Back to gluten sensitivity and coeliac disease?

As a man of my word I have, in this post, come back to the recent paper published by Sapone and colleagues in BMC Medicine detailing some apparent gastrointestinal differences between coeliac disease and non-coeliac gluten sensitivity.

The authorship team to this paper reads like a Who's Who in gluten research. Two authors stick out for me: Alessio Fasano who many would argue is one of the leaders in the field of gluten, coeliac disease (CD) and intestinal permeability research, and Laura de Magistris, who autism research followers will know from the recent intestinal permeability paper which I blogged about here.

Their paper is quite a complex one and in some areas I am a little baffled myself - more to do with the limitations of my knowledge rather than their manuscript - so please excuse any errors in my interpretation.
What I think I can decipher from the recent paper is that the main aim of the study was to look at intestinal barrier function and various immune responses in non-coeliac gluten sensitivity (GS) compared to coeliac disease.

The participant numbers: 26 well-defined GS (-ve CD serology, normal gut mucosa and an effect from use of a gluten-free diet), 42 with active CD and just for good measure, 39 controls (not CD or GS). All participants were adults (mid-20s to 30s) and mostly female.

The findings:

• quite a few of the GS participants showed positive for one or more of the DQ2 / DQ8 heterodimers, 
• intestinal hyperpermeability was not as prevalent in the GS group compared to the CD group, associated with a milder gut histology in GS potentially due to the expression of various tight junction (TJ) related genes, 
• GS participants presented with increased CD3+ intraepithelial lymphocytes (IELs) relative to the control group but lower than that of the CD group; along with a few other parameters this suggests an 'intermediate, low-level' role for the adaptive immune system in GS and a role for innate immune mechanisms (inflammation).

So there we have it. My simple reading of these results (and I do stress 'simple') is that outside of the immune system differences highlighted, whether or not intestinal hyperpermeability is present is an important differentiating factor between CD and GS.

Where does autism fit into this?

Well, the paper by de Magistris and colleagues related to autism did indicate intestinal hyperpermeability as being present in about a third of cases that they looked at. They also reported that use of gluten-free diet seemed to 'reduce' the level of permeability present (similar to what might happen in CD). They did however rule out CD in the autism participant group, so findings were not due to CD.

One area of interest in the latest study overlaps with the de Magistris autism paper and perhaps requires further study. That is the role of anti-gliadin antibodies (AGA) (IgA / IgG). Nearly 50% of the GS patients in the latest trial were AGA +ve compared with about 3/4 of the CD group (all the controls were -ve). de Magistris reported that 2 of her autism groups showed high AGA IgG which in both cases were associated with 'normal' intestinal permeability (similar to the GS group?) and elevated fecal calprotectin levels associated with inflammation. Elevated IgG AGAs have been reported previously in autism by Vojdani and colleagues (see here and here) although without accompanying gastrointestinal findings detailed in the recent paper.

What this potentially suggests is that the effect of gluten on some cases of autism is perhaps due to more than one scenario: intestinal hyperpermeability (as in CD) linked perhaps to other compounds, or high AGA IgG (IgA?) levels and inflammation or perhaps due to bog standard co-morbid CD. I would hasten to add that there may well be other mechanisms to add to this list.

This is a fascinating area of research and along with several other recent papers is providing further insights into the shadowy nature of our relationship with gluten, outside of coeliac disease.