Is gluten avoidance linked to a lower risk for depression?

I've talked a few times on this blog about how avoiding dietary gluten both within (see here) and outside of (see here) the context of coeliac (celiac) disease, the archetypal 'gluten is baddie' autoimmune condition, might have some pretty interesting effects on some aspects of a person's psychology. Today's post reflects yet more peer-reviewed science suggesting that there may indeed be something to see in this potentially important area; particularly pertinent to the presentation of depression or depressive symptoms.

So, the findings reported by Haley Zylberberg and colleagues [1] based on data from some 22,000 participants taking part in the US 2009-2014 National Health and Nutrition Examination Survey are the source material today. Some background material related to this cohort can be found here. They specifically looked at the "prevalence of depression, insomnia, quality-of-life variables, and psychotropic medication use in CD [coeliac disease] participants and PWAGs [people who avoid gluten] to controls." People who avoid gluten - PWAG - represent a group who don't have a diagnosis of CD but nonetheless similar to those who were diagnosed with CD, reported avoiding dietary gluten.

Results: "Depression was present in 8.2% of controls compared with 3.9% of participants with CD... and 2.9% of PWAGs." Even after adjustment for various confounding variables ("age, sex, race, income, and access to healthcare") those gluten avoiders (without CD) less frequently presented with depression compared with data from controls.

Added to the previous occasions where gluten consumption seems either to be linked to [some] depression or removal of gluten seems to positively impact on depressive symptoms at least for some, this is interesting work. Yes, quite a few more controlled trials are required to examine such relationships between food and mood. Although we can speculate on possible mechanisms [2] we don't really know why there may be an effect from gluten removal, but this is an emerging area of science; particularly in the context of how disruptive/disabling/damaging depression can be to someone.

Bearing in mind the caveats of this blog - no medical or clinical advice is given or intended - please don't assume that I'm advocating gluten removal for anything (unless clinically indicated) on the basis of this or other posts. If in doubt, consult your medical physician.

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[1] Zylberberg HM. et al. Depression and insomnia among individuals with celiac disease or on a gluten-free diet in the USA: results from a national survey. Eur J Gastroenterol Hepatol. 2017 Jun 27.

[2] Pruimboom L. & de Punder K. The opioid effects of gluten exorphins: asymptomatic celiac disease. J Health Popul Nutr. 2015 Nov 24;33:24.

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Gastrointestinal response to A1 vs A2 milk

I want to talk about the findings from Ho and colleagues [1] today, and in particular their observation of: "differences in gastrointestinal responses in some adult humans consuming milk containing beta-casein of either the A1 or the A2 beta-casein type". If you're wondering why such a paper finds it's way on to a blog predominantly about autism research, well stay with me on this rather long blogging entry...

Start your engines... @ Wikipedia 

Before progressing, I am going to put a sort of COI (conflict of interest) statement into this blog post. As part of my day job, I have, down the years, been party to some conversations on A2 milk and how one might scientifically test some of the claims / assumptions made about this milk with specific populations in mind. That also our lab has been looking at analytical ways of differentiating A1 and A2 milk from each other is another COI, allowing for the fact that I am neither a consumer of, nor advocate for, anything to do with any of the white stuff.

In case you're not up to speed with A1 and A2 milk, well, it all boils down to type of cow and type of milk produced. Anyone with a handle on autism research history will have probably heard about the opioid-excess hypothesis [2]. The long-and-short-of-it is that casein, the protein found in milk and dairy products, is eventually metabolised into it's constituent amino acids. Along the way, short chains of amino acids called peptides are formed. Some of these peptides look (chemically) similar to compounds like morphine and are hence referred to as the casomorphins (casein derived morphine-like). The opioid-excess hypothesis suggested that these exogenously derived peptides mimic some of our own naturally occurring morphine-like compounds that we all have, and disrupt typical functioning in this area to such an extent that it may correlate with some of the signs and symptoms called autism. I talked about something similar quite recently.

Granted, such a model looks a little simplistic these days knowing what we think we know about the very plural autisms and the ESSENCE of cormorbidity. Still, such a hypothesis did seem to fit in well with the suggested effectiveness of a casein-free (and gluten-free) diet for some on the autism spectrum, and also some work looking at the opioid receptor blocker that is naltrexone (see here) and autism. It is with the structure of those peptides in mind that we come to the differences suggested for A1 and A2 milk. Y'see not every cow or other mammal produces the same kind of casein protein in their milk and hence peptide formulations can vary also. For A2 casein, the idea is that beta-casomorphin fragment 1-7 (BC 1-7), a peptide formed during digestion is not the same as the BC1-7 from A1 milk (see here) particularly when it comes to a single amino acid change (proline over histidine) [3].

After such a long-winded explanation, we come back to the Ho paper and some interesting findings...

• First things first, this was a double-blind, randomised cross-over study looking at "gastrointestinal effects" in adults under conditions of either A1 or A2 milk consumption. Two weeks of either A1 or A2 milk consumption (with an appropriate washout period in between) were completed.
• The very informative Bristol Stool Chart was used to grade poop (stool) consistency alongside other more physiological measures such as faecal calprotectin.
• Results: "The A1 beta-casein milk led to significantly higher stool consistency values". That and a correlation between stool consistency and reports of abdominal pain for participants when on the A1 milk compared with when on A2 milk. Ergo, it didn't seem that A2 milk did anything over and above A1 milk, rather that consumption didn't seem to be linked to the symptoms noted when drinking A1 milk. 

Appreciating the authors' call for further study in this area, I was intrigued by these results. Not so many moons ago, I came across the paper by Barnett and colleagues [4] talking about greater gastrointestinal (GI) transit time in rats fed A1 milk over A2 milk (see here for some additional commentary from one of the study authors). One might very well overlap those rodent reports with the more recent Ho results in terms of how longer transit time from A1 milk might mean greater discomfort bearing in mind some of the literature on longer transit time and "pain and distension" [5] in certain conditions. Interestingly, the authors ask that research not only focus on confirmation of their results but: "confirmation in a larger study of participants with perceived intolerance to ordinary A1 beta-casein-containing milk" which begs the question: who and what ailments are being reported?

That all being said, not all the literature on A2 milk is so directional. Take for example the paper by Crowley and colleagues [6] (open-access) looking at the question of milk consumption correlating with the functional bowel issue constipation. They concluded that: "that removal of CMP [cow's milk protein] from the diet of children with CFC [chronic functional constipation] significantly increased the number of bowel motions and improved constipation". Their results however did not show any significant effect based on casein type when looking at A1 and A2 milk. Constipation, by the way, is also something talked about with some autism in mind (see here) and particularly the findings from Afzal and colleagues [7] which concluded: "Multivariate regression analysis showed consumption of milk to be the strongest predictor of constipation in the autistic group".

I am quite interested in this whole area of different milks from different animals potentially possessing different qualities which might impact on physiology particularly if eventually applied to conditions like autism, or at least some comorbidity. I think back to the post I did on milk derived opioid peptides and methylation status (see here) as also being important, as might be the work on something like the use of camel milk (see here) bearing in mind the adverse publicity our humped friends have received recently. As per my previous caveat, I don't think we are in a position yet to advocate changes in milk drinking practices for specific groups based on the available literature, but there might be quite a bit more research to do in this important area...

To close, I know this might sound a little odd but am I the only father with young children who know Barry Scott on sight?

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[1] Ho S. et al. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Jul 2.

[2] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[3] Truswell AS. The A2 milk case: a critical review. Eur J Clin Nutr. 2005 May;59(5):623-31.

[4] Barnett MP. et al. Dietary A1 β-casein affects gastrointestinal transit time, dipeptidyl peptidase-4 activity, and inflammatory status relative to A2 β-casein in Wistar rats. Int J Food Sci Nutr. 2014 Mar 20.

[5] Cann PA. et al. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut. May 1983; 24(5): 405–411.

[6] Crowley ET. et al. Does Milk Cause Constipation? A Crossover Dietary Trial. Nutrients 2013; 5: 253-266

[7] Afzal N. et al. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

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Ho, S., Woodford, K., Kukuljan, S., & Pal, S. (2014). Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study European Journal of Clinical Nutrition DOI: 10.1038/ejcn.2014.127

Dipeptidyl peptidase (DPP) IV and autism: supporting opioid-excess?

Serum levels of dipeptidyl peptidase (DPP) IV were found to be lower in children with autism compared to asymptomatic controls according to the study by Shahid Bashira & Laila AL-Ayadhi [1]. Based on analysis by ELISA, researchers concluded that "alterations in the plasma level of DPP IV play a role in the pathophysiology of autism".

A sailor went to sea, sea, sea... @ Wikipedia 

Anyone who has followed the autism research scene for any length of time might have already heard about DPP-IV and autism. The paper by Hunter and colleagues [2] (open-access here) and subsequent response [3] highlights some of the discussions in this area relating to the use of the opioid-excess hypothesis [4] as a means to potentially explain some autism. The idea stemming from some earlier work (see here) being that a defect in the functioning of DPP-IV with regards to its ability to degrade proline-rich proteins such as gliadin (gluten) might account for the build-up of gluten derived opioid peptides suggested as part of the opioid-excess theory. Earlier accounts of issues with DPP-IV in relation to the classic gluten-related autoimmune condition coeliac disease (see here for an overview) kinda set the tone [5] for some analysis with autism in mind. Indeed, at least one trial of enzyme-based therapy has also talked about the potential involvement of DPP-IV in some cases of autism [6].

The Bashira paper did not specifically set out to look at the relationship between DPP-IV and dietary elements potentially linked to autism. Instead their focus seemed to be on the involvement of this peptidase in brain physiology and "its possible link to neuroinflammation in autism". DPP-IV has, for example, been discussed with cerebral ischemia in mind as per the results from Röhnert and colleagues [7] although I hasten to add that I am not equating autism and brain ischemia.

I personally feel that quite a bit more research effort is needed in the area of DPP-IV. Lower plasma levels of DPP-IV have been noted in cases of other conditions such as depression [8]. The recent results from Simone Peters and colleagues [9] which talked about "Short-term exposure to gluten specifically induced current feelings of depression" in their cohort (see this post) could fit well with the reduction in gluten peptide degrading abilities potentially present as a consequence of something like lower DPP-IV levels. Indeed, one might also speculate that the suggestion of non-coeliac gluten sensitivity (NCGS) may actually reflect involvement of opioid peptides on the basis of such a correlation...

I'm also taken back to some work by Vojdani and colleagues [10] which talked about anti-CD26 autoantibodies being present in a "significant percentage of children with autism". CD26, a surface glycoprotein used synonymously with DPP-IV, was suggested to show involvement as a function of "dietary peptides, bacterial toxins and xenobiotics bind[ing] to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism". Their follow-up study [11] further added to the literature in this area and how "Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity" in relation to autism. Autoimmunity and autism y'say?

As per the cycles of scientific research, where research areas fall in and out of favour, it does appear that there is a resurgence of interest in elements of the opioid-excess theory with a specific focus on the role of food-derived peptides in relation to at least some autism. The Roy review looking at naltrexone for autism (see here) is one element given the opioid antagonistic effects of this pharmaceutic. The Sokolov paper (with its flaws) looking at beta-casomorphin - the opioid peptide derived from the casein protein - in relation to autism is another. The Trivedi paper (see here) on exogenous opioid peptides and DNA methylation levels adds to the research bundle. Dare I even mention the camel milk and autism connection also being made in the research literature too as a function of different milks and different protein/peptide configurations?

Music to close. Epic by Faith No More.

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[1] Bashir S. & AL-Ayadhi L. Alterations in plasma dipeptidyl peptidase IV in autism: A pilot study. Neurology, Psychiatry and Brain Research. 2014; 20: 41-44.

[2] Hunter LC. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8.

[3] Shattock P. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2004 May;46(5):357.

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Smith MW. & Phillips AD. Abnormal expression of dipeptidylpeptidase IV activity in enterocyte brush-border membranes of children suffering from coeliac disease. Exp Physiol. 1990 Jul;75(4):613-6.

[6] Brudnak MA. et al. Enzyme-based therapy for autism spectrum disorders -- is it worth another look? Med Hypotheses. 2002 May;58(5):422-8.

[7] Röhnert P. et al. Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia. J Neuroinflammation. 2012 Feb 28;9:44.

[8] Maes M. et al. Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs. Acta Psychiatr Scand. 1996 Jan;93(1):1-8.

[9] Peters SL. et al. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity - an exploratory clinical study. Aliment Pharmacol Ther. 2014 May;39(10):1104-12.

[10] Vojdani A. et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

[11] Vojdani A. et al. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

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Bashir, S., & AL-Ayadhi, L. (2014). Alterations in plasma dipeptidyl peptidase IV in autism: A pilot study Neurology, Psychiatry and Brain Research, 20 (2), 41-44 DOI: 10.1016/j.npbr.2014.03.001

Got milk [opioid peptides]?

"Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake".

Those were the findings from the paper by Malav Trivedi and colleagues [1] (open-access) including Richard Deth on the authorship team. I was really interested to read this paper having met Malav and Dick a few months back and listened very attentively to some potentially important investigations on-going in their lab. Indeed, such results potentially cast a whole new light on some of my own autism research interests looking at the use of a gluten- and casein-free (GFCF) diet (see here) and more latterly, the reformulation of a great opioid antagonist naltrexone, into a handy cream (see here).

Call me a liar? @ Wikipedia 

A few starting details might be useful:

• Without hopefully just regurgitating what the authors said, the focus of this study was to look at whether "morphine and food-derived opioid-peptides can induce alterations in the cellular redox status, DNA methylation... and transcription process, by altering cysteine uptake in SH-SY5Y cells". As far as I see it, there are 3 important elements to explain, all with an autism slant...
• Opioid peptides - short chains of amino acids with opiate-like activity - have been the topic of quite a bit of discussion when it comes to autism. No-one really disputes the fact that when we eat foods containing gluten and casein, the respective proteins are broken down into peptides, some of which have an affinity to our own opioid (morphine) receptors. The controversy when it comes to autism is the suggestion that said opioid peptides might be part and parcel of the effect noted when some people with autism embark on a diet devoid of gluten and casein - the GFCF diet - and might be detectable in certain biofluids (see here). 
• Redox and oxidative stress also have some research form when it comes to autism (see here) and in particular the quite consistent literature on the antioxidant glutathione being perturbed in quite a few cases of autism (see here). No-one really knows why levels of glutathione (GSH) are coming out so consistently low in relation to autism but one suggestion is that a transporter called EAAT3 involved in the uptake of cysteine, an important building block of glutathione, might be misbehaving. This authorship team together with a few other notable names have talked about this process in relation to autism [2] previously which was the topic of a past post on this blog (see here). 
• DNA methylation is also something talked about quite a bit on this blog. Part of that rising star discipline known as epigenetics, the idea is that adding a methyl group to specific sites on DNA has the ability to modify the expression of certain genes. Hypermethylation is generally taken to mean gene silencing.

And then to the paper itself bearing in mind it is open-access:

• This was a study carried out using "SH-SY5Y and Caco2 cancer cell lines". Said cell lines were subjected to the addition of morphine, bovine [cow] beta-casomorphin 1-7, human beta-casomorphin 1-7 or gliadinomorphin 7 at varying doses. The casomorphins are derived from casein, the milk protein and the gliadinomorphin from the gluten protein.
• Radio-labelled cysteine uptake was monitored in cells and was found to be inhibited by the addition of morphine and the various food-derived opioid peptides. Morphine was most effective at inhibiting cysteine uptake followed by bovine beta-casomorphin 1-7 then human beta-casomorphin 1-7 and finally the opioid peptide derived from gliadin. Interestingly, this effect was "blocked by naltrexone".
• Levels of "metabolic intermediaries involved in transsulfuration and methionine methylation cycle pathways" were also examined. This included looking directly at levels of cysteine and GSH alongside other important compounds in this pathway such as methionine and homocysteine (the big H). Again, changes were noted to these compounds as a function of the addition of morphine and opioid peptides: "consistent with decreased GSH synthesis, decreased activity of methionine synthase, and increased transsulfuration of homocysteine to cystathione". Methionine synthase is again, something already talked about by this authorship group (see here).
• Global DNA methylation status was also examined as a function of morphine and opioid peptide addition to the SH-SY5Y cell line. "A 4 h[our] treatment with morphine or milk-derived opioid peptides... caused a significant shift towards increased methylation (i.e. promoter hypermethylation) in the immediate TSS [transcription start site] region". Morphine was once more most effective at increasing genome-wide methylation followed by bovine and then human beta-casomorphin. Ergo, "opioid-induced changes in cysteine uptake, redox status... are associated with significant genome-wide changes in DNA methylation levels".

I find these results to be absolutely fascinating. Of course, as the authors point out, this was a study of cell lines and hence "need to be replicated in other systems before they can be confidently extrapolated to clinical manifestations". But the possibility that elements of food may have such profound knock-on effects pertinent to the way we 'detox' (yes, it is a real concept) and the expression of some of our genes has endless connotations. I might add that the reported effects of human beta-casomorphin for example, on the processes described may also indicate that not all effects are going to be adverse from an evolutionary perspective.

From the point of view of the use of a GFCF diet in cases of autism, this work potentially adds another string to the various explanations as to why diet may be useful for some on the spectrum. So, outside of other ideas on effect including: lactose intolerance (see here), coeliac disease (see here), non-coeliac gluten sensitivity (see here), altering intestinal hyperpermeability (see here), folate receptor autoantibodies (see here), FPIES (see here), et al, linking gluten and/or casein opioid peptides to something like glutathione production or methylation capacity provides even more research fodder for any interested parties.

Finally(!) there is one small additional point to mention about the Trivedi paper. Tucked in at the end of a sentence in the discussion section are the words: "It should be noted that bovine form of BCM7 [beta-casomorphin 1-7] is only released from cows with the A1 genotype and not A2 genotype cows". I've kinda alluded to the concept that not all mammalian forms of casein are the same in a previous post talking about camel milk and autism (see here). As bizarre as it might sound, there is a growing appreciation that different animals (including humans) might not necessarily produce the same kind of milk [3] and that some types of milk might be advantageous over others. The paper by Barnett and colleagues [4] hinted at one effect - gastrointestinal transit time - when comparing A1 and A2 milks. At the moment however, the science is still a little hazy for suggesting that the differences between the various types of milk might make some more useful for some groups/individuals over others. But certainly there is a potentially intriguing hypothesis requiring some experimental testing there...

Music to close. Paolo Nutini and Pencil Full of Lead.

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[1] Trivedi MS. et al. Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences. Journal of Nutritional Biochemistry. 2014. June 9.

[2] Waly MI. et al. Prenatal and Postnatal Epigenetic Programming: Implications for GI, Immune, and Neuronal Function in Autism. Autism Res Treat. 2012;2012:190930.

[3] Kamiński S. et al. Polymorphism of bovine beta-casein and its potential effect on human health. J Appl Genet. 2007;48(3):189-98.

[4] Barnett MP. et al. Dietary A1 β-casein affects gastrointestinal transit time, dipeptidyl peptidase-4 activity, and inflammatory status relative to A2 β-casein in Wistar rats. Int J Food Sci Nutr. 2014 Mar 20.

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Trivedi, M., Shah, J., Al-Mughairy, S., Hodgson, N., Simms, B., Trooskens, G., Van Criekinge, W., & Deth, R. (2014). Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences The Journal of Nutritional Biochemistry DOI: 10.1016/j.jnutbio.2014.05.004

Can a gluten-free diet positively affect cognitive performance?

No, I am not suggesting that a gluten-free diet is the new nootropic (cognitive enhancer) of choice with the title of this post despite previous media headlines on the subject.

"Got gluten?"☺  @ Wikipedia 

I am however very, very interested in the results reported by Irene Lichtwark and colleagues [1] (open-access here) which suggested that in "newly diagnosed coeliac disease, cognitive performance improves with adherence to the gluten-free diet in parallel to mucosal healing".

For those who might not be familiar with coeliac (celiac) disease (CD), I wrote a sort of training post about what we (think we) know about the condition a few months back (see here). An autoimmune condition managed in the most part by the lifelong use of a gluten-free (GF) diet, CD remains the focal point of an increasing 'spectrum' of conditions where gluten might play some kind of role (see here) including those linked to brain and behaviour (see here). Indeed the Lichtwark paper starts with the assumption that outside of the classical genetic, gastrointestinal (GI) and immunological markers/effects of CD, there is a growing recognition that other biological systems may be affected, something I've talked about before on this blog.

The Lichtwark paper is open-access but as ever, here are a few pointers:

• A small participant group of 11 adults (mean age 30 years old) diagnosed with CD but not yet commencing with a GF diet were followed over the course of 1 year. Various assessments were periodically carried out at weeks 0 (baseline), week 12 and week 52 over the course of a GF diet being introduced/used. This included duodenal biopsies to assess the intensity of mucosal damage based on the Marsh criteria, a measure of intestinal permeability (IP) (yes, leaky gut) and various other tests, some of which are linked to the serology of CD (see here). Interestingly, vitamin D and vitamin B12 were also part of the testing suite.
• Various cognitive assessments were also included in the study covering aspects of memory, attention and language abilities, alongside a patient report measure on the presence of anxiety and depressive symptoms (something very topical at the moment).
• Results: bearing in mind this was a pilot study and involved only participants with CD all of whom were [knowingly] following a GF diet, there were some interesting points raised. The classical markers of CD saw their usual change as expected following use of a GF diet (compliance to which was described as excellent). The authors also note that: "IP was elevated in three participants, one of these at baseline the other two at week 12". Further: "All IP levels were within the normal range at 52 weeks".
• Based on the results of cognitive testing: "Four of the eight cognitive tests demonstrated a significant improvement in performance between time 0 and 52 weeks". These were predominantly tests in areas of attention, motor skills and verbal fluency. The authors note that this may be "the beginnings of an evidence-base for the ill-defined, yet frequently reported symptoms of brain fog in CD".
• The paper also reports some initial correlation values between some psychometric test scores and the CD histological and serological data. Obviously with 11 participants you would probably not imagine the correlation values, whether positive or negative, to be 'up there' but some of them were described as significant, and at better than just p<0.05.

Of course there is lots more to do in this area not least a larger and more controlled trial looking at the possibility of a relationship between CD, the GF diet and cognitive performance. The fact also that this was a study of adult CD also leaves questions to be answered about whether similar effects might be noticeable for paediatric cases of CD which appear to be on the rise. The other question resides in that murky grey area of non-coeliac gluten sensitivity (NCGS) and, assuming that this is a real phenomena (see here), whether a GF diet might also aid cognitive performance for cases there too? The paper by Volta and colleagues [2] (open-access) talks about a "foggy mind" as being apparent in some of their identified cases of NCGS...

This is not the first time that cognition has been talked about with CD in mind. "A possible association exists between progressive cognitive impairment and celiac disease, given the temporal relationship and the relatively high frequency of ataxia and peripheral neuropathy, more commonly associated with celiac disease". That was the conclusion of the study by Hu and colleagues [3]. Interestingly, they reported that out of a total of 13 participants, 3 people "improved or stabilized cognitively with gluten withdrawal". Terrone and colleagues [4] reported that in a paediatric cohort of kids recently diagnosed with CD, a measure of "cognitive, emotional and behavioural problems" was statistically higher than in another group of participant with CD symptoms controlled following the use of a GF diet. I was also quite interested to see that they reported a lower frequency of "chronic fatigue" in their CD remission group which brought back memories of a distant blog post I wrote on a similar topic (see here).

But the research is not yet cut-and-dried on the issue of cognitive dysfunction and untreated CD and any role for a GF diet. Take for example the small study by Hallert & Aström [5] (open-access here) who concluded "no consistent signs of cognitive impairment" to be found in their cohort. These results should also be take in light of other findings such as those by Casella and colleagues [6] looking at cognitive performance in older adults diagnosed with CD following a GF diet who concluded that: "Cognitive performance is worse in elderly coeliac disease than control patients, despite prolonged gluten avoidance in coeliacs". It's complicated.

Just before I leave you to further ponder the Lichtwark results, a few final points raised by the authors are also worthwhile mentioning. They speculate on the possible mechanisms by which "cognition might be impaired in patients with untreated CD". They do kinda rule out nutrient deficiencies on the basis of no association detected in their cohort with some of the nutritional parameters looked at. Personally, I don't think we can rule this out altogether at the moment given what we are still learning about good nutrition and behavioural and cognitive indicators (see here for one example). Inflammation and in particular, cytokine involvement receives a more favourable review to account for the results which should also be investigated further (see here). One final hypothesis revived by the authors is that of opioid peptides and any potential effects on "higher brain functions". I know brows become furrowed when the words 'opioid-excess' are talked about with reference to particular conditions, but given my own interest in this area, and recently our very preliminary paper on the formulation of low doses of the opiate blocker naltrexone into a cream [7] (see here), an intriguing question emerges about whether a GF diet might be the only avenue to enhancing cognitive performance under such circumstances? Oh and then there is the leaky gut angle too. At least one author [8] has asked the question of whether intestinal hyperpermeability might show some involvement in cognitive dysfunction albeit not necessarily directly pertinent to the issues of CD. More to do methinks.

To close, for those of you who might remember the film 'Limitless' and the fictional nootropic NZT-48, just think you could have it all. But also remember: "discontinued use will result in death". (And no, it's not real, not yet anyway).

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[1] Lichtwark IT. et al. Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Aliment Pharmacol Ther. 2014 May 28.

[2] Volta U. et al. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Medicine 2014, 12:85.

[3] Hu WT. et al. Cognitive impairment and celiac disease. Arch Neurol. 2006 Oct;63(10):1440-6.

[4] Terrone G. et al. The Pediatric Symptom Checklist as screening tool for neurological and psychosocial problems in a paediatric cohort of patients with coeliac disease. Acta Paediatr. 2013 Jul;102(7):e325-8.

[5] Hallert C. & Aström J. Intellectual ability of adults after lifelong intestinal malabsorption due to coeliac disease. J Neurol Neurosurg Psychiatry. 1983 Jan;46(1):87-9.

[6] Casella S. et al. Cognitive performance is impaired in coeliac patients on gluten free diet: a case-control study in patients older than 65 years of age. Dig Liver Dis. 2012 Sep;44(9):729-35.

[7] Dodou K. et al. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharm Dev Technol. 2014 May 2.

[8] Brenner SR. Hypothesis: intestinal barrier permeability may contribute to cognitive dysfunction and dementia. Age Ageing (2010) 39 (2): 278-279.

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Lichtwark IT, Newnham ED, Robinson SR, Shepherd SJ, Hosking P, Gibson PR, & Yelland GW (2014). Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Alimentary pharmacology & therapeutics PMID: 24889390

Formulating low dose naltrexone into a cream

The opioid receptor antagonist naltrexone has been on the periphery of my autism research career for as long as I can remember. As unusual as it might sound, some of the early interpretations for example, on why installation of a gluten- and casein-free (GFCF) diet seemed to correlate with changes to behavioural presentation for some on the autism spectrum, relied heavily on the notion of opioid-excess [1] as a function of the proposed bioactivity of gluten and casein derived peptide species. This allied with a body of evidence more directly linking administration of naltrexone as affecting some peripheral facets observed in cases of autism [2] touched upon in a recent post (see here).

No, not that type of cream... @ Herrick @ Wikipedia 

This line of thought of excess opioid activity being related to cases of autism has not been without its critics down the years [3]. Certainly I'd be the first to admit that a degree of naivety existed in terms of appreciating the complexity of autism (sorry, the autisms) in those early times. That being said, I'm not yet ready to consign the opioid-excess theory to the scientific trash-heap just yet, as one of the other parts of the theory - abnormal gut permeability (leaky gut) - enjoys some well deserved research attention (see here and see here).

The connection made between autism, opioid-excess and naltrexone has also evolved as time as gone on. Accepting the anti-opioid power of naltrexone, there has at the same time been a shift in our understanding of naltrexone as also being an immunomodulating agent. I can't readily provide you with the full picture of how naltrexone affects immune function because there is still more to be done on this topic. What I can say is that (i) opioids can have effects on immune function [4] and (ii) anti-opioid drugs such as naltrexone also seem to have some effects on immune function [5].

On the back of this very long introduction, I'm talking today about an interesting piece of work [6] which I had a very, very small part in, looking at the formulation of low doses of the drug naltrexone into a cream and some of the chemistry behind it. You'll note the addition of the words 'low dose' to naltrexone indicating an increasing body of evidence discussing, well, low doses of naltrexone (LDN), for all manner of health issues including Crohn's disease [7], fibromyalgia [8] and multiple sclerosis [9]. Indeed, I've mentioned this topic in an earlier blog post (see here).

So what did we do and why did we do it?

Well discussions about this project began some years back. Quite a few of the medications suggested for tackling facets of autism and other developmental conditions generally tend to rely on the oral route of administration i.e. swallowing pills. Whilst this is a good way of getting the active part of a drug into the body, there are a few issues surrounding this method including having the ability and desire to want to swallow a tablet or capsule and sticking to a regime of tablet swallowing often over quite a long period of time. Little things that people take for granted such as drinking water when swallowing a tablet might not necessarily be so implied for everyone. And then there are the various biological processes that any orally administered medication needs to go through before producing a therapeutic effect, even the possibility of an effect from those trillions of bacteria in our gut which call us home... In short, oral drug delivery is not necessarily always the best drug delivery route for everyone.

As it happens, there are lots of other ways of getting medication into the body such as through the skin (transdermal) or under the tongue (sublingual) (and erm, other routes) provided you can formulate your medicine appropriately. We had quite a few discussions about what medicines were out there and how we could formulate them into something a little more versatile when it comes to administration. Naltrexone was an obvious candidate because it has quite a nice chemical structure and also, as I've discussed, there is growing interest in its usefulness for various different conditions not just for cases of autism.

It was then a case of making a cream containing naltrexone which our collaborators are pretty good at doing based on their other work formulating things like transdermal patches [10]. Our part (the Royal 'We') involved testing said cream using our Q-ToF mass spectrometer for how well the cream performed in terms of releasing naltrexone and its metabolite 6-β-naltrexol. In short, it did pretty well: "It was concluded that the cream may be an effective formulation for the sustained transdermal delivery of LDN".

On this occasion, we stopped short of actually testing the cream on real people with real conditions in terms of things like safety and effectiveness simply because clinical trials are a whole other ballgame. That being said, I'd like to think there might be other groups who would be willing to have a look at our formulation and perhaps take up the research gauntlet too (hint, hint).

Music to close. Something lively I think, so how about Icona Pop and 'I Love It' (with a parental advisory for some of the lyrics...)

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[1] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[2] Elchaar GM. et al. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother. 2006 Jun;40(6):1086-95.

[3] Cass H. et al. Absence of urinary opioid peptides in children with autism. Arch Dis Child. 2008 Sep;93(9):745-50.

[4] Zhang EY. et al. Depletion and recovery of lymphoid subsets following morphine administration. Br J Pharmacol. 2011 Dec;164(7):1829-44.

[5] Boyadjieva NI. & Sarkar DK. Opioid-like activity of naltrexone on natural killer cell cytolytic activity and cytokine production in splenocytes: effects of alcohol. J Interferon Cytokine Res. 2010 Jan;30(1):15-22.

[6] Dodou K. et al. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharm Dev Technol. 2014 May 2.

[7] Smith JP. et al. Low-dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol. 2007 Apr;102(4):820-8.

[8] Younger J. et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38.

[9] Sharafaddinzadeh N. et al. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010 Aug;16(8):964-9.

[10] Ho KY. et al. Effect of drug-polymer binary mixtures on the in-vitro release of ibuprofen from transdermal drug-in-adhesive layers. Drug Discov Ther. 2008 Oct;2(5):277-81.

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Dodou K, Armstrong A, Kelly I, Wilkinson S, Carr K, Shattock P, & Whiteley P (2014). Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharmaceutical development and technology PMID: 24785567

Casomorphins and autism reignited?

For those who know me and some of my particular autism research interests, they'll understand that I was always going to be intrigued by the results reported by Oleg Sokolov and colleagues [1] on elevated levels of bovine casomorphin-7 immunoreactivity being reported in a small group of children with autism. Indeed, as per my last post plugging my new book (apologies for the very blatant plug!), casomorphins, the peptide breakdown products from the protein casein complete with opioid activity, are something that I've known about for quite a few years.

BC1-7 @ Wikipedia 

From the outset I have to come clean and say that I did peer-review a version of the Sokolov paper when submitted to another journal last year (2013). Without hopefully creating too many waves, my comments whilst supportive did highlight a few areas of contention with that previous submission. Not that this should influence yours or my interpretation of the current findings; neither should it seem unusual that papers are reviewed in one journal and end up finding a home at another journal (some of my manuscripts have endured a similar journey).

Anyhow, with thanks to Natasa for passing the full-text version of the published paper to me, a few details:

• This was a small trial comprising 10 children (4-8 years old) diagnosed with an autism spectrum condition (including autism and Asperger syndrome) and 10 control children.
• First production spot urine samples were collected and some initial preparation carried out (SPE) prior to the main event which was analysis by ELISA looking at immunoreactivity to bovine (cow) casomorphin-7 (CM-7). Just in case you didn't know CM-7 is the same as beta-casomorphin 1-7 (BC1-7) which as I've indicated previously, is a peptide fragment derived from cow milk protein (or at least some types of cow) which has some history in autism research (see here).
• Looking at the current method and the comments I made on the previous incarnation of this manuscript, quite a few of the issues I had highlighted originally did seem to have been answered in this paper including a much more detailed explanation of the analytical methods employed on samples such as things like limits of detection (LOD). Indeed, the authors report: "The minimal detectable limit of CM-7 immunoreactive material was 25 fmol" which is pretty low: a billionth of a millionth (10-15).
• Results: some important trends emerged from the data not totally out-of-line with other findings [2]. So: "autistic children have significantly higher levels of urine CM-7 than control children". Bearing in mind the already discussed small participant numbers included, further analysis of CM-7 results for those children with autism (N=5) and those with Asperger syndrome (n=5) seemed to suggest a link with the "severity of autistic symptoms" too, confirmed in a plot of CM-7 levels and CARS scores achieving a correlation coefficent of 0.85. Ergo, cows milk or at least some of the by-products from cows milk might show involvement with some cases of autism [3].

OK, to reiterate, this was a study of 10 children with autism/Asperger syndrome vs. 10 asymptomatic children. There is still very much more to do on this topic before one might entertain discussions about trends and facts in this area including the question of what effect dietary intervention such as the use of a casein-free diet might do to the CM-7 results obtained. You may well be saying 'dietary intervention should see CM-7 levels drop' but I'd personally like to see the cold data showing this effect before any assumptions are made.

Glancing through some of my review notes made about the original incarnation of this paper and it's current format, I do note that at least one important point that I originally raised does not seem to be answered in the most recent version. The authors note: "The identity of bovine CM-7 detected by ELISA was confirmed by reverse phase and gel-filtration HPLC". The point I made was that whilst I've published on the use of HPLC (high-performance liquid chromatography) for the analysis of urine samples, this technique alone and without any reference to the type of detection method used is pretty meaningless. Certainly unless detection is via mass spectrometry (MS) or even nuclear magnetic resonance (NMR) there will always be questions about accuracy and precision.

In amongst some of the discussions included in the Sokolov paper, I noted a few points of added interest which should be mentioned. There is for example, some chatter about dietary intervention and autism, and as I suggested a few sentences back, how removal of casein (and gluten) from the diet should affect the source materials of those peptides as per what is done in coeliac disease with gluten peptides (see here). I note also that the authors make mention of different types of milk as potentially being useful: "casomorphin-free casein" although incorrectly sourcing it back to A1 cows when it should be A2 cows (see here). Indeed, it is timely that the paper by Barnett and colleagues [4] has also entered the peer-reviewed publication domain but I'm not going to say too much more on that for now aside from saying that cows are not the only makers of milk.

I've probably been a little harsher than usual on the Sokolov paper given the history in this area of food and autism and finding data to fit models and hypotheses around the use of dietary intervention with a specific focus on peptides [5] and on more than one occasion [6]. By no means do I wish to belittle the potentially important observations made in the current paper; merely stating however that technology can help in this area and we should be using it where and whenever possible to cast further scientific light on the unusual connection between food and its potential effects on at least some cases of autism.

Oh, and whilst we're on the topic of gluten and casein peptides and autism, I'd like to introduce some rather novel findings from Dick Deth and colleagues [7] on a potentially important link to cysteine and glutathione which might also be relevant to some autism...

Something a little bit different to finish today. For those who know a little about kata and karate, how about a little synchronised kata? (my brood have already started their training...)

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[1] Sokolov O. et al. Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity. Peptides. 2014. March 20.

[2] Reichelt KL. et al. Peptides’ role in autism with emphasis on exorphins. Microbial Ecology in Health & Disease. 2012; 23: 18958.

[3] Kost NV. et al. Beta-casomorphins-7 in infants on different type of feeding and different levels of psychomotor development. Peptides. 2009 Oct;30(10):1854-60.

[4] Barnett MP, et al. Dietary A1 β-casein affects gastrointestinal transit time, dipeptidyl peptidase-4 activity, and inflammatory status relative to A2 β-casein in Wistar rats. Int J Food Sci Nutr. 2014. March 20.

[5] Hunter LC. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8.

[6] Cass H. et al. Absence of urinary opioid peptides in children with autism. Arch Dis Child. 2008 Sep;93(9):745-50.

[7] Shah JJ. et al. Casein and gluten-derived opiate peptides affect cysteine uptake and redox status. FASEB J. 2013; 27: 1075.1.

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Sokolov, O., Kost, N., Andreeva, O., Korneeva, E., Meshavkin, V., Tarakanova, Y., Dadayan, A., Zolotarev, Y., Grachev, S., Mikheeva, I., Varlamov, O., & Zozulya, A. (2014). Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity Peptides DOI: 10.1016/j.peptides.2014.03.007

New life for naltrexone and autism?

During the very earliest days of the life of this blog I posted about the opiate antagonist naltrexone (ReVia®) and some research on its history with autism in mind; in particular, the various emerging speculations on low dose naltrexone (LDN) (see here). Today I'm following up that entry based on the results of a systematic review by Ashok Roy and colleagues [1] on the value (or not) of naltrexone for "attenuating the core symptoms of autism spectrum conditions in children".

"Yadwigha in a beautiful dream" @ Wikipedia 

The authors report: "Naltrexone may improve hyperactivity and restlessness in children with autism but there was not sufficient evidence that it had an impact on core features of autism in majority of the participants. It is likely that a subgroup of children with autism and abnormal endorphin levels may respond to naltrexone and identifying the characteristics of these children must become a priority".

I am not unhappy with this statement. Realising that autism is probably better represented by the plural 'autisms' and, as with just about every intervention put forward for the autisms, there is not one-size-fits-all measure, it makes good sense to seek out those best- and non-responders to something like naltrexone therapy. The fact that the authors also talk about "abnormal endorphin levels" as potentially being one guide for responder status harks back to the work of Gillberg and colleagues [2] from decades ago. I've also talked before about how other interventions such as the use of a gluten- and casein-free (GFCF) diet (which may very well be related to any naltrexone effect) seem to also affect more peripheral functions over core behaviours when it comes to autism (see here).

As odd as it might sound that a drug more normally used for the management of opioid dependence or alcohol dependence should potentially affect the presentation of at least some autism, there is perhaps some logic to its use. Opioid, by the way, refers to drugs such as morphine and codeine which bind to the opioid receptors we all have and produce various effects, most famously analgesia (pain relief) or in the case of abuse of such drugs, euphoria (happiness and wellbeing) at least for a short time. Naltrexone and other opioid antagonists produce an effect by blocking those opioid receptors, such that opioids cannot bind to them and so don't carry their prescribed effects. This similarly applies to our own internal opioid system including the endorphins. This euphoria blocking effect has also been put forward as a possible counteraction to the placebo effect too [3].

Of course one has to accept that one of three potential scenarios may be related to autism if one is to believe that naltrexone might seriously affect the presentation of symptoms for some:

1. that autism, some autism or its comorbidity, may have an element of opioid involvement to underlying biochemistry as per the Gillberg endorphin findings or even speculations that something like the opioid-excess hypothesis [4] may show involvement to cases, bringing in the GFCF diet angle. I hasten to add that I am not insinuating that autism is due to opioid addiction or anything like that.
2. that some autism may have an element of immune system involvement in light of the proposed action of something like LDN on inflammatory processes [5] and the preliminary signs of an effect on some cases of inflammatory bowel diseases such as Crohns disease [6] which might yet be relevant to other autism research (see here).
3. that any effect is purely epiphenomenal; just coincidence or a placebo effect, bearing in mind the Samokhvalov paper [3].

I'm not on this occasion going to offer any particular opinion about those options. I'd like to think that scenarios 1 and 2 are the more likely options in light of some [limited] results under double-blind, placebo-controlled conditions [7] for naltrexone acting on autism, but echoing the sentiments of Roy et al, there is much more investigation required in this area.

I do find the topic of naltrexone and autism to be a particularly interesting area of research. As also mentioned in a previous post on drug refractory aggression and autism, naltrexone continues to find favour for aiding some people on the autism spectrum, with the promise of so much more. You will be hearing more from me on this topic in future, particularly on some of our own research which has just cleared the peer-reviewed hurdle with drug delivery methods in mind...

Now, some music to liven things up... AC/DC and a very famous guitar riff...

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[1] Roy A. et al. Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. J Intellect Disabil Res. 2014 Mar 4.

[2] Gillberg C. et al. Endorphin activity in childhood psychosis. Spinal fluid levels in 24 cases. Arch Gen Psychiatry. 1985 Aug;42(8):780-3.

[3] Samokhvalov AV. et al. Naltrexone may block euphoria-like placebo effect. BMJ Case Rep. 2013 Aug 7;2013. pii: bcr2013010098. 

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Younger J. et al. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014 Feb 15. 

[6] Segal D. et al. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2014 Feb 21;2:CD010410.

[7] Willemsen-Swinkels SH. et al. The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study. Biol Psychiatry. 1996 Jun 15;39(12):1023-31.

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Roy A, Roy M, Deb S, Unwin G, & Roy A (2014). Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. Journal of intellectual disability research : JIDR PMID: 24589346

Soy infant formula and seizures in autism

Spring @ Wikipedia 

'Association' is a word I'm sure many people with a connection to autism will have heard a lot about. Y'know gene X or compound Y is the plat du jour when it comes to autism aetiology; more often than not carrying the caveat 'requires further investigation'. As to whether such investigations are ever truly carried out would perhaps be an interesting piece of research on autism research.

Today I'm talking about another association, another variable to throw into the statistical risk mix derived from the paper by Cara Westmark [1] (open-access here) suggesting that where seizures or epilepsy present alongside (or as part of) autism, there may be a curious correlation to be had with the use of soy infant formula.

I'll readily admit that when first reading the title to this study I was more than a little reluctant to blog about it. I can't really explain why - whether it was yet another study of 'association' or something about what appears to be quite a well-used feeding strategy for infants where traditional methods are not indicated - there wasn't the initial appetite to talk about it. Following some light reading around the topic and what looks to be some quite strongly held views on the use of infant soy formula (see this BBC report) including mention of a possible relationship with ADHD (see here) I eventually decided that this might be something to cover. The press release covering the study also helped (see here and see here) in making my decision.

A few details:

• The hypothesis: "the use of soy-based infant formulas could be contributing to seizure incidence in autism and other neurodevelopmental disorders" came about apparently on the basis of some earlier work by the authors [2] (open-access here) which suggested that a component of soy-feed (daidzein) given to rats might have the ability to induce seizures after a few days consumption. More discussion about this earlier trial can be found here.
• So, based on an analysis of data derived from the Simons Foundation Autism Research Initiative (SFARI), Westmark and colleagues looked at the occurrence of seizures and if available, the types of seizures reported, alongside the frequency of soy infant formula use, using sex as a differentiating variable in cases of autism.
• Results: "There was a 2.6-fold higher rate of febrile seizures in the soy-fed cohort (4.2% seizures with soy and 1.6% seizures without soy)". That being said, the results only passed significance for females who were fed soy formula; males were more likely to present with seizures after soy feeding "but [results] were not statistically significant".
• Also: "A comorbid diagnosis of autism and epilepsy was more prevalent in males fed soy-based formula (odds ratio = 2.4, 95% confidence interval 1.1–5.2; P = 0.02) than females (odds ratio = 1.4, 95% confidence interval 0.056–14; P = 0.8)". This does sound a little counter-intuitive given what the last sentence said about febrile seizures and gender but I would draw your attention to the use of the diagnostic term 'epilepsy' as opposed to 'febrile seizure'.

I'm pretty sure that you can see from the collected data included in this paper there are some potentially interesting details which require further analysis. I'm for example interested in seeing more about the proposed mechanism to account for the correlation reported between soy formula use and an elevated frequency of seizures/epilepsy in relation to autism. The authors suggest "the effects of an underlying genetic mutation that lowers seizure threshold may be exacerbated, for example, by dietary exposure to high concentrations of phytoestrogens". Yes, possibly; although with various other autism-related research areas in mind, I'd be interested to see whether there may other effects from for example, the gut microbiota [3] and how they might also play their part.

Perhaps another question would be whether the underlying reason why soy infant formula was used in the first place might also have played some role in the results. The authors do approach this topic as per the sentences: "A possible criticism is that subjects, who were fed soy-based infant formula because they were allergic to cow's milk, had allergies that made them vulnerable to illnesses associated with fever-induced convulsions. Though the retrospective nature of the data does not allow us to make definitive conclusions regarding this point, we found that 2.7% of females and 1.7% of males in the study population reported allergies, but no subjects reported both allergies and febrile seizures suggesting that this criticism may not be valid". I'd perhaps chime in here and suggest that 'allergy' might be a bit of a red herring here as per the research looking at something like lactose intolerance in relation to autism (see here) and the still quite speculative role of milk peptides (see here). There is also the potential issue of something like those folate receptor autoantibodies to consider (see here) which also seem to be affected by old fashioned milk although I am speculating here. There is the odd study (case report) talking about something like lactose intolerance and epilepsy for example [4] but still a lot more scope for further investigation in this area.

As per my introduction to this post on the role of 'association' when it comes to autism research, one always needs to be a little careful when interpreting such data and drawing too many conclusions. I'm not saying that seizures or epilepsy in autism may not be linked to something like early infant feeding choice, but with the same logic, I'd be hard pressed to say there is conclusive evidence of any association yet. And remember, the plural condition of autisms are a very complicated set of conditions indeed.

Finally, quite by coincidence, just yesterday I received an email invite to submit to a Frontiers journal topic headed by Dr Westmark on a favourite topic of mine (diet and the brain) which reminded me of an equally interesting research area on the use of ketogenic diets with autism and epilepsy in mind... more food for thought? (without any medical or clinical advice given or intended)

Music to close. Bowie and Jagger and a great video with some contrasting dancing styles. Condolences also to Sir Mick and the family of L'Wren Scott.

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[1] Westmark CJ. Soy infant formula and seizures in children with autism: a retrospective study. PLoS One. 2014 Mar 12;9(3):e80488.

[2] Westmark CJ. et al. Soy-based diet exacerbates seizures in mouse models of neurological disease. J Alzheimers Dis. 2013;33(3):797-805.

[3] Atkinson C. et al. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med (Maywood). 2005 Mar;230(3):155-70.

[4] Yaman H. et al. Epileptic seizures associated with lactose intolerance in a child: A causal relationship? J Pediatr Neurology. 2012; 10: 151-154.

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Westmark CJ (2014). Soy infant formula and seizures in children with autism: a retrospective study. PloS one, 9 (3) PMID: 24622158