for the impairment of mitochondrial function, leading to a self-induced vicious cycle that finally culminates in necrosis and apoptosis of cells and organ failure. We are now starting to understand the mechanisms of a large list of mitochondrial-related diseases (cancer, diabetes, obesity, cardiovascular and neurodegenerative diseases, and aging); all of them seem to share the common features of disturbances of mitochondrial Ca2+, ATP, or ROS metabolism (Sheu et al., 2006). Therefore, selective prevention of such phenomena should be an effective therapy in a wide range of human diseases (Smith et al., 1999; Sheu et al., 2006). Melatonin, as was described in the previous section, has many of the characteristics of a perfect candidate for the treatment of these kinds of illnesses.

  

Conclusion

Mitochondrial dyshomeostasis and related events have begun to reveal themselves as possible etiologies of several diseases of unknown origin. In the next years, conscientious investigation about this topic should be undertaken by scientists of different research areas to achieve a better understanding of the molecular mechanisms implied, which will ultimately allow the development and clinical application of efficacious treatments."

Recent posts looked at disturbed calcium homeostasis in autism, particularly low bone density.  Melatonin may play a role here as well.

     Melatonin Osteoporosis Prevention Study (MOPS)

Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women.

Abstract

The purpose of this double-blind study was to assess the effects of nightly melatonin supplementation on bone health and quality of life in perimenopausal women. A total of 18 women (ages 45-54) were randomized to receive melatonin (3mg, p.o., n=13) or placebo (n=5) nightly for 6months. Bone density was measured by calcaneal ultrasound. Bone turnover marker (osteocalcin, OC for bone formation and NTX for bone resorption) levels were measured bimonthly in serum. Participants completed Menopause-Specific Quality of Life-Intervention (MENQOL) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after treatment. Subjects also kept daily diaries recording menstrual cycling, well-being, and sleep patterns. The results from this study showed no significant change (6-month-baseline) in bone density, NTX, or OC between groups; however, the ratio of NTX:OC trended downward over time toward a ratio of 1:1 in the melatonin group. Melatonin had no effect on vasomotor, psychosocial, or sexual MENQOL domain scores; however, it did improve physical domain scores compared to placebo (mean change melatonin: -0.6 versus placebo: 0.1, P<0.05). Menstrual cycling was reduced in women taking melatonin (mean cycles melatonin: 4.3 versus placebo: 6.5, P<0.05), and days between cycles were longer (mean days melatonin: 51.2 versus placebo: 24.1, P<0.05). No differences in duration of menses occurred between groups. The overall PSQI score and average number of hours slept were similar between groups. These findings show that melatonin supplementation was well tolerated, improved physical symptoms associated with perimenopause, and may restore imbalances in bone remodeling to prevent bone loss. Further investigation is warranted.

           Melatonin Effects on Hard Tissues: Bone and Tooth

Melatonin, as an endogenous hormone, participates in many physiological and pharmacological processes. The above analyzed data indicate that melatonin may be involved in the development of the hard tissues bone and teeth. Decreased melatonin levels may be related to bone disease and abnormality. Due to its ability of regulating bone metabolism, enhancing bone formation, promoting osseointegration of dental plant and cell and tissue protection, melatonin may used as a novel mode of therapy for augmenting bone mass in bone diseases characterized by low bone mass and increased fragility, bone defect/fracture repair and dental implant surgery. The investigation of melatonin on tooth still insufficient and requires further research.

The following very interesting study, looking at the broader effects of high dose melatonin in autism, has been completed, but the results have yet to be published

Melatonin Dose-effect Relation in Childhood Autism (MELADOSE)

the objective of this clinical trial is to study the relation between the melatonin dose administered and its effect on severity of autistic impairments especially in verbal communication and play.

Experimental: 2 mg melatonin 1 tablet of 2mg melatonin and 4 tablets of its placebo once a day, an hour before falling asleep, for 6 weeks.
Experimental: 4 mg melatonin 2 tablets of 2mg melatonin and 3 tablets of its placebo once a day, an hour before falling asleep, for 6 weeks.
Experimental: 10 mg melatonin 5 tablets of 2mg melatonin once a day, an hour before falling asleep, for 6 weeks.

The science part

The following is an extract from an excellent paper about the use of melatonin to treat ulcerative colitis:-

Melaton in and Ulcerative Colitis: Evidence, Biological Mechanisms, and Future Research

Melatonin was first described as a secretion from the pineal gland with multiple neurohormonal functions, including regulation of the circadian rhythm, reproductive physiology, and body temperature, but has since also been found to inhibit the Cox-2 and NF-_B pathways and several aging processes. The multifactorial role of this hormone, however, has only relatively recently been appreciated (Fig. 1) as it circulates unimpeded across anatomical barriers, the blood– brain barrier included, and exhibits both receptor-dependent and receptor-independent effects.

Furthermore, melatonin exhibits a high degree of conservation across the evolutionary ladder, pointing to a critical function in various forms of life, even in organisms devoid of a pineal gland. In fact, the analysis of extrapineal sources of melatonin have highlighted the GI tract as a major source of this factor, with concentrations of melatonin as much as 100 times that found in blood and 400 times that found in the pineal gland.40 GI melatonin comes from both pineal melatonin and de novo synthesis in the GI tract and may have a direct effect on many GI tissues, serving as an endocrine, paracrine, or autocrine hormone, influencing the regeneration and function of epithelium, modulating the immune milieu in the gut, and reducing the tone of GI muscles by targeting smooth muscle cells.40 Melatonin may also influence the GI tract indirectly, through the central nervous system and the mucosa, by a receptor-independent scavenging of free radicals leading to reduction of inflammation, reduction of secretion

of hydrochloric acid, stimulation of the immune system, COX-2 fostering tissue repair and epithelial regeneration, and increasing microcirculation. Human intestinal motility follows a circadian rhythm with reduced nocturnal activity. Abnormalities in colonic motor function in patients with UC have been well documented.

Melatonin appears to be involved in the regulation of GI motility, exerting both excitatory and inhibitory effects on the smooth musculature of the gut.  The precise mechanism through which melatonin regulates GI motility is not clear, although some studies suggest that this may be related to blockade of nicotonic channels by melatonin and/or the interaction between melatonin and Ca2+ activated K channels.

Melatonin may also function as a physiological antagonist of serotonin. In a recent rodent model, melatonin administration was shown to reverse lipopolysaccharide-induced GI motility disturbances through the inhibition of oxidative stress. The net motor regulation by melatonin is, therefore, likely multifactorial.

In addition, several lines of in vitro studies as well as animal studies, have reported that melatonin regulates the extensive gut immune system and has important general antiinflammatory and immunomodulatory effects. Given its

presence in GI tissue and its suggested importance in GI tract physiology, it is reasonable to hypothesize that melatonin could influence inflammation-related GI disorders, including UC. In various animal experiments, melatonin administration was (among other immunomodulatory effects) shown to increase

IL-10 production and inhibit production of IFN-_, TNF-_, IL-6, and NO, suggesting that melatonin may exert benefits in UC by reducing or controlling inflammation.

Melatonin administration has also inhibited the TNF-_-induced mucosal addressin cell adhesion molecule (MAd-CAM)-1 in vitro, and intercellular adhesion molecule (ICAM)-1 in vivo, limiting the influx of activated _4_7_ and LFA-1_ leukocytes to the mucosal environment. During inflammation, the mucosal microvasculature controls the selection and magnitude of influx of T-cell subsets into the gut through cell adhesion molecules expression and chemokine secretion, which further amplify the communication with other leukocytes and cells. In animal experiments neutralization of MAdCAM-1 and ICAM-1 led to attenuation of mucosal damage in colitis.

If you made your way through the above section, and regularly read this blog you will appreciate the multiple possible beneficial actions for many types of autism.

I was going to have a post about GI issues, but I will put some of the melatonin part in this post.  In summary, very many GI problems are associated with low levels and melatonin and numerous studies have shown that giving oral melatonin is an effective treatment to varying degrees. Melatonin is a useful adjunct (add-on) therapy in these conditions. 

Not only does melatonin appears to promote healing of the esophagus but also the tightening of the LES (The lower esophagealsphincter)

Failure of this sphincter to close is why people get reflux/GERD/GORD.

One possibility is that the night time spike in melatonin signals your brain that it is time to sleep and also signals your LES to shut tightly, so that during the night acid does not rise up your esophagus while you are horizontal.

The potential therapeutic effect of melatonin in gastro-esophageal reflux disease

Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole.   

Melatonin and Ulcerative Colitis:Evidence, Biological Mechanisms, and Future Research  

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

Which is the best choice for gastroesophageal disorders: Melatonin or proton pump inhibitors?

Conclusion

Melatonin may already be the most widely used drug to treat autism, but generally at the lower sleep-inducing doses.

It would seem that those with GI problems, mitochondrial problems or more general oxidative stress may very well benefit from the higher doses of melatonin already used by some.

Older people, people with esophagitis/duodenitis or IBS/IBD, people with type 1 or 2 diabetes and even people with osteoporosis may also want to look into melatonin supplementation.

Given the supplement is ending up in your intestines, where much melatonin should already be being produced, the impact on pineal melatonin production becomes less of an issue.  People giving thyroid hormones T3 and T4 to children who are euthyroid (ie normal thyroid function) should be aware of the consequences (thyroid shutdown).

For various reasons, production of ROS (reactive oxygen species) that are the oxidants varies throughout the day, the morning is the worst time supposedly.  Ideally you would match this with your antioxidant intake.  One combination would be melatonin before bed, a larger dose of NAC at breakfast and then NAC throughout the day.  As highlighted in an earlier post, sustained release NAC is also interesting, but it would help if there was a more potent version. 

Hopefully Dr Tordjman will publish the results of her high dose melatonin in autism study soon.

  

Most people struggle to access the really effective autism drugs, but antioxidants are available in abundance.

Oxidative stress is not a cause of autism, but it is a common side effect.  Treating oxidative stress does indeed seem to help many people with autism, but since the source of those oxidants may vary so should the most effective therapy.  Melatonin may be a useful part of that antioxidant mix, particularly if there are GI, mitochondrial or sleep issues.

Melatonin has a half-life of less than an hour, people who respond well might consider sustained release versions, which are available quite cheaply (5 and 10 mg sustained release forms look interesting).  There are even some clinical trials measuring the resulting plasma levels.