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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
  1. 1 Department of Medicine, Columbia University Medical Center, New York, New York, USA
  2. 2 Celiac Disease Center, Columbia University Medical Center, New York, New York, USA
  3. 3 Institute of Human Nutrition, Columbia University Medical Center, New York, New York, USA
  4. 4 Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
  5. 5 Bateman Horne Center, Salt Lake City, Utah, USA
  1. Correspondence to Dr. Armin Alaedini, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; aa819{at}

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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 2 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.

Table 1

Demographic characteristics of study cohorts

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.



  • Contributors AA had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AA, SDV. Contribution to study design: MU, ACI, RDG, PHRG, UV. Acquisition of data: MU, ACI, XBY, RDG, UV. Analysis and interpretation of data: MU, ACI, XBY, RDG, PHRG, UV, AA. Drafting of the manuscript: MU, AA. Critical revision of the manuscript for important intellectual content: MU, ACI, XBY, RDG, PHRG, UV, AA. Statistical analysis: MU, AA. Administrative, technical or material support: RDG, PHRG, UV, SDV, AA. Obtained funding: AA. Study supervision: AA.

  • Funding This study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, through Grant Number R21AI121996 (AA), the Solve ME/CFS Initiative (AA) and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1 TR000040 (to AA). The funding agencies had no role in the design and conduct of the study; in the collection, analysis and interpretation of the data or in the preparation, review or approval of the manuscript.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Columbia University Medical Center institutional review board.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement Data will be shared in a transparent fashion with all investigators requesting such information.