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Letter to BMJ: Markers of non-coeliac wheat sensitivity in patients with ME/CFS



Markers of non-coeliac wheat sensitivity in patients with myalgic encephalomyelitis/chronic fatigue syndrome
  1. Melanie Uhde1,2,
  2. Alyssa C Indart1,
  3. Xuechen B Yu1,3,
  4. Sophie S Jang1,3,
  5. Roberto De Giorgio4,
  6. Peter H R Green1,2,
  7. Umberto Volta4,
  8. Suzanne D Vernon5,
  9. Armin Alaedini1,2,3
We recently reported in Gut that non-coeliac wheat sensitivity (NCWS) is associated with a state of systemic immune activation in conjunction with a compromised intestinal epithelium.1 Patients with NCWS experience GI symptoms, most commonly including abdominal pain and bloating, as well as extraintestinal symptoms, among which fatigue, headache and cognitive difficulties feature prominently.1

A principal component analysis of the generated data from our study, including markers of antibody reactivity to wheat gluten, intestinal cell damage and systemic innate and adaptive immune responses to microbial components, found clustering of the patients and controls into discernible groups and demonstrated the potential utility of the identified biomarkers for identifying patients with NCWS.1

Extreme fatigue, in particular one that does not improve with rest, is a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).3 Immune system abnormalities have been found to be associated with symptoms in a substantial number of patients with ME/CFS.4 5 Furthermore, many patients complain of GI symptoms of unknown aetiology.6–8

We considered whether a subset of patients with ME/CFS may exhibit serologic markers associated with NCWS, which might explain some of the corresponding symptoms. We screened serum samples from 131 patients with ME/CFS and 86 healthy controls (table 1), recruited as previously described,9 for the same markers as those in the above-mentioned study on NCWS.1

Questionnaires were used to assess GI symptoms within the past 6 months, including abdominal pain, bloating and nausea. Severity of individual symptoms was scored from 1 to 5 (1=absent; 2=mild; 3=moderate; 4=severe; 5=very severe), and a total score, based on the sum of individual symptom scores, was calculated for each subject.

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Using the previously generated data from the original cohorts of NCWS, coeliac disease and control subjects (table 1),1 we configured a discriminant function to identify potential cases of NCWS and coeliac disease among the subjects in the ME/CFS and associated control groups. Linear discriminant analysis (Minitab 17 (Minitab) software) was used to calculate the probability of each ME/CFS and control subject belonging to any one of the three categories of NCWS, coeliac disease and healthy control.

The threshold for assigning a subject to a category was arbitrarily set at a calculated probability of 0.75. Accordingly, the algorithm identified one (0.76%) patient with ME/CFS and two (2.3%) control subjects as belonging to the coeliac disease group (P=0.3). In contrast, 20 (15.3%) patients with ME/CFS and 4 (4.6%) control subjects were categorised in the NCWS group (P=0.015). There was also a significant correlation between the calculated NCWS probability and the GI symptom severity total score in patients with ME/CFS (r=0.231, P=0.011).

Our results suggest that there may be a subset of patients with ME/CFS who have sensitivity to wheat and related cereals in the absence of coeliac disease, with potential relevance to some of their symptoms. ME/CFS is recognised as a condition with a spectrum of clinical phenotypes and underlying aetiologies. Characterisation of patients into subsets based on clinical and biological data is essential to gaining a better understanding of the condition and identifying useful biomarkers and therapeutic targets. The results of this analysis provide a rationale for examining the clinical and therapeutic relevance of food sensitivity, particularly NCWS, in the context of ME/CFS in future studies.


Senior Member
Armin Alaedini has done a good deal of work in Lyme, and also Lyme as it relates to celiac disease, if I am not mistaken. Small world.
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Senior Member
I've been low on wheat since my 16th ( that was when ME hit me, 54 now) advice of a friendly, elderly GP/classic homeopath. I recovered fully. Since that time I've always been low on wheat. Two bouts of bedbound and a lot of problems later I am now on total glutenfree + no cowsdairy + no soy.
It helped with brainfog and mood.

some years ago I was tested for coeliac and allergy. But now think these tests must have been worthless, because I hardly took any gluten/wheat at the time. I think only the contamination of the oats I did then still use. I quit that too. Did help in brainfog.


Senior Member
When I got sick, wheat avoidance was the first thing I found that helped. Especially for my IBS symptoms, it works wonders.
For me the difference between wheat and gluten was pretty big. Wheat gives me a lot of problems. Other grains with gluten in it, don't give me the same problems.


Senior Member
I had non-celiac gluten sensitivity all my life before ME/CFS, but it disappeared once I developed ME/CFS. But then it's not unusual to have a change in status of allergies once you get ME/CFS (existing allergies can disappear, or new ones can appear).

This is a good article on non-celiac gluten sensitivity (ie gluten intolerance):

Non-Celiac Gluten Sensitivity Research

It details how Dr Alessio Fasano in 2011 demonstrated that in gluten intolerance, only the innate immune system attacks gluten that is ingested, but that in celiac disease, both the innate and the adaptive immune system attack the gluten.

This double immune attack in the case of celiac creates a more severe disease, and as we know, in celiac, the villi of the intestines are attacked and destroyed by the immune response.

Fasano says that gluten intolerance may affect about 6% to 7% of the population, though other researchers have come up with higher figures.


Senior Member
Virginia, USA
Wheat gives me a lot of problems. Other grains with gluten in it, don't give me the same problems.

This might have something to do with it.

Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity

Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity.
We performed a double-blind crossover challenge of 59 individuals on a self-instituted gluten-free diet, for whom celiac disease had been excluded. The study was performed at Oslo University Hospital in Norway from October 2014 through May 2016. Participants were randomly assigned to groups placed on diets containing gluten (5.7 g), fructans (2.1 g), or placebo, concealed in muesli bars, for 7 days. Following a minimum 7-day washout period (until the symptoms induced by the previous challenge were resolved), participants crossed over into a different group, until they completed all 3 challenges (gluten, fructan, and placebo). Symptoms were measured by Gastrointestinal Symptom Rating Scale Irritable Bowel Syndrome (GSRS-IBS) version. A linear mixed model for analysis was used.
Overall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1 ± 13.3, 38.6 ± 12.3, and 34.3 ± 13.9, respectively (P = .04). Mean scores for GSRS-IBS bloating were 9.3 ± 3.5, 11.6 ± 3.5, and 10.1 ± 3.7, respectively, during the gluten, fructan, and placebo challenges (P = .004). The overall GSRS-IBS score for participants consuming fructans was significantly higher than for participants consuming gluten (P = .049), as was the GSRS bloating score (P = .003). Thirteen participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and 22 had the highest score after consuming placebo. There was no difference in GSRS-IBS scores between gluten and placebo groups.
In a randomized, double-blind, placebo-controlled crossover study of individuals with self-reported non-celiac gluten sensitivity, we found fructans to induce symptoms, measured by the GSRS-IBS.


Senior Member
Overall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1, 38.6 and 34.3 respectively

There was not much differences between gluten, fructan and placebo responses, so this does not look like a very good study.

Going gluten-free is a bit of a trendy thing these days, so I wonder how many patients in their cohort had genuine non-celiac gluten sensitivity. There may be some people who just stopped eating wheat / gluten because they had some misplaced belief that gluten-free may be better for their health, rather than because wheat causes any specific symptoms.

In my case, I was very careful to self-diagnose gluten intolerance: I initially did a full exclusion diet for 3 months to detect any food intolerances (that's the gold standard method of testing).

Then when I found wheat was a problem, I rested this multiple times, just to be sure. In my case, wheat-containing food would cause a bout depression that kicks in around 1 hour after eating wheat, and then lasts for around 6 to 8 hours; but I have no other gluten intolerance symptoms besides than that.


Senior Member
verall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1 ± 13.3, 38.6 ± 12.3, and 34.3 ± 13.9, respectively (P = .04).

If you read the paper, the results are even less impressive.

Corrected for multiple comparisons, the overall GSRS-IBS was borderline significant for fructan vs gluten (P < .049). No significant differences were found for fructan vs placebo (P = .19) and gluten vs placebo (P = .99).

The best they can scrape up is a borderline difference between fructan and gluten response. Note there is no difference between fructan and placebo response so really does this mean anything at all? If it does mean anything, they are saying that, for the overall group, there was a slightly increased response to fructans.

They go on to look at individual response within the group and report

Thirteen participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and 22 had the highest score after consuming placebo.

The group size was 59, so about 1/4 participants had the highest response to placebo, just slightly more had the highest response to fructans and about 1/5 had the highest response to gluten.

Not really anything to get terribly excited about and we are still none the wiser about the cause of non-coeliac gluten sensitivity.

As for the letter which is the subject of this thread, its a preliminary observation, but it does suggest a possible mechanism, one which may be present in a subset of ME/CFS patients.

Let's hope this is followed by more extensive studies to better define the subset.