Wednesday, 14 August 2013

Leaky gut, food antibodies and autism

I'm back. After a couple weeks of hot Greek sunshine and good times it's back to work.

So... food and autism.

It's a research topic that's interested me for quite a few years now*. In particular, how certain dietary interventions might be able to 'affect' the presentation of autism**, at least some autism or at least some comorbidity?

In recent weeks there have been some pretty exciting developments in this area, not least because of the Lau paper (see here) suggestive of some potential issues with immune reactivity to gluten - one of the food components singled out as being related to autism - to be present in some cases and potentially explanatory of why dietary intervention might be useful for some on the spectrum.
Gluten and casein KOed? @ Wikipedia  

In a similar vein, I want to talk today about the paper by Laura de Magistris and colleagues*** (open-access) and their important findings reporting an increased frequency of immune reactivity to gluten and casein (the protein found in mammalian milk sources) in pediatric cases of autism following on from the Lau data.

I had mentioned this paper in a previous [mega] post on leaky gut and autism (see here). The authorship group on the de Magistris paper reads like a who's who in gluten research at the moment.

Laura de Magistris, as some readers might remember, published that groundbreaking study on gut hyperpermeability (leaky gut) in relation to autism****. Then we have the likes of Anna Sapone (the spectrum of gluten sensitivity) and finally, but by no means least, Alessio Fasano, a real research favourite for this blog and its sister (see here). Prof. Fasano is one to watch in autism research, mark my words.

Enough of the research hero-worship, the aim of the research was to look at various facets of how children with autism handle foods containing gluten and casein from an immunological and gut permeability point of view.

Some of the details:

  • One cannot say that this was an under-powered study as de Magistris and colleagues set about investigating gut permeability and a variety of gluten-coeliac markers (tTG, HLA-DQ2/DQ8 haplotypes, IgA-IgG-IgE antibodies, IgA-IgG anti-gliadin antibodies, IgA-IgG antibodies to deamidated gluten peptide, IgG-IgE casein, etc.) in 162 children diagnosed with an autism spectrum disorder (ASD) compared with 44 'healthy' controls. If all those measures sound like gibberish to you (a) don't worry, just follow the hyperlinks and (b) tune into my 'what is coeliac disease' post where quite a few of the measures were discussed.
  • The kids with autism were all fully ADOS-ed and ADI-ed to make sure that they met criteria for autism. Various other details were also collected about things like gastrointestinal (GI) history and whether or not participants were following interventions like a gluten- and casein-free (GFCF) diet. Indeed 31 participants were following - sorry "embraced" - the GFCF diet (~20%). Importantly too, among the exclusion criteria for study non-participation was a previous diagnosis of coeliac disease or inflammatory bowel disease (IBD). In other words, these were kids with autism not previously diagnosed with a serious GI complaint
  • Results: two of the children with autism were "serologically positive" for coeliac disease (1.2%) compared with none of the controls. This finding accords with other research suggesting that coeliac disease is probably not over-represented in cases of autism (bearing in mind this does not mean autism is somehow protective against coeliac disease). . 
  • Gut permeability testing revealed that about a quarter of the children with autism had "impaired intestinal barrier function" compared with about 2% of control participants (41 ASD kids vs. 1 control). As per the previous de Magistris paper, being on a GFCF diet also tended to "normalize the barrier impairment" although diet did not curb permeability altogether in comparison to the asymptomatic control group.
  • Anti-gliadin antibodies (IgG) were "higher in ASDs compared to controls and are not influenced by changes in intestinal permeability". Following a GFCF diet did, as one might expect, influence the presence of this immune response.
  • Interestingly, when it came to measuring levels of anti-deamidated gliadin peptide antibodies (IgG) the grouped values were increased in children with autism compared with controls. I'll come back to this finding shortly.
  • Total IgE titer levels (IgE being a marker for classical allergy) were not significantly different between the groups in line with other findings; although specific IgE antibodies to milk were reduced for those children with ASD on the GFCF diet. IgG antibodies to casein were increased in the autism group compared to controls (and again were influenced by the use of a GFCF diet).

Take my word for it, there are lots of potentially important findings here. That leaky gut (gut hyperpermeability if you wish) is a very real finding for quite a few children on the autism spectrum is important. I know for some people this might be difficult news to take in but, added to the fact that GFCF dietary intervention might abate this issue to some degree, one perhaps needs to put aside any prejudice about GI involvement in autism and whatever image(s) that conjures up and start to focus on how science can move this finding on further.

The deamidated gliadin peptide antibody finding is also particularly interesting. Basically the process of deamidation comes about when tTG (tissue transglutaminase also known as TG2) gets hold of gluten peptides and starts doing funny things to parts of their structure (see here*****). This then has knock-on effects for their relationship with antigen presenting cells of the immune system and the cascade of effects that brings to a condition like coeliac disease. The implication here is that whilst not being coeliac disease - indeed the lack of any significant HLA-DQ2/DQ8 haplotype findings in the autism group is testament to that - gluten peptides might still be acting on some cases of autism. I should mention that some involvement for tTG in relation to cases of autism has been previously discussed on this blog (see here). I hasten to add that we are not necessarily talking about the opioid-excess hypothesis and opioid peptides - not yet at least. If you want some more information about the whole coeliac disease process, you could do worse than have a look at my recent post on what we think we know about it (see here).

What these findings and that from Lau and colleagues****** (open-access) point to is a complicated picture of how dietary variables might affect biology in some cases of autism. It's a picture which contains several important elements not least potential issues with the breakdown (metabolism) of foods which contain gluten and casein (think CM-AT??), problems with the intestinal barrier and its proper function and even hints of autoimmunity as per tTG and the deamidated gluten peptide findings.

I personally think that autism research is starting to catch-up with other conditions that are being looked at with a dietary element to them such as schizophrenia and the work of Emily Severance and colleagues (see here and here) and David Niebuhr (see here). Whether there are any relationships between the findings in autism and schizophrenia is a question which perhaps needs answering, particularly in these days of common ground (see here) and spectrums overlapping (see here).

What's missing from the de Magistris paper? Well, given the authorship group in this study, I was expecting to hear something about [General] zonulin and whether or not that protein was measured and showed anything as per its other links (see here) with tight junctions in mind. That and mention of those other words bacterial translocation which seem to go hand-in-hand with leaky gut, (think Sutterella and autism for example).

Still I can't argue with the fact that autism research has, at last, started to delve into the very complicated world of diet and potentially offer some new avenues for further investigation. Allied to the albeit 'soft evidence' of potential effects from dietary intervention in some cases, I forsee some interesting times ahead.

Some music to close: A Small Victory perhaps?

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* Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012;6:344. doi: 10.3389/fnhum.2012.00344.

** 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. doi: 10.1179/147683010X12611460763922.

*** de Magistris L. et al. Antibodies against food antigens in patients with autistic spectrum disorders (ASDs). BioMed Research International. 2013 (2013), Article ID 729349.

**** 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. doi: 10.1097/MPG.0b013e3181dcc4a5.

***** van de Wal Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol. 1998 Aug 15;161(4):1585-8.

****** Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS ONE 8(6): e66155. doi:10.1371/journal.pone.0066155

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ResearchBlogging.org de Magistris L (2013). Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders BioMed Research International DOI: 10.1155/2013/729349