Thursday, 26 September 2013

Gluten and autism: probably not coeliac disease but...

No link between autism and coeliac (celiac) disease.

That's the very loud proclamation from quite a bit of the media talking about the study by Jonas Ludvigsson and colleagues* as per sources like this one. That being said, the idea that issues with gluten reported in cases of autism might be reflective of something separate from coeliac disease (CD) has definitely gained some traction with the publication of the Ludvigsson results.
Non coeliac gluten sensitivity celebrates? @ Wikipedia 

For those who might not know CD is an autoimmune condition which basically represents the archetypal 'gluten is the baddie' condition. I've already posted a quite detailed entry on the basics of CD, or at least what we currently think we know about CD, which can be viewed here.

That post includes some of the biochemistry involved which revolves around (a) parts of the gluten protein not being easily degraded by the various enzymes charged with this task, (b) said peptides - short chains of amino acids formed during the digestion of the gluten protein - gaining entry to a part of the gut barrier, (c) the 'super-charging' of the those gluten peptides by something called tissue transglutaminase, and finally (d) the sparks that fly as a result of a certain kind of immune system meeting these modified peptides. References for the diagnostic serological criteria for CD are also included in that post.

Back to the Ludvigsson paper. The basic premise of the study was to look at Swedish registry data from patients with various stages of small bowel pathology linked to CD based on the Marsh criteria. This included those with Marsh stage 3 illustrative of villous atrophy (n=26,995), Marsh stages 1 & 2, categorised as 'inflammation' (n=12,304) and those with Marsh stage 0 (i.e. a normal gut mucosa) (n=3,719) but still with the serological markers of CD.

These cases were then compared against a control group (n=213,208) not presenting with CD in order to calculate "estimated odds ratios (ORs) for having a prior diagnosis of an ASD" (autism spectrum disorder). As per the headlines: "A prior ASD was not associated with CD".

But... with an OR of 4.57 a prior diagnosis of ASD was associated with having the serological markers of CD without the flattened or inflamed mucosa. Ergo, not full blown CD but having the serology indicating that gluten is immunologically active and potentially exerting an effect. The authors even found that presenting with CD or inflammation of the mucosa "were both associated with moderate excess risks of later ASDs". One question in that scenario could be: was CD and/or inflammation a possible factor in the development of autism?

Most people with some interest in autism, whether professionally or personally, will have heard about the various research rumblings suggestive that adoption of a gluten (and casein) free diet might, just might, have some impact on the presentation of autism - or at least some of the comorbidity which seems to follow autism. The body of work making up this suggestion is still a little bit methodologically 'frail' (including some of my own contribution to this area**) but isn't that the same for most intervention areas when it comes to the autisms?

The explanations as to why the gluten- and casein-free (GFCF) diet might impact on the presentation of at least some autism are still a matter of some debate. Although there is probably no condition-wide link to CD as per the Ludvigsson results, that doesn't mean that CD is not associated with some individual cases of autism (see here). A diagnosis of autism is after all, seemingly protective of nothing when it comes to other comorbidity. There is also an increasing realisation that issues with gluten might not just be reflective of CD as per the rise and rise of something called non-coeliac gluten sensitivity (see here). Efforts continue to describe this spectrum of gluten-related conditions outside of just CD (see here) and it is indeed timely that part of those additional efforts have just been published*** even mentioning autism.

This year (2013) has seen some quite important papers published which imply that the immune system is probably involved in some way (see my discussions of the Lau paper) in that gluten-autism relationship. That and the distinct possibility that, horror of horrors, leaky gut (gut hyperpermeability) might also show some connection (as per the de Magistris papers). That last paper by Laura de Magistris and colleagues**** also in many ways, pre-empted some of the latest findings from Ludvigsson insofar as reporting on a pattern overlapping serological parameters with CD in their cohort of children with autism, but not necessarily demonstrating enough to warrant a formal diagnosis of CD. This on top of related work (see here).

I'm going to finish with a quote from one Alessio Fasano on the Ludvigsson results: "In the past, we have had the believers and nonbelievers when it came to the role of gluten in autism ... Hopefully this paper can clarify, once and for all, that a subset of those with autism has gluten sensitivity, a condition triggered by gluten but distinct from celiac disease."

Who am I to argue?

To close, something up-beat to finish with... I've linked to this before but how about the Housemartins and Happy Hour?

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* Ludvigsson JF. et al. A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders. JAMA Psychiatry. 2013. Sept 25.

** Whiteley P. et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100.

*** Catassi C. et al. Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders. Nutrients. 2013: 5: 3839-3853.

**** de Magistris L. et al. Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders. BioMedRes Int. 2013: 729349.

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ResearchBlogging.org Jonas F. Ludvigsson (2013). A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2013.2048