Jessica Biesiekierski on non-coeliac gluten sensitivity (NCGS)

It's not often that I dedicate a blog post to a specific individual and their views and opinions on a particular topic. Today however, I'm doing just that to provide you with a link to the paper from Jessica Biesiekierski on the topic of non-coeliac gluten sensitivity (NCGS) [1] (open-access).

The reason? Well, aside from being one of the primary protagonists in the research topic of gluten-related ills outside of the autoimmune condition known as coeliac (celiac) disease (itself the topic of some considerable bafflement to me), the work from Dr Biesiekierski and others has also invited quite a bit more inspection of other dietary components ("FODMAPs: Fermentable Oligo-, Di-, and Mono-saccharides And Polyols") as potentially taking the strain off just gluten/wheat when it comes to ideas about health and wellbeing.

The review paper is open-access so no need for any grand discussions from me on the topic. I will however extract a choice quote or two from the paper with some comment. So: "There is some evidence that NCGS may exist, but probably only in a small number of people." I would second that statement particularly in light of recent discussions (see here). I might also direct you to some of the discussions from Brusca [2] too, and the idea that: "About half of NCGS patients are DQ2 positive and have IgG AGA [Anti-gliadin antibodies]."

Also: "Currently, there is no evidence for efficacy of gluten exclusion in mental disorders... therefore care must be given when discussing these early results and awareness given to understanding that a major effect of gluten in NCGS patients may be in the perception of their general well-being." Accepting that the term 'mental disorders' is not one that I would necessarily use and certainly not when using it in the context of referencing the paper from Millward and colleagues [3] and the Cochrane Review of gluten- and casein-free diets for [some] autism, I'd be minded to disagree with such a final statement. As has been mentioned previously on this blog, there is evidence for issues with gluten in some cases of conditions like schizophrenia (see here) and autism (see here). Insofar as 'no evidence of efficacy of gluten exclusion', well, again I'd be minded to suggest there have been hints that there may be more to see in this area (see here for example) albeit with the requirement for further, more experimentally strong research to be conducted. This also includes the notion that there may be best and non-responders to this type of intervention (see here) and that core autism symptoms might not be the primary 'target' of such dietary interventions.

And if you really want yet more reviews of NCGS, then look no further [4] or further [5] or further [6]...

Music: OutKast - Ms. Jackson. Oh, and how would art look without the gluten?

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[1] Biesiekierski JR. Non-coeliac gluten sensitivity: piecing the puzzle together. United European Gastroenterology Journal. 2015; 3: 160-165.

[2] Brusca I. Overview of biomarkers for diagnosis and monitoring of celiac disease. Adv Clin Chem. 2015;68:1-55.

[3] Millward C. et al. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003498.

[4] Czaja-Bulsa G. Non coeliac gluten sensitivity – A new disease with gluten intolerance. Clinical Nutrition. 2015; 34: 189-194.

[5] Molina-Infante J. et al. Systematic review: noncoeliac gluten sensitivity. Aliment Pharmacol Ther. 2015 May;41(9):807-20.

[6] Fasano A. et al. Nonceliac Gluten Sensitivity. Gastroenterology. 2015 Jan 9. pii: S0016-5085(15)00029-3.

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Biesiekierski, J., & Iven, J. (2015). Non-coeliac gluten sensitivity: piecing the puzzle together United European Gastroenterology Journal, 3 (2), 160-165 DOI: 10.1177/2050640615578388

More evidence for non-coeliac gluten sensitivity?

"In a cross-over trial of subjects with suspected NCGS [non-coeliac gluten sensitivity], the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo."

That was the conclusion reached in the study by Antonio Di Sabatino and colleagues [1] who applied the gold standard research methodology - "a randomized, double-blind, placebo-controlled, cross-over trial" - to studying the effects of small amounts of gluten on those "who believe ingestion of gluten-containing food to be the cause of their intestinal and extra-intestinal symptoms" despite being free of the autoimmune condition coeliac (celiac) disease or wheat allergy. Further information about this research can be seen on the trial registration page.

Various symptoms were reported to be increased following gluten ingestion (4.375 g/day gluten) over and above placebo (rice starch) including abdominal bloating/pain. Extra-intestinal symptoms - that is symptoms that are not necessarily centred on the gastrointestinal (GI) tract - also seemed to increase during the active supplementation of gluten including: "foggy mind.., depression..., and aphthous stomatitis [mouth ulcers]". Depression potentially being linked to gluten consumption is something that has appeared [in quite preliminary form] before in the peer-reviewed research literature and this blog (see here). 'Foggy mind' is not a very technical term but again has been mentioned in other research papers talking about the use of a gluten-free diet and cognitive performance in cases of coeliac disease (CD) (see here).

I was rather interested in these results given that NCGS has been to topic of quite a bit of material on this blog (see here for example) and the idea of something of a spectrum of gluten-related issues being present outside of those classical examples of coeliac disease and wheat allergy (see here). In recent times, attention has shifted away from gluten (or wheat) as being the potential culprit in such cases as per the rise and rise of FODMAP sensitivity as another potential explanator based on research such as that from Jessica Biesiekierski and colleagues [2]. I've watched this area closely and often thought that there may be room for both FODMAP sensitivity and NCGS being present in different people or even the same person. It appears from the results of the controlled trial from Di Sabatino et al, this might not be too far off the mark. Other research might also agree with such sentiments [3].

Then to the questions: (a) what is the potential mechanism/s of effect? and (b) are we moving closer to identifying those who might fall into that NCGS category and so benefit from a gluten-free diet or even beyond [4]? Well, unfortunately I can't definitively answer either of those questions at the moment, but can perhaps offer a few areas where further investigations might be indicated.

I was privileged to review the paper by Catassi and colleagues [5] (open-access) which provides quite a nice overview of NCGS and some directions where science is heading. One of the papers cited in that overview was that from Anna Sapone and colleagues [6] and their 2012 consensus paper on "new nomenclature and classification" when it came to gluten sensitivity (see here). I'm not altogether sure how well their 'proposed algorithm' has done in clinical practice but it strikes me that it's a good start when ruling out CD and wheat allergy. I might also add that there may be quite a bit more to see when it comes to looking at serology vs. histopathology at differentiating CD from NCGS [7] as per what has been talked about with [some] autism in mind (see here) and [some] cases of schizophrenia too (see here). Transglutaminase is also something in need of a lot more study with autism in mind (see here) by the way.

The other area that I think would be rather interesting to look at is gut barrier function. Again, wearing my autism research hat, I'm pretty impressed with what has been reported in the peer-reviewed literature when it comes to 'leaky gut' and some autism (see here). Although by no means a universal aspect to autism (see here) it does happen, and more generally is in the research ascendancy (see here) for quite a few reasons. Allied to the the idea that (General) zonulin might be something related (see here) I'm also wondering whether it might be a good idea to look at this parameter comparing CD, wheat allergy and NCGS? I'm not expecting too much based on the work by Hollon and colleagues [8] on intestinal permeability and gluten for example, but you never know.

And then there is the review from Molina-Infante and colleagues [9] to bring to your attention...

Music then. Hey Joe by Jimi et al.

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[1] Di Sabatino A. et al. Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clin Gastroenterol Hepatol. 2015 Feb 19. pii: S1542-3565(15)00153-6.

[2] Biesiekierski JR. et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013 Aug;145(2):320-8.e1-3.

[3] Carroccio A. et al. Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. Am J Gastroenterol 2012; 107:1898–1906.

[4] Makharia GK. Current and emerging therapy for celiac disease. Front Med (Lausanne). 2014 Mar 24;1:6.

[5] Catassi C. et al. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sep 26;5(10):3839-53.

[6] Sapone A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13.

[7] Brottveit M. et al. Mucosal Cytokine Response After Short-Term Gluten Challenge in Celiac Disease and Non-Celiac Gluten Sensitivity. Am J Gastroenterol 2013; 108:842–850.

[8] Hollon J. et al. Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity. Nutrients. 2015; 7: 1565-1576.

[9] Molina-Infante J. et al. Systematic review: noncoeliac gluten sensitivity. Alimentary Pharmacology & Therapeutics. 2015. March 6.

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Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, & Corazza GR (2015). Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association PMID: 25701700

Fructose and lactose intolerance are common and frequently overlap in FGID

The title of this post is a quote taken from the paper by Clive Wilder-Smith and colleagues* (open-access) who reported that issues with the metabolism of the short chain carbohydrates (sugars) fructose found in fruits and lactose found in milk and dairy products may very well be common in functional gastrointestinal disorder (FGID).

Soup again! @ Wikipedia 

I was interested in this paper on two levels.

First is a passing interest in all things FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) and some potential relationship to cases of FGIDs specifically with irritable bowel syndrome (IBS) in mind**. Indeed, I've passed mention about this on a previous post on a sister blog (see here).

Second is, as those who read this blog regularly (thank you!) might know, my interest in all things comorbidity with the autisms in mind. Specifically that growing body of evidence (peer-reviewed of course) suggesting that gastrointestinal (GI) issues might be present in a fair few cases of autism (see here). That and the links suggested between such GI issues and reports of various dietary links (see here).

Certainly on that last point, I'm entertaining the possibility that where clinician-defined FGID (constipation, diarrhoea, even IBS) is found in cases of autism  one might be so inclined to enquire whether there may be issues with fructose and lactose also comorbid.

Just in case you're thinking that I'm getting a little ahead of myself with such speculation, I should point out that: (a) autism is seemingly protective of nothing when it comes to comorbidity and (b) certainly on the issue of lactose, and in particular lactose intolerance, there is more than one study suggesting issues to be present in cases (see here) and perhaps even issues more generally with carbohydrate metabolism as per the 'game-changer' work of Brent Williams and colleagues (see here) and subsequent others (see here). At the very least there is a study there waiting to happen. Fructose by the way, has also been mentioned with autism in mind albeit rather speculatively (see here).

Just before I go there were a few other pertinent points to take from the Wilder-Smith study. "Dietary modification based on fructose and lactose intolerance testing was clearly beneficial". In other words, when it came to the presentation of FGIDs, for those who were shown to be "sugar" intolerant, there was quite a bit of relief reported. Interesting too that the authors talk about an "elevated prevalence of non-GI functional syndromes" to accompany FGID - with fatigue being the most commonly reported in their cohort. One could interpret this in several ways including taking some inspiration from the name of the author's research group  - the Brain-Gut Research Group - and perhaps even some overlap into other conditions too (see here).

I could also go on about gut bacteria and gut hyperpermeability also mentioned in the paper, but to save me getting too obsessed with these areas, I'll stop right there apart from reiterating that no medical or clinical advice was offered or intended in this blog post.

Music to close: I've linked to this record before but it is a classic so worth again a link... Buddy Holly by Weezer (including The Fonz dancing - what a mover!).

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* Wilder-Smith CH. et al. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2013 Jun;37(11):1074-83. doi: 10.1111/apt.12306.

** Shepherd SJ. et al. Short-Chain Carbohydrates and Functional Gastrointestinal Disorders. Am J Gastroenterology. 2013; 108: 707-717.

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Wilder-Smith CH, Materna A, Wermelinger C, & Schuler J (2013). Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Alimentary pharmacology & therapeutics, 37 (11), 1074-83 PMID: 23574302