To follow up on my article “A balanced look at gluten sensitivity” that was posted on Science-Based Medicine in August, we look at the latest results presented on the role of gluten and FODMAPs in IBS. Are IBS sufferers really the best place to look for evidence of gluten sensitivity, or are researchers headed down the wrong road?
Searching for evidence of gluten sensitivity
As it stands, the existence of non-celiac gluten sensitivity (NCGS) has neither been proven nor disproven by anyone, and there is no clear picture of what gluten sensitivity actually entails. True, there is a working definition on the table – in 2011, an international panel of experts defined NCGS as “a non-allergic and non-autoimmune condition in which the consumption of gluten can lead to symptoms similar to those seen in celiac disease” . However, in the hunt for definitive proof on whether or not it exists, researchers are looking at things from three different perspectives, in the form of three potential models of the disorder [1,2]:
- A model that is reminiscent of celiac disease, which can include a family history of celiac disease or the celiac genes but no increase in intestinal permeability and no auto-immune response.
- A model that is reminiscent of irritable bowel syndrome (IBS), which can include intestinal motility issues but also a greater frequency non-intestinal symptoms.
- A model that is reminiscent of food allergies, which can include a prior history of allergy or current food sensitivities and some markers for celiac disease, but no allergic reaction to gliadin.
So far, though, the IBS model is not panning out. Last year, researchers at Monash University suggested that the fructans in wheat – and not gluten – were actually responsible for aggravating IBS symptoms.  Fructans belong to a group of short-chain carbohydrates known as FODMAPs that are readily fermented by bacteria in the colon; other FODMAPs include galactans (in beans), polyols (in stone fruits and sugar substitutes), fructose (in soft drinks and fruits), and lactose (in dairy products). When a group of gluten-free IBS sufferers were placed on a low-FODMAP diet and then given either gluten or a placebo, no evidence of gluten-specific effects were found.
Along these lines, researchers from Rome recently presented the results of a study that compared the effects of three different diets on IBS symptoms – a low FODMAP/no gluten diet, a low FODMAP/normal gluten diet, and a normal FODMAP/normal gluten diet (the control). The control group saw no change in symptoms, while both low-FODMAPs groups saw a significant reduction in pain and bloating. Gluten elimination did not increase the effectiveness of a low-FODMAP diet, and, in fact, the researchers commented on a “trend” favoring the low FODMAP/normal gluten diet over the low FODMAP/no gluten diet.  Without the full details in a published article, we can’t go so far as to say that the gluten-free diet was actually detrimental, however gluten reduction doesn’t appear to be the reason why low-FODMAP diets are successful.
Is the IBS model a good candidate?
At this point, one might wonder whether researchers should continue to look for evidence of gluten sensitivity in IBS patients. The rationale for doing so was summarized last year by Catassi et al. , who are some of the biggest proponents of NCGS. Their argument is based on the following points, along with some counterpoints by me.
Overlapping symptoms. IBS and proposed gluten sensitivity symptoms overlap. According to Catassi :
The “classical” presentation of NCGS is a combination of IBS-like symptoms, including abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), and systemic manifestations such as “foggy mind”, headache, fatigue, joint and muscle pain, leg or arm numbness, dermatitis (eczema or skin rash), depression, and anemia.
IBS and celiac disease symptoms also overlap. A meta-analysis by Sainsbury et al.  found that almost 30% of celiac patients on a gluten free diet, and almost 40% of celiac sufferers overall, experience IBS-like symptoms.
It is worth noting, though, that many extraintestinal symptoms are already associated with IBS [6,7], so Catassi’s distinction between IBS and NCGS (above) may be artificial. Furthermore, wheat isn’t the only food implicated in IBS – milk, tea, coffee, wine, tomatoes, potato, corn, nuts, chocolate, and yeast are also reported to trigger symptoms . Technically, reactions to these foods in IBS are not food sensitivities, since the mechanisms behind functional digestive symptoms are thought to be related to the enteric nervous system and not directly to specific foods. Renaming wheat-sensitive IBS as gluten sensitivity doesn’t seem to be offering us any new insight into the source of the problem.
A possible role for celiac genes in IBS. Wahnschaffe et al.  found that a 6-month gluten free diet was more likely to alleviate symptoms in diarrhea-predominant IBS (IBS-D) patients who tested positive for HLA-DQ2 (one of the genes required for celiac disease) and celiac-related IgG antibodies (IgG AGA and TTG). Unfortunately, we don’t have any details on the foods allowed during the gluten free diet, but it is reasonable to think that fructans were also eliminated or significantly reduced, clouding the results. And while it is attractive to think that gluten sensitivity might be found in a specific subgroup of IBS-D sufferers, this doesn’t necessarily fly – in the Monash group’s low-FODMAP gluten study , “the predominant bowel habits, body mass index, age, sex, duration of GFD [gluten-free diet] and HLA-DQ status did not predict the responses to any of the diets.”
A relationship between IBS and food allergies. Carroccio et al.  at the University of Palermo reclassified 30% of 920 known IBS patients as suffering from wheat sensitivity after carrying out a series of food challenges on this group. In the quest for gluten sensitivity, the Palermo group is most interested in the model reminiscent of food allergies, so they also checked for reactions to other foods. Of those testing positive for ‘wheat sensitivity,’ the majority were also sensitive to milk when challenged separately, and half were also sensitive to eggs and tomato.
Again, though, a link between IBS and atopy is nothing new.  Although serum IgE levels and skin prick tests indicate that IgE-mediated (classical) allergies do not play a role in IBS, many sufferers report a history of allergy. This could connect with the observation that IBS sufferers have a higher density of (activated) mast cells in their small and/or large intestines and with the view of IBS as a low-grade inflammatory disorder. There is a question, though, as to the nature of the inflammation that would be present in NCGS. Inflammation in IBS or IBS-D and NCGS may involve different sets of cytokines (messenger chemicals) and infiltrates of immune system cells [10-13]; furthermore, Sapone et al.  have proposed that gluten sensitivity is more likely related to the innate immune system than an adaptive (allergic) response.
What we’d like to see
Despite the reports of genes, inflammation, and overlapping food sensitivities, all researchers except the Monash group have either tested for gluten sensitivity using wheat challenges or have asked us to take on faith that their elimination diets and challenges truly separated out the effects of gluten from other suspected components in wheat, like fructans or amylase trypsin inhibitors . For example, Sapone et al. report on their approach as follows :
Typically, the diagnosis is made by exclusion, and an elimination diet and “open challenge” (that is, the monitored reintroduction of gluten-containing foods) are most often used to evaluate whether the patient’s health improves with the elimination or reduction of gluten from the diet.
Sadly, the most important step in establishing the existence of NCGS is given only a sentence in a paper describing an elaborate workup of potentially gluten-sensitive patients.
So what do we need to see in order to sort out whether gluten sensitivity is real? At a minimum, we need to see the details of the elimination diets and challenges conducted so far to make sure that they were carried out properly. It would also be great to see, for example, Carroccio’s wheat-sensitive patients rechallenged with gluten, although this is certainly easier said than done. The point is that we are currently at an impasse with regards to NCGS not because of confusing biomarkers, but because no one has conducted any double blind placebo-controlled food challenge studies using the correct elimination diets and correct challenges on both IBS and non-IBS sufferers. As I explained in “A balanced look at gluten sensitivity,” this is the only way that a food sensitivity like NCGS can be proven to exist.
1. Mansueto P, Seidita A, D’Alcamo A, Carroccio A. Non-Celiac Gluten Sensitivity: Literature Review. Journal of the American College of Nutrition. 2014 Feb;33(1):39–54. http://dx.doi.org/10.1080/07315724.2014.869996
2. Catassi C, Bai J, Bonaz B, Bouma G, Calabrò A, Carroccio A, et al. Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders. Nutrients. 2013 Sep 26;5(10):3839–53. http://dx.doi.org/10.3390/nu5103839
3. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. 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):320–328.e3. http://dx.doi.org/10.1053/j.gastro.2013.04.051
4. Piacentino D, Rossi S, Alvino V, Cantarini R, Badiali D, Pallotta N, et al. Effects of Low-Fodmap and Gluten-Free Diets in Irritable Bowel Syndrome Patients. A Double-Blind Randomized Controlled Clinical Study. Gastroenterology. 2014 May;146(5):S–82.
5. Sainsbury A, Sanders DS, Ford AC. Prevalence of Irritable Bowel Syndrome–type Symptoms in Patients With Celiac Disease: A Meta-analysis. Clinical Gastroenterology and Hepatology. 2013 Apr;11(4):359–365.e1. http://dx.doi.org/10.1016/j.cgh.2012.11.033
7. February 19, 2009. Irritable bowel syndrome [Internet]. [cited 2014 Sep 16]. Available from: http://www.nursingtimes.net/nursing-practice/specialisms/gastroenterology/irritable-bowel-syndrome/1994694.article
8. Gibson PR. Food intolerance in functional bowel disorders: Food intolerance. Journal of Gastroenterology and Hepatology. 2011 Apr;26:128–31. http://dx.doi.org/10.1111/j.1440-1746.2011.06650.x
9. Wahnschaffe U, Schulzke J, Zeitz M, Ullrich R. Predictors of Clinical Response to Gluten-Free Diet in Patients Diagnosed With Diarrhea-Predominant Irritable Bowel Syndrome. Clinical Gastroenterology and Hepatology. 2007 Jul;5(7):844–50. http://dx.doi.org/10.1016/j.cgh.2007.03.021
10. Carroccio A, Mansueto P, D’Alcamo A, Iacono G. Non-Celiac Wheat Sensitivity as an Allergic Condition: Personal Experience and Narrative Review. The American Journal of Gastroenterology. 2013 Nov 5;108(12):1845–52. http://dx.doi.org/10.1038/ajg.2013.353
11. Philpott H, Gibson P, Thien F. Irritable bowel syndrome – An inflammatory disease involving mast cells. Asia Pac Allergy. 2011 Apr;1(1):36–42. http://dx.doi.org/10.5415/apallergy.2011.1.1.36
12. Vazquez–Roque MI, Camilleri M, Smyrk T, Murray JA, Marietta E, O’Neill J, et al. A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology. 2013 May;144(5):903–911.e3. http://dx.doi.org/10.1053/j.gastro.2013.01.049
13. Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011 Mar 9;9:23. http://dx.doi.org/10.1186/1741-7015-9-23