Roger Moore's eyebrows, ADHD and coeliac disease part 2

Consider this post an extension of some previous blogging chatter (see here) about how behaviourally defined diagnostic labels such as attention-deficit hyperactivity disorder (ADHD) seem to rarely exist in some sort of clinical vacuum. Part of that vacuum also potentially encompasses a range of somatic symptoms and/or diagnostic labels.

The findings reported by Vendel Kristensen and colleagues [1] set out to "assess self-reported symptoms of impaired concentration in coeliac disease before and after treatment with gluten-free diet, compared with healthy controls and patient controls." Coeliac (celiac) disease, in case you didn't know, refers to the archetypal 'gluten can affect biology' condition, where a certain genetic predisposition (or two) adds to gluten exposure to start a whole cascade of biological actions that impact on physical health and well being. Alongside things like bowel symptoms, there is an increasing recognition that coeliac disease (CD) also potentially brings with it certain psychological symptoms, particularly when it is not properly treated/managed (see here).

Kristensen et al asked some 30 people - "newly diagnosed coeliac patients" - to complete various questionnaires pertinent to the presentation of ADHD type symptoms, depression and anxiety and gut issues. These were compared with responses from those diagnosed with an inflammatory bowel disease (IBD) and controls (healthcare professionals).

They reported that those diagnosed with CD before implementation of a gluten-free diet had "significantly higher scores than healthy controls" in relation to the presence of self-reported ADHD and depression/anxiety symptoms. Further: "After a gluten-free diet, their scores improved and were not significantly different from healthy controls." That gluten-free diet by the way, was in place for a minimum of 12 months.

One has to be careful not to make too many sweeping generalisations from the Kristensen data. The data do not, for example, mean that all cases of ADHD are somehow the product of undiagnosed coeliac disease. Not even close. What do they do (cautiously) suggest, is that preferential screening for something like coeliac disease *might* be a good idea as and when ADHD is diagnosed or significant ADHD-like symptoms present. Such findings also resonate with the idea that certain dietary interventions to manage *some* ADHD could be a research area to consider (see here) and bring into play an interesting concept: the gut-brain axis.

Oh, and in case you were wondering about the 'Roger Moore's eyebrows' bit, well, he was the best James Bond wasn't he?

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[1] Kristensen VA. et al. Attention deficit and hyperactivity disorder symptoms respond to gluten-free diet in patients with coeliac disease. Scand J Gastroenterol. 2019 May 3:1-6.

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A gluten-free diet for "schizophrenia positive for antigliadin antibodies (AGA IgG)"

Short post alert...

"This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder."

So said the findings reported by Deanna Kelly and colleagues [1] as the conference abstract [2] of their study finally hits the peer-reviewed science literature (see here).

As per my previous musings on this study, this was the "first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA [anti-gliadin antibodies] IgG." Results were interesting insofar as "participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale... and in negative symptoms." Net result: encouraging findings with the need for more study; also with a nice focus on effect sizes too...

'Nuff said.

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[1] Kelly DL. et al. Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci. 2019 Mar 27;44(3):1-9.

[2] Kelly D. et al. Randomized double-blind feasibility study of a gluten-free diet in people with schizophrenia and elevated antigliadin antibodies (AGA IgG). Schizophrenia Bulletin. 2018; 44: S190.

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Gluten, mimicry and schizophrenia

The findings reported by Daniela Čiháková and colleagues [1] provide the rather long blogging fodder today, and some interesting observations on how the immune system 'reacting' to gluten in some cases of schizophrenia might have some pretty far-reaching consequences when it comes to other proteins with a similar chemical structure.

OK, first things first, gluten is a protein. It's made up of long chains of amino acids; the building blocks of proteins. As gluten is digested in the gastrointestinal (GI) tract, various enzymes get to work on the protein to break it down into it's constituent amino acids, forming peptides (short chains of amino acids) along the way. The protein gluten and its components like gliadin has a characteristic shape like every protein has. For reasons that aren't yet completely understood, the immune system of some people can sometimes 'mark' normally fairly harmless proteins like gliadin as something that needs dealing with. It does this via the production of antibodies. Antibodies usually mark pathogens like bacteria or viruses, and by doing so, set off a cascade of biological processes to [try and] ensure that such invaders don't take hold and also to remind the immune system of what to look out for. Marking something like gliadin out (which is neither bacteria nor virus!) probably means that the body is detecting gliadin in places it shouldn't be; something that I'll come back to in a minute.

It's not beyond the realms of possibility that when the immune system marks a specific protein as something to keep an eye on, it can make mistakes. If for example, two proteins 'look' similar to each other in a chemical arrangement sense, despite being different proteins with different functions, the immune system can sometimes become a little confused and start to mark both as being an invader on the basis of one already having 'special interest' status. Several descriptions describe such a process: "cross reactivity or mimicry." This accidental marking can sometimes have important repercussions, where such a process is thought to be a basis for autoimmunity.

Čiháková et al detail findings suggesting that just such a process - mimicry - could well be pertinent to some cases of schizophrenia. As already mentioned, they started with the observation that some people diagnosed with schizophrenia have high levels of specific antibodies to gliadin (see here and see here). This follows quite a lot of history linking gluten and schizophrenia together (see here). They wanted to see if as well as presenting with antibodies to gliadin, a cohort of people diagnosed with schizophrenia might also present with elevated antibodies to something called GRINA - Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1. They focused in on GRINA because it has a "similar protein structure to gliadin representing a potential target for cross reactivity or mimicry." GRINA also links into glutamate system functioning, something which has also already been mentioned with schizophrenia in mind (see here).

There's another detail about the Čiháková study which relates to a point I touched upon earlier, on the possible hows-and-whys of gliadin antibodies being found in cases of schizophrenia: enhanced gut permeability a.k.a leaky gut. Researchers also analysed serum samples for the presence of something called Anti-Saccharomyces Cerevisiae antibodies (ASCA) which they say are "related to gut permeability." This follows other research in a similar vein (see here) and the suggestion that something like abnormal gut permeability *could* be implicated in some cases of schizophrenia.

Results: looking at serum samples of 160 people diagnosed with schizophrenia and 80 not-schizophrenia controls, researchers observed "a higher prevalence of positivity to ASCA IgA... and IgG" in those with schizophrenia. This tallies with the leaky gut hypothesis. They also reported that "GRINA IgG was higher in schizophrenia patients than in healthy controls." Putting these results together, they concluded that the mimicry hypothesis might well be pertinent to some schizophrenia.

There is a lot more work required in this area for sure. This will need to involve further investigation of the hows-and-whys of any such mimicry, and whether such a process could be a potential target for intervention. Indeed, in that intervention vein, I'm wondering whether use of a gluten-free diet for some with schizophrenia who have such antibodies (to gluten and other things like GRINA) might be an option. There's also merit in looking further at the issue of gut permeability and schizophrenia; whether again adoption of a gluten-free diet (which can positively affect gut permeability measurements) might be indicated, perhaps alongside other therapeutic targets.

But this area of research is interesting, and adds to the quite long research history linking food components and some behavioural / psychiatric labels...

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[1] Čiháková D. et al. Gut permeability and mimicry of the Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) as potential mechanisms related to a subgroup of people with schizophrenia with elevated antigliadin antibodies (AGA IgG). Schizophr Res. 2019 Jan 23. pii: S0920-9964(19)30007-6.

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The gastrointestinal (GI) effects of a gluten- and casein-free diet in autism (continued)

It took a few attempts for me to get this blog post discussing the the paper by Carlo Alessandria and colleagues [1] right. The reasons? Well, predominantly it was because I'm no expert when it comes to the gastrointestinal (GI) tract and autism and, in particular, some of the intricacies of the clinical findings in that context. Don't get me wrong, I am a very keen observer of the peer-reviewed science literature on the bowel and autism (see here and see here  and see here for examples) but I'm no gastroenterologist.

What I did take away from the Alessandria findings is that science is continually looking at the possibility of a link between the various GI issues identified in cases of autism and the still-important peer-reviewed literature on how use of a gluten- and/or casein-free diet (GCFD) seems to have a positive impact for some people on the autism spectrum (see here). Indeed, that there may be lots more to see when it comes to a gut-diet-behaviour interface in relation to (some) autism...

So, slowly does it. First, the aim of the Alessandria study: "evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD [autism spectrum disorder] with GI symptoms, together with its correlation with duodenal histology and response to GCFD."

HLA-DQ2/DQ8 'typing' are words more commonly found in relation to the prototypical 'dietary gluten can affect health' condition that is coeliac disease. They describe some of the genetics of coeliac disease (CD), and are key components involved in risk for the condition and perhaps other diagnoses of a similar autoimmune ilk. From the 150 or so participants - "with ASD with GI symptoms referred to our outpatient clinic" - who were screened for HLA-DQ2/DQ8, around half were positive (72/151). But researchers did not just stop there. Alongside they also screened for "CD-specific antibodies" (see here and see here for the flavour of what this includes) and concluded that "134 (89%) were negative." To summarise, around half of participants with autism and bowel symptoms possessed the genetics of coeliac disease. But, only around 10% showed a pattern of antibodies related to CD indicative of an immune response to gluten as well as other issues (see here).

And there was more: "Patients were prescribed a 6-month GCFD, and then clinically reassessed." This is where another 'assessment' also becomes relevant to the Alessandria findings. As part of their clinically indicated procedures, participants also underwent endoscopy. This allowed researchers to both look at the inner workings of some of the GI tract and also potentially take biopsy samples. At baseline, before any diet was put in place, they observed that: "56 (37%) showed duodenal microscopic inflammation." 'Duodenal' refers to the duodenum, a part of the GI tract fairly close to the exit of the stomach. Inflammation means just that. And something interesting seemed to connect such bowel findings and dietary response: "Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern)." In other words, and accepting that correlation is not the same as causation, issues identified in the duodenum - "duodenal histology" - seem to be a possible predictor of response to a gluten- and casein-free diet in relation autistic people.

There is a need for lots more study in this area. Alessandria and colleagues reported their observations on the basis of patients presenting at their clinic with medical needs. This was not a clinical trial in the respect of being randomised (e.g. receiving a diet or not or some other medication to treat such identified bowel issues) or being blinded (researchers and patients not knowing who got what intervention). Knowing a little bit about the use of a GCFD in the context of autism (see here) I'm also acutely aware that 6 months following such a diet is a long time. Even with the best will in the world, some people will not be able to follow such a restrictive diet day-in, day-out. There are issues.

But the Alessandria results are important and promising. They provide a template for further study and an addition to the wealth of biologically-based information on who, on the autism spectrum, might be a 'best candidate' for dietary intervention which excludes gluten and/or casein. I know some people might start up with the 'it's too invasive' arguments in relation to the use of endoscopic and indeed, colonoscopic inquiry when it comes to autism. My counter-argument is that if physicians were presented with a child or adult who did not have autism yet had the same bowel problems as this and other cohorts, would they not be afforded the best healthcare available to them including such inquiry? And why then should a diagnosis of autism but exclusionary to accessing such healthcare? Oh, and it's worth mentioning that at least one of the authors on the Alessandria paper has talked about how technology might eventually make such invasive techniques that little less invasive [2]. Indeed, they've also talked about what else aside from a gluten- and casein-free diet might be clinically indicated for some people on the autism spectrum [3] too with GI issues in mind...

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[1] Alessandria C. et al. HLA-DQ Genotyping, Duodenal Histology, and Response to Exclusion Diet in Autistic Children With Gastrointestinal Symptoms. J Pediatr Gastroenterol Nutr. 2019 Feb 7.

[2] Balzola F. et al. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Am J Gastroenterol. 2005 Apr;100(4):979-81.

[3] Campion D. et al. The role of microbiota in autism spectrum disorders. Minerva Gastroenterol Dietol. 2018 Dec;64(4):333-350.

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"A strict and lifelong gluten-free diet can help recover vitamin D level without any supplementation"

The quote titling this post - "A strict and lifelong gluten-free diet can help recover vitamin D level without any supplementation" - comes from the results published by Fabiana Zingone & Carolina Ciacci [1].

These authors inspected the peer-reviewed literature looking at vitamin D levels in relation to the archetypal 'diet can affect health' autoimmune condition that is coeliac (celiac) disease. They looked at both something called calcifediol, otherwise known as 25-hydroxyvitamin D (25(OH)D), and also something called calcitriol, also known as 1,25-dihydroxyvitamin D3. The difference between the two 'forms' of vitamin D is that one represents the 'pre-hormone' version  - (25(OH)D) - that is typically quantified to give a 'where you're at' measurement of biological vitamin D levels, and the other - 1,25-dihydroxyvitamin D3 - is the 'active' metabolite. Through the wonders of something called mass spectrometry, these and other 'forms' of vitamin D are able to be quite accurately measured [2] in various biological fluids.

Zingone & Ciacci reported that "most of the studies on vitamin D in adult CeD [coeliac disease] report a 25 (OH) vitamin D deficiency at diagnosis that disappears when the patient goes on a gluten-free diet, independently of any supplementation." This finding really intrigued me. It got me thinking of a few things; notably about mechanisms and biological relationships and indeed, how applicable such a finding could be to the general 'not coeliac' population or those 'around the diagnostic edges' of CeD.

OK, it should be noted that part-and-parcel of CeD is an issue with malabsorption, where 'the body does not fully absorb nutrients' (see here). The inflammatory processes at work in CeD do some pretty awful things to the structure and functioning of the mucosal lining of the bowel which aren't really conducive to optimal absorption of nutrients from food. The implementation of a gluten-free diet does help matters; and so logic dictates that absorption of something like vitamin D from food sources will be improved when a gluten-free diet is implemented. I've also blogged about how this process *may* also be part of the effect noted in relation to [some] autism and the use of similar dietary intervention strategies (see here). Alongside, I'll mention that, done right, a gluten-free diet is actually not the most unhealthiest diet in the world either.

Having already sort-of mentioned something like non-coeliac gluten/wheat sensitivity in the contest of the 'diagnostic edges' of CeD, I do wonder if there could be a further plan of research there too. Y'know to look at questions like whether such not-quite-coeliac-disease conditions also (a) manifest as having low levels of vitamin D when not diet treated and (b) whether the use of a gluten-free or other diet (see here) might similarly positively effect vitamin D levels in those circumstances?

There's also another potentially important explanation to consider which was tweeted by Dr Emily Deans (she of the fabulous Evolutionary Psychiatry blogs): could vitamin D deficiency be a marker of something more general? To quote from Dr Deans' tweet (shown pictured above): "Because it’s [vitamin D] an inverse acute phase reactant and goes down with illness and up with health." There is some sound logic behind such an observation insofar as vitamin D insufficiency/deficiency being associated with all manner of physical and behavioural/psychiatric diagnoses/conditions/states (see here and see here for examples). Correction of vitamin D deficiency is all well and good when it comes to correcting biological measures, but outside of treating something like rickets, the evidence for extra-skeletal effects from such supplementation is currently not that great.

Finally, I'll draw your attention back to some work suggesting that vitamin D might itself have some interesting effects on gut barrier function (at least in mice) (see here). One wonders what this could also mean for CeD and the spectrum of gluten-related issues?

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[1] Zingone F. & Ciacci C. The value and significance of 25(OH) and 1,25(OH) vitamin D serum levels in adult coeliac patients: A review of the literature. Dig Liver Dis. 2018 Apr 13. pii: S1590-8658(18)30702-3.

[2] van den Ouweland JM. et al. Vitamin D and metabolites measurement by tandem mass spectrometry. Rev Endocr Metab Disord. 2013 Jun;14(2):159-84.

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"Gluten-free prescribing is in a state of flux"

Consider this off-core-topic post an extension of previous other off-topic chatter on this blog talking about the prescription of gluten-free foods here in Blighty (see here). On that previous blogging occasion, I discussed a 'head-to-head' debate on whether the prescription of gluten-free foods for conditions such as coeliac disease was still 'relevant' in an age when supermarkets have shelves loaded with gluten-free products as part of a societal fascination with 'going gluten-free'. Whether there may be other models - such as the use of a voucher scheme - that could save time and money yet still ensure that the important use of a gluten-free diet in relation to coeliac disease is maintained and supported.

Well, the recent findings reported by Alex Walker and colleagues [1] add to this debate, and their look at "long-term national trends in gluten-free prescribing, and practice and Clinical Commissioning Group (CCG) level monthly variation in the rate of gluten-free prescribing (per 1000 patients) over time." CCGs by the way, are groups here in England "responsible for the planning and commissioning of health care services for their local area."

Walker et al relied on a retrospective cohort study design that analysed prescribing and spending data from various sources, and covered various geographical areas of England in relation to gluten-free prescribing. Alongside, other potentially pertinent data were included in the statistical mix, for example: "Index of Multiple Deprivation (IMD) score; patients with a long-term health condition (%); patients over 65 (%) and whether each practice is a ‘dispensing practice’ with an in-house pharmacy service (yes or no)."

Results: including data from over 7600 medical practices, authors reported that between July 2012 and June 2013, some 1.8 million prescriptions for gluten-free products were dispensed costing around £25.4 million. Fast forward to the period July 2016 - June 2017 and fewer prescriptions were made: "1.3 million gluten-free prescriptions nationally... with a total expenditure of £18.7 million." This, bearing in mind, that rates of diagnosed coeliac disease are seemingly only going in one direction - up [2].

Researchers also reported that there was "substantial variation in prescribing rates among practices" which was captured by some other reporting on the Walker paper as per bylines such as: "Prescribing of gluten-free products in England differs largely and “without good reason”, researchers have concluded." Indeed Walker and colleagues concluded that much of the geographical discrepancy in the gluten-free prescribing rates was "driven at the CCG level, where there is also a great deal of variation." For some CCGs, the decision was to provide gluten-free prescriptions; for others, there seems to be "a partial or complete withdrawal of prescriptions." A bit of a postcode lottery if you like.

As to those other variables included in the analysis, a few other important details emerged. So: "practices in the most deprived areas had a significantly lower rate of gluten-free prescribing than those in less deprived areas." Further: "We also found that percentage of patients over 65 is strongly associated with gluten-free prescribing, which is unsurprising given that coeliac disease prevalence increases with age." That first finding in relation to deprivation *might* be linked to things like an under-diagnosis of something like coeliac disease in those areas. But it could point to other factors potentially coming into play as well...

At the time of writing / publishing this post, we are still living in the age of austerity here in Blighty. Government in particular, [still] wants to 'balance the books' yet is still expecting national services such as health to provide for the population they serve. Set within that context, and also how health budgets are having to deal with more people with more complex needs, it's probably not surprising that for some geographical areas, 'low hanging fruit' such as gluten-free prescriptions are seen as fair game when it comes to balancing the books. It shouldn't, but there you go.

I do stand by the idea that if things are seemingly 'on the downward slide' in terms of gluten-free prescribing patterns, there may be other models to look at that could help (i.e. that voucher scheme idea). Patients and their relevant organisations need to have a voice in this process to ensure that gluten-free diets are maintained and health does not unduly suffer. Food, for people with coeliac disease - gluten-free food - is medicine, and one should never forget that and the absolute requirement to provide such medical provision.

To close, and entirely unrelated to today's post, I see Belgium have some historical and/or statistical advantage when it comes to the World Cup starting soon...

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[1] Walker AJ. et al. Trends, geographical variation and factors associated with prescribing of gluten-free foods in English primary care: a cross-sectional study. BMJ Open. 2018 Apr 16;8(3):e021312.

[2] Holmes GKT. & Muirhead A. Epidemiology of coeliac disease in a single centre in Southern Derbyshire 1958-2014. BMJ Open Gastroenterol. 2017 Apr 1;4(1):e000137.

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Allergy and autism linked (again)

There was something rather timely about the publication of the result by Guifeng Xu and colleagues [1] observing that: "In a nationally representative sample of US children, a significant and positive association of common allergic conditions, in particular food allergy, with ASD [autism spectrum disorder] was found."

Timely, because earlier the same day I read a rather disparaging piece titled 'oversold diets' *trying* to condense down the findings reported by Gogou & Kolios [2]. This duo looked at the "current literature data about the effect of therapeutic diets on autism spectrum disorder", where certain diets are often put in place because of a perceived allergy or intolerance to certain foodstuffs and effects on behaviour and physiology. Gogou & Kolios concluded that: (a) "No serious adverse events have been reported" ('first, do no harm' and all that) and (b) the currently available peer-reviewed data on things like the use of a ketogenic diet and/or a gluten- and casein-free (GFCF) diet 'for' autism is promising but: "More research is needed to provide sounder scientific evidence." I agree that lots more resources and money need to be put into the scientific examination of such diets in the context of autism (see here and see here) including identifying potential best-responders [3]. I'd also like to see gastrointestinal (GI) issues included in the research agenda, in light of other promising peer-reviewed data too on a potential tie-up with said diets and autism (see here)...

Anyhow, back to the Xu findings, which have seemingly attracted some media attention (see here for example). The source of the data was the "National Health Interview Survey [NHIS] collected between 1997 and 2016", a US initiative designed to 'monitor the health of the United States population through the collection and analysis of data on a broad range of health topics'. Including parent or guardian responses on a questionnaire used as part of the NHIS, and specifically the questions: "during the past 12 months, has your child had (1) any kind of food or digestive allergy; (2) any kind of respiratory allergy; (3) eczema or any kind of skin allergy?", data was crunched for nearly 200,000 children.

Authors reported that as a total group (N=199,520), the weighted prevalence of food allergy being reported was about 4%. For a respiratory allergy, the prevalence came in at about 12% and 9% for a skin allergy.

Then to the autism vs. not-autism comparisons where: "A diagnosis of ASD was reported in 1868 children (weighted prevalence, 0.95%; 95% CI, 0.89%-1.01%)." Parents/guardians of those diagnosed with autism were significantly more likely to report all of those various allergies compared to the not-autism group. The figures were: food allergy (autism: 11.25% vs. not-autism: 4.25%), respiratory allergy (autism: 18.7% vs. not-autism: 12%) and skin allergy (autism: 16.8% vs. not-autism: 9.8%). Further: "After adjustment for age, sex, race/ethnicity, family highest education level, family income level, and geographical region, the OR [odds ratio] of ASD was more than doubled (OR, 2.72; 95% CI, 2.26-3.28; P < .001) among children with food allergy compared with those without food allergy." This last observation basically said that there was more chance of autism being reported among those with a food allergy than those without a food allergy.

Caveats? Well, a few to mention. First of all, you'll have noted the words 'parent or guardian responses on a questionnaire' being used, which need to be taken into consideration. No, I'm not casting any aspersions on reporting accuracy of anything like that (parents can be very sensitive to lots of things), but this was not a study of hospital records and tests or anything like that. Second is the use of the word 'allergy'. The medical definition of allergy (see here) is something like 'a biological response to a normally harmless substance'. Allergy is obviously immune-related and typically involves something called IgE (immunoglobulin E) among other things. Whilst some people might think they have an allergy to this, that or t'other, there is still some confusion about whether 'allergy' is the most suitable word in that context without for example, suitable allergy testing being undertaken. I might be being a bit pedantic, but words count...

That all being said, the Xu findings are not the first time that allergy and autism has been raised as being *associated* (see here and see here for examples). Indeed, allergic illness such as something like asthma, has quite a long association with autism (see here) and hints at a possible 'immune-related' connection to at least 'some' autism. That also one of the most common 'comorbid' conditions over-represented in relation to autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger connection with allergy (see here) is also important to mention, and further strengthens some immune system involvement where there is diagnostic intersection. It also *might* have intervention implications too (see here) (with no medical advice given or intended)...

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[1] Xu G. et al. Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children. JAMA Network Open. 2018; 1: e180279.

[2] Gogou M. & Kolios G. Are therapeutic diets an emerging additional choice in autism spectrum disorder management? World Journal of Pediatrics. 2018. May 30.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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A gluten-free diet for schizophrenia "with elevations in antigliadin antibodies (AGA IgG)"

Although published on 1st April, the study abstract published by Deanna Kelly and colleagues [1] as part of the 6th Biennial Schizophrenia International Research Society conference is no joke.

Discussing some preliminary results based on the use of a gluten-free (GF) diet with a small participant group diagnosed with schizophrenia and also registering "elevations in antigliadin antibodies (AGA IgG)", authors reported a few things potentially significant to see in terms of the impact of such dietary intervention on presented symptoms.

Such a research topic might be 'new news' to some people but not to me. I've covered the topic of schizophrenia and gluten a few times on this blog (see here and see here for examples), and how names like Curt Dohan and Kalle Reichelt (rest in peace Tiny) really were pioneers of the idea that cereal based foods *might* have quite a few effects on both body and mind. Quite a bit of this early work on gluten and schizophrenia has also 'drifted' over to other diagnostic labels too (see here) (including stretching more generally to a 'secure ward' population [2]) and continues to make some peer-reviewed science waves (see here).

On this research occasion, Kelly et al  - who are not strangers to this area of scientific research - reported initial results based on the use of a randomised, double-blind trial where 16 participants were all assigned to a gluten-free diet and either given "10 gm of gluten flour or 10 gm of rice flour daily in a protein shake" in an inpatient setting for 5 weeks. Various schedules were used to assess symptoms at baseline and again at 5 weeks. Importantly, authors noted that: "The study was not powered to find a treatment effect, but designed to examine the feasibility of conducting an inpatient gluten removal study and examine trends in treatment."

Although not necessarily looking for a treatment effect at this stage, there were some potentially important changes noted between baseline and endpoint as a function of a GF diet. So: "During the clinical trial, participants receiving the gluten free diet had an improvement in negative symptoms as compared to placebo (treatment difference) with an ES=0.53." ES stands for effect size and negative symptoms form part of the clinical profile of schizophrenia. Likewise, scores on one scale (attention) of a cognitive battery also pointed to something potentially to see as a function of dietary intervention. I'll reiterate that this was a pilot trial and the participant number was low... but these results are interesting. And, perhaps as expected, strict adoption of a GF diet affected those antigliadin antibody levels too: "The AGA IgG levels decreased by 35% in the five weeks in the gluten free diet group relative to a 17% decrease in the gluten containing group."

"The feasibility study provided data to design the now ongoing fully powered confirmatory double-blind trial in people with schizophrenia with negative symptoms using a higher gluten amount (30 grams daily) and with aims to examine associated mechanisms, with targets of inflammation, neuroimaging and gut permeability." I'll be keeping my research eyes open for the results of that one on the basis of the presented Kelly results and some other previous research gems (see here and see here)...

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[1] Kelly D. et al. Randomized double-blind feasibility study of a gluten-free diet in people with schizophrenia and elevated antigliadin antibodies (AGA IgG). Schizophrenia Bulletin. 2018; 44: S190.

[2] Vlissides DN. et al. A double-blind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry. 1986 Apr;148:447-52.

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Non-coeliac gluten avoiding groups: autism included

"Nonceliac gluten-avoiding patients have higher prevalences of inflammatory bowel disease, irritable bowel syndrome, thyroid disease, lupus, and autism spectrum disorder, suggesting patients with these disorders have turned to a GFD [gluten-free diet] for perceived benefit, despite a scant evidence basis."

So concluded the study published by John Blackett and colleagues [1] who set out to "characterize the medical conditions and demographic backgrounds of hospitalized patients without celiac disease who adhere to a GFD." Coeliac (celiac) disease by the way, represents the archetypal autoimmune 'gluten is baddie' condition, where treatment via a gluten-free diet is (currently) primary.

Based on inpatient data - "inpatients at Columbia University Medical Center on a GFD in 2011-2016" - researchers reported on some 770 individuals. Most of them (~60%) did not have coeliac disease (CD) but were reported to have a range of diagnoses "compared with age-matched and sex-matched inpatients on a regular diet." Gluten-free dieters showed a higher prevalence of those conditions listed at the start of this post, with the diagnosis autism spectrum disorder (ASD) specifically providing the highest odds ratio (OR) of all of them for being on a GFD: "autism spectrum disorder (OR: 23.42; 95% CI: 5.29-103.73)." Interesting too that those on a GFD had a lower prevalence of hypertension (high blood pressure) and diabetes compared with those on a regular diet. I'm not saying that this was as a result of the GFD, but other independent data [2] has talked about "a lower prevalence of hypertension" for example, in those who avoid wheat/gluten.

Am I particularly surprised by the Blackett findings? No. Despite the need for more controlled studies on the use of a gluten-free diet 'for autism', there is a wealth of peer-reviewed evidence suggesting that (a) conditions are 'right' for the use of a GFD in relation to SOME autism (see here for example) outside of a separate diagnosis of CD (see here), and (b) there is SOME evidence that a GFD does seem to impact on some facets of autism (see here) both core and peripheral (see here). I know there are some out there who would disagree - and take great pleasure in disagreeing😁! - with such sentiments, but that's what the peer-reviewed science currently suggests and is not just speculation.

Oh, and following a gluten-free diet needn't be unhealthy either (see here) with no medical or clinical advice given or intended...

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[1] Blackett JW. et al. Characteristics and comorbidities of inpatients without celiac disease on a gluten-free diet. Eur J Gastroenterol Hepatol. 2018 Jan 8.

[2] Tavakkoli A. et al. Characteristics of patients who avoid wheat and/or gluten in the absence of Celiac disease. Dig Dis Sci. 2014 Jun;59(6):1255-61.

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"A Blood Based Diagnostic Test for Coeliac Disease" (minus dietary gluten?)

The findings reported by Vikas Sarna and colleagues [1] have the potential to excite. Excite because, as the authors note: "A diagnosis of celiac disease based on serologic and histologic evidence and duodenal histology requires patients to be on gluten-containing diets" but a "growing number of individuals adhering to a gluten-free diet (GFD) without exclusion of celiac disease complicates its detection." A diagnostic test therefore, that could confirm/reject a diagnosis of coeliac disease (CD) without someone having to have gluten in their diet for some weeks, might be a rather exciting prospect.

Having previously posted their study aims and objectives on the ClinicalTrials.gov website (see here), authors tested the idea that "multimerized HLA bound to different gliadin-peptides (tetramer) and with the help of a flow-cytometer identify (along with other relevant T-cell-markers) gluten specific T-cells."

If all that sounds a little 'science-y' the long-and-short of it is the suggestion that the specific gene variants linked to CD - HLA-DQ2 and HLA-DQ8 variants - produce molecules -  HLA-DQ8 and HLA-DQ2 molecules - that bind to 'super-charged' gluten peptides to form a more complex molecule (tetramer) that has some rather important effects on components of the immune system, specifically on CD4+ T cells. Looking for such 'gluten specific T-cells' could be done by adding HLA-DQ-gluten tetramers to blood samples from patients with suspected/diagnosed CD. I think...

Anyhow, examining blood samples from a range of people - "62 subjects with celiac disease on a GFD, 19 subjects without celiac disease on a GFD [due to self-reported gluten-sensitivity], 10 subjects with celiac disease on a gluten-containing diet, and 52 presumed healthy individuals [controls]" - researchers put their test to the test. Most samples were analysed blind: "except for samples from subjects with celiac disease on a gluten-containing diet" and results were compared.

"An HLA-DQ-gluten tetramer-based assays that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether the individuals are on a GFD." The sensitivity and specificity figures reported by Sarna are pretty good when authors managed to 'optimise' their results based on the values obtained. Indeed: "The values identified subjects with celiac disease on a gluten-containing diet with 100% sensitivity (95% CI, 1.00-1.00]) and 90% specificity (95% CI, 0.83-0.98) vs controls." Even a couple of the control participants - 'presumed healthy individuals' - were actually found to have unrecognised CD.

More science needs to be done before this potential diagnostic test is rolled out further and potentially across many, many groups. Larger participant numbers and a greater diversity of participants in terms of ethnicity, sex/gender and age need to included for study. I'm also wondering whether those with other autoimmune conditions/diagnoses could also be included in future research plans too, on the basis that birds of an autoimmune feather tend to flock together (see here and see here).

Things do seem to be getting rather interesting when it comes to CD these days. Alongside this rather exciting work, there is also the prospect of preparations that degrade gluten peptides also coming into the mainstream (see here) and how nutrients like vitamin D might also show some potentially important gastrointestinal effects [2] (see here also) pertinent to CD and beyond. No, it's not quite the end of the 'lifelong gluten-free diet' (yet!), but science is seemingly moving just a little bit closer...

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[1] Sarna VK. et al. HLA-DQ-Gluten Tetramer Blood Test Accurately Identifies Patients With and Without Celiac Disease in Absence of Gluten Consumption. Gastroenterology. 2017 Nov 13. pii: S0016-5085(17)36352-7.

[2] Scricciolo A. et al. Vitamin D3 Versus Gliadin: A Battle to the Last Tight Junction. Dig Dis Sci. 2017 Nov 20.

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Antibodies against gluten in autism don't correlate with leaky gut markers

The paper by Jan Józefczuk and colleagues [1] provided some intriguing observations pertinent to quite a few topics previously discussed on this blog. Not only was there mention of anti-gliadin antibodies (AGA) and more specifically the finding that increased IgG-AGA was found in a quarter of their 77 participants with autism included for study, but also the important point: "An increased production of antibodies related to gliadin and neural TG6 [neural transglutaminase 6] in ASD [autism spectrum disorder] children is not related to serological markers of an impaired intestinal barrier."

It's worthwhile breaking down some of the details of the Józefczuk findings and what they might mean. I'll warn you that this is likely to be a bit of a long-read blog post so please, get comfy and read on...

So, AGA and more specifically, IgG-AGA represent the immune system 'recognising' gliadin, an important part of the protein gluten. IgG-AGA are typically found in many people diagnosed with the archetypal gluten-related autoimmune condition called coeliac (celiac) disease (although this measure is not considered diagnostic) but also alongside other more 'non-coeliac' gluten sensitivity conditions too (see here). The finding of elevated IgG AGA in cases of autism is by no means a new one (see here) (yes, this data came from the AGRE program [2] so no quibbling about the diagnosis of autism or anything like that). Other data has indicated that the presence of such antibodies seems to be a good reason to attempt a gluten-free diet (see here) which is music to my autism research ears (see here) and a good evidence-based reason to quiet down those who might 'challenge' such dietary intervention in the context of [some] autism. Then also is the idea that the presence of IgG AGA in conditions not totally unrelated to autism (see here) *might* play an important role in something like 'peripheral' inflammation [3] and whether the same could be true for [some] autism...

Next: "antibodies against neural transglutaminase 6 (TG6)" described by the authors as present in about 5% of their cohort is also an important finding. Turning up in a variety of different conditions [4] (although not yet considered 'mainstream' in certain quarters), some of the most interesting, and potentially relevant, labels where TG6 might be present include something called gluten ataxia [5], a neurological 'sign' characterised by a 'lack of voluntary coordination of muscle movements that includes gait abnormality.' Again, the data is compelling insofar as the use of a gluten-free diet as an intervention option [6] where gluten ataxia is diagnosed. With specific regards to autism and TG6 antibodies, I think the Józefczuk paper provides the first research outing for the two together (at least in a PubMed search). Other transglutaminase antibodies however, have been reported in the context of autism (see here for example) with the need for lots more investigations including with reference to the overlap between autism and coeliac disease (see here). At this point, I'll also note that gluten ataxia has not yet been linked to autism despite ataxia potentially showing some connection to some cases [7].

Moving on and we have the finding that: "Mean levels of zonulin and I-FABP [intestinal fatty acid binding proteins] in ASD [autism spectrum disorder] patients were similar to those found in healthy controls." Further: "Serum concentrations of zonulin and I-FABP showed no statistically significant association with antibody positivity." OK, zonulin is another topic of interest to this blog particularly in light of other recent findings with autism in mind (see here). Still the topic of considerable debate, zonulin has been described as "a biomarker of impaired gut barrier function for several autoimmune, neurodegenerative, and tumoral diseases" [8]. The data so far seems to indicate that gliadin - that component of gluten - 'induces' zonulin release [9] hinting that diet may be an important variable when it comes to 'impaired gut barrier function' otherwise known as intestinal hyperpermeability (or more imprecisely, leaky gut). I-FABP is something I'm a little less sure about in any context. It has been mentioned in the peer-reviewed research arena with autism in mind [10] but I can claim not expertise on this specific marker.

The Józefczuk findings report that zonulin levels in their cohort with autism were similar to "to those found in healthy controls" which is contrary to those previous findings in autism published by Erman Esnafoglu and colleagues [11]. They (Esnafoglu et al) concluded that: "Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL). " Forgetting (but not excusing) the incorrect use of 'healthy controls' in that paper, there is something of a difference between the Esnafoglu and Józefczuk results. One could argue that this is simply reflective of 'conflicting' autism research more generally (see here) but one might also question things like the analytical ways-and-means of assaying for something like zonulin too (see here).

The observation that zonulin (and I-FABP) levels showed 'no statistically significant association with antibody positivity' whilst informative is something I've been thinking about quite a bit. I don't have any easy answers as to why they found what they found aside from assuming that such data is evidence for how "increased immune reactivity against gluten" might not be specifically related to "the effect of intestinal barrier abnormalities" in relation to autism. This relationship assumes that abnormal gut permeability is the route through which gluten fragments (peptides) gain access to the wider central nervous system (CNS) which then elicits that immune response. It is a little surprising that no relationship was found given that one of the ways that zonulin is released is ingestion of gliadin and the assumption that gluten needs to be present in the diet for antibodies to be formed against it. But there you go. I suppose one might entertain the possibility that zonulin as a biomarker of impaired gut barrier function might not be the optimal way of measuring gut barrier function and including other more direct measures [12] could be the way forward to resolving this issue further.

Either way, research on immunological responses to gluten and notions of atypical gut permeability in the context of 'some autism' are seemingly not going away any time soon. Indeed, even medical professionals are seemingly not adverse to prescribing a gluten-free diet in the context of [some] autism [13]...

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[1] Józefczuk J. et al. The Occurrence of Antibodies Against Gluten in Children with Autism Spectrum Disorders Does Not Correlate with Serological Markers of Impaired Intestinal Permeability. J Med Food. 2017 Oct 26.

[2] Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155.

[3] Kelly DL. et al. Anti Gliadin Antibodies (AGA IgG) Related to Peripheral Inflammation in Schizophrenia. Brain Behav Immun. 2017 Oct 23. pii: S0889-1591(17)30476-2.

[4] Gadoth A. et al. Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015 Jun;72(6):676-81.

[5] Hadjivassiliou M. et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008 Sep;64(3):332-43.

[6] Hadjivassiliou M. et al. Dietary treatment of gluten ataxia. Journal of Neurology, Neurosurgery, and Psychiatry. 2003;74(9):1221-1224.

[7] Ahsgren I. et al. Ataxia, autism, and the cerebellum: a clinical study of 32 individuals with congenital ataxia. Dev Med Child Neurol. 2005 Mar;47(3):193-8.

[8] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012;1258(1):25-33.

[9] Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003 Feb;52(2):218-23.

[10] Pusponegoro HD. et al. Maladaptive Behavior and Gastrointestinal Disorders in Children with Autism Spectrum Disorder. Pediatr Gastroenterol Hepatol Nutr. 2015 Dec;18(4):230-7.

[11] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. Journal of Pediatrics. 2017; 188: 240-244.

[12] Bischoff SC. et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology. 2014;14:189.

[13] Rubenstein E. et al. The prevalence of gluten free diet use among preschool children with autism spectrum disorder. Autism Res. 2017 Nov 20.

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Gluten & casein free diet vs. ketogenic diet for autism: Fight!

OK, use of the word 'fight' in the title of this post looking at the study results published by Omnia El-Rashidy and colleagues [1] is a bit melodramatic but the findings do provide some rather interesting talking points when it comes to the whole 'diet and autism' thing (see here). Not least that this is, I think, the first peer-reviewed research occasion when the use of a gluten and casein-free (GFCF) diet in the context of autism has been pitted under experimental conditions against another dietary intervention of some interest, the ketogenic diet. The GFCF diet by the way, involves the removal of foods containing the proteins gluten, found in bread and other cereal-based products and casein, the primary protein found in milk and other dairy products. The ketogenic diet is not a million miles away from the GFCF diet but focuses more on the use of high fat and low carbohydrate foods (see here). Both diets have at least some experimental evidence to suggest that they may impact on autistic and related symptoms at least for some on the autism spectrum. But the evidence is not exactly strong yet [2] for any universal effect(s)...

The results of the El-Rashidy study: both diets seemed to be associated with improvements on various autism-related measures (including the ATEC) when compared with a "third group" who "received balanced nutrition and served as a control group" for 6 months. But on some measures the ketogenic diet (KD) came out on top: "ketogenic scored better results in cognition and sociability compared to GFCF diet group."

The authors rightly note that more needs to be done in this area before any sweeping generalisations are applied. So: "this study is a single center study with a small number of patients and a great deal of additional wide-scale prospective studies are however needed to confirm these results." Add to that issues such as a lack of double-blinding (a real Achilles heel when it comes to dietary intervention research in the context of autism) and there are several more investigations needed in this area; also potentially including measurement of some biological parameters to further elucidate possible mechanisms of effect (see here for one important suggestion). But don't completely disregard all of the peer-reviewed literature in this area as bunk just yet (see here). And that for some on the autism spectrum, there may truly be a diet-sensitive phenotype to examine [3]...

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[1] El-Rashidy O. et al. Ketogenic diet versus gluten free casein free diet in autistic children: a case-control study. Metab Brain Dis. 2017 Aug 14.

[2] Piwowarczyk A. et al. Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review. Eur J Nutr. 2017 Jun 13.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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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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"a gluten-related subgroup of schizophrenia"?

A quote to begin this post: "this preliminary study demonstrates that altered AGDA [antibodies against gliadin-derived antigen] levels in the circulation are associated with schizophrenia and could serve as biomarkers for the identification of a schizophrenia subgroup that may need an alternative therapy or precision treatment."

So said the findings reported by McLean and colleagues [1] (open-access) looking at an area of some interest to this blog (see here) on how dietary gluten might show something of an important relationship to at least some cases of schizophrenia. Just in case you weren't aware, there is quite a history when it comes to gluten and schizophrenia (see here) as per the very forward-thinking of people such as Curt Dohan and Karl Reichelt.

Researchers on this latest occasion set about looking in a little more detail at the suggestion that circulating anti-gliadin antibodies (AGAs) reflective of an immune response to a component of dietary gluten might show some connection to schizophrenia. Indeed they note that "all the tests for circulating AGAs in schizophrenia have been developed with mixtures of full-length native gliadins consisting of ~300 amino acid residues" suggesting that such a scatter gun approach may have included epitopes "that are unlikely to survive digestion in the gut." So, they instead "measured plasma levels of IgG and IgA against indigestible peptide fragments derived from γ- and α-gliadins" in archived plasma samples from "169 patients with schizophrenia and 236 control subjects."

The results - based on the use of an "In-house ELISA for antibodies against gliadin-derived antigens" - were rather intriguing. So: "There was no significant difference in the levels of plasma antibodies against native gliadins between the patient group and the control group." If I'm reading this right, this finding is in contrast to other independent research occasions [2]. Indeed, when it came to looking at both IgA and IgG plasma anti-gliadin antibodies, there was no significant difference between the schizophrenia and non-schizophrenia participants as groups.

But... when it came to a specific gliadin (γ-Gliadin) derived fragment  - AAQ6C - with the amino acid sequence HPKCSIMRAPFASIVAGIGGQYRD - researchers reported on something potentially important to see: "patients with schizophrenia had significantly higher levels of plasma anti-AAQ6C IgG than control subjects." Importantly too, authors also noted that anti-psychotic medication did not appear to influence their antibody results. This was important given that seemingly all of the participants diagnosed with schizophrenia were taking one or more of this class of medicine. In line with the opening quote to this post, the authors make a preliminary foray into the possible 'biomarker' usefulness of the various anti-gluten antibodies for schizophrenia. I have to say on this point however, that the data is not that impressive as things currently stand.

There is more to do when it comes to the possible effects of dietary elements containing gluten (and casein) in relation to cases of schizophrenia. This work adds something to the idea that diet can affect psychiatry/behaviour/development but what is perhaps missing is the recognition that schizophrenia is probably a heterogeneous and plural condition (see here and see here for examples) and as such, not every case is going to be gluten and/or casein-related. I do agree with the authors that more research is needed in this area alongside the idea that intervention via either dietary changes [3] and/or other options might also be on the research agenda...

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[1] McLean RT. et al. Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational Psychiatr. 2017. May 9.

[2] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[3] Jackson J. et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophrenia Res. 2012;140(0):262-263.

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McLean RT, Wilson P, St Clair D, Mustard CJ, & Wei J (2017). Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational psychiatry, 7 (5) PMID: 28485731

Welcoming zonulin into autism research

I was VERY happy to read the paper published by Erman Esnafoglu and colleagues [1] suggesting that: "zonulin, which regulates intestinal permeability, plays a role in the development of symptoms of ASD [autism spectrum disorder]."

Zonulin - something that "can be used as a biomarker of impaired gut barrier function for several autoimmune, neurodegenerative, and tumoral diseases" [2] - is a compound that I've been interested in for a while on this and other blogs (see here). The primary reason for the interest is that connection to intestinal permeability and how 'leaky gut' may well show some relevance to some autism (see here and see here). The thing that was up-to-now missing from the research chatter about intestinal hyperpermeability and autism was the measurement of zonulin on the basis that elevated levels of zonulin show a connection to dietary elements such as gliadin (a facet of gluten) [3]. This is particularly relevant because previous data has observed a possible link between use of a gluten-free diet and a reduction in intestinal permeability in relation to autism [4]. All this is [peer-reviewed] research music to my ears (see here)...

Esnafoglu et al set about measuring serum levels of zonulin in 32 participants diagnosed with an autism spectrum disorder (ASD) compared with 33 not-autism controls. Yet again, the words 'healthy controls' are used by the authors to define the control group and yet again, the assumption is that those participants with autism are somehow 'unhealthy'. Researchers, please just call it what it is: not-autism controls (the term 'neurotypical' also tells us nothing about control groups either). Measurement of zonulin was via ELISA (enzyme-linked immunosorbent assay) and researchers also threw in a measure of autism severity based on use of the Childhood Autism Rating Scale (CARS).

Results: well, the results seemed to be in the expected direction: "Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL)." Authors also identified a fairly healthy correlation between the CARS score and zonulin levels. These results imply that issues with intestinal permeability - leaky gut - seem to be present in relation to at least some autism. A shocker, I know.

Obviously there is more research to do in this area; not least to increase the sample size, look at dietary intake/status as a function of zonulin measurement and explore the possibility that the genetics of zonulin production might also be *involved* in some autism [5]. I might add that other research on zonulin in relation to diagnoses not necessarily uncommon to autism might also be revealing (see here).

Insofar as what to do about elevations in zonulin as and when detected in cases of autism, well the dietary link to zonulin production implies that the horror that is a gluten-free (GF) diet might be something to consider. The suggestion of a 'bacterial link' to zonulin production also suggests another possible intervention target in these days of gut microbiomes and autism (see here) although I think we have to be slightly careful about the use of some preparations. There is also another avenue for research speculation based on the development of zonulin (receptor) inhibitors such as Larazotide acetate [6] (otherwise known as AT-1001). With no medical or clinical advice given or intended, the evidence base for this zonulin-affecting compound is looking promising [7] with much more to come...

In conclusion, zonulin has arrived on the autism research scene, and I'm expecting to see more peer-reviewed science on this topic in future times. Intestinal hyperpermeability, diet and [some] autism looks to be squarely back on the research agenda.

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[1] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. J Pediatrics. 2017. May 11.

[2] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012; 1258(1) :25-33.

[3] Lammers KM. et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008 Jul;135(1):194-204.e3.

[4] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

[5] Tripathi A. et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16799-804.

[6] Fasano A. Intestinal Permeability and its Regulation by Zonulin: Diagnostic and Therapeutic Implications. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2012;10(10):1096-1100.

[7] Leffler DA. et al. Larazotide Acetate for Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: A Randomized Controlled Trial. Gastroenterology. 2015; 148: 1311-1319.

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Esnafoglu, E., Cırrık, S., Ayyıldız, S., Erdil, A., Ertürk, E., Daglı, A., & Noyan, T. (2017). Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects The Journal of Pediatrics DOI: 10.1016/j.jpeds.2017.04.004