Special Issue "Gluten-Related Disorders: Time to Move from Gut to Brain"

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutritional Immunology".

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editors

Prof. Dr. Nigel Hoggard
E-Mail Website
Guest Editor
Academic Unit of Neuro Radiology, University of Sheffield, Sheffield, UK
Interests: Imaging of the ataxias and brain imaging in gluten related disorders
Prof. Dr. David S Sanders
E-Mail Website
Guest Editor
Academic Unit of Gastroenterology, Royal Hallamshire Hospital & University of Sheffield, UK
Interests: Coeliac Disease
Special Issues and Collections in MDPI journals
Prof. Dr. Marios Hadjivassiliou
E-Mail Website
Guest Editor
Academic Department of Neurosciences, University of Sheffield, Sheffield S10 2JF, UK
Interests: ataxias; neurological manifestations of coeliac disease and gluten sensitivity
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The extraintestinal manifestations of coeliac disease (CD) are now well recognised. We have previously edited a special issue for Nutrients covering all aspects of the extraintestinal manifestations in the context of CD. In this issue we wish to concentrate just on the neurological manifestations. The identification of TG6 autoantibodies in patients with neurological manifestations and its use in the diagnosis of such patients seems to be a good opportunity to focus on the neurological aspect of CD. In addition it is now clear that such manifestations can occur even in the absence of enteropathy but in the presence of antigliadin antibodies. Given that such antibodies can be found in up to 10% of the “healthy” population we anticipate that the neurological manifestations are likely to be very common. Apart from the well characterised neurological manifestations such as gluten ataxia, gluten neuropathy and gluten encephalopathy we would also welcome submissions that cover the whole spectrum of neurological involvement including cognitive deficits and psychiatric manifestations. We look forward to your submissions.

Prof. Nigel Hoggard
Prof. David S Sanders
Prof. Marios Hadjivassiliou
Guest Editors

Manuscript Submission Information

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Keywords

  • Coeliac disease
  • Gluten sensitivity
  • Gluten ataxia
  • Gluten neuropathy
  • Gluten encephalopathy
  • Neurological dysfunction

Published Papers (11 papers)

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Research

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Article
Frequency and Clinical Aspects of Neurological and Psychiatric Symptoms in Patients with Non-Celiac Wheat Sensitivity
Nutrients 2021, 13(6), 1971; https://doi.org/10.3390/nu13061971 - 08 Jun 2021
Viewed by 523
Abstract
Background: Non-Celiac Wheat Sensitivity (NCWS) is characterized by both intestinal and extra-intestinal symptoms. The study aims to investigate the frequency of neuropsychiatric manifestations in NCWS patients and identify their clinical and demographic characteristics. Methods: 278 clinical records of NCWS patients, diagnosed by a [...] Read more.
Background: Non-Celiac Wheat Sensitivity (NCWS) is characterized by both intestinal and extra-intestinal symptoms. The study aims to investigate the frequency of neuropsychiatric manifestations in NCWS patients and identify their clinical and demographic characteristics. Methods: 278 clinical records of NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge between 2006 and 2020, were retrospectively revised. Fifty-two patients with Celiac Disease (CD) and 54 patients with Irritable Bowel Syndrome (IBS) served as controls. Results: 87% of the NCWS patients had an IBS-like clinical presentation. The NCWS group showed a longer duration of symptoms, a higher frequency of positive serum anti-nuclear antibodies than CD and IBS patients, and a higher frequency of DQ2/DQ8 haplotypes and duodenal mucosa lymphocytosis than IBS controls. In addition, 50% of NCWS patients showed neuropsychiatric manifestations, while lower percentages were observed in CD (25%) and IBS (28%) controls. Neuropsychiatric symptoms in NCWS were more frequently associated with the male sex, longer duration of symptoms, and IBS-diarrhea-like clinical presentation. Conclusions: Our data suggest that in patients with IBS-like symptoms and neuropsychiatric manifestations of unknown cause, it could be useful to investigate a correlation of these symptoms with wheat ingestion to identify NCWS patients with this ‘atypical’ manifestation. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Article
Neurological Evaluation of Patients with Newly Diagnosed Coeliac Disease Presenting to Gastroenterologists: A 7-Year Follow-Up Study
Nutrients 2021, 13(6), 1846; https://doi.org/10.3390/nu13061846 - 28 May 2021
Viewed by 563
Abstract
We have previously shown that 67% of patients with newly diagnosed coeliac disease (CD) presenting to gastroenterologists have evidence of neurological dysfunction. This manifested with headache and loss of co-ordination. Furthermore 60% of these patients had abnormal brain imaging. In this follow-up study, [...] Read more.
We have previously shown that 67% of patients with newly diagnosed coeliac disease (CD) presenting to gastroenterologists have evidence of neurological dysfunction. This manifested with headache and loss of co-ordination. Furthermore 60% of these patients had abnormal brain imaging. In this follow-up study, we re-examined and re-scanned 30 patients from the original cohort of 100, seven years later. There was significant reduction in the prevalence of headaches (47% to 20%) but an increase in the prevalence of incoordination (27% to 47%). Although those patients with coordination problems at baseline reported improvement on the gluten free diet (GFD), there were 7 patients reporting incoordination not present at baseline. All 7 patients had positive serology for one or more gluten-sensitivity related antibodies at follow-up. In total, 50% of the whole follow-up cohort were positive for one or more gluten-related antibodies. A comparison between the baseline and follow-up brain imaging showed a greater rate of cerebellar grey matter atrophy in the antibody positive group compared to the antibody negative group. Patients with CD who do not adhere to a strict GFD and are serological positive are at risk of developing ataxia, and have a significantly higher rate of cerebellar atrophy when compared to patients with negative serology. This highlights the importance of regular review and close monitoring. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Article
Intracortical and Intercortical Motor Disinhibition to Transcranial Magnetic Stimulation in Newly Diagnosed Celiac Disease Patients
Nutrients 2021, 13(5), 1530; https://doi.org/10.3390/nu13051530 - 01 May 2021
Viewed by 457
Abstract
Background: Celiac disease (CD) may present or be complicated by neurological and neuropsychiatric manifestations. Transcranial magnetic stimulation (TMS) probes brain excitability non-invasively, also preclinically. We previously demonstrated an intracortical motor disinhibition and hyperfacilitation in de novo CD patients, which revert back after a [...] Read more.
Background: Celiac disease (CD) may present or be complicated by neurological and neuropsychiatric manifestations. Transcranial magnetic stimulation (TMS) probes brain excitability non-invasively, also preclinically. We previously demonstrated an intracortical motor disinhibition and hyperfacilitation in de novo CD patients, which revert back after a long-term gluten-free diet (GFD). In this cross-sectional study, we explored the interhemispheric excitability by transcallosal inhibition, which has never been investigated in CD. Methods: A total of 15 right-handed de novo, neurologically asymptomatic, CD patients and 15 age-matched healthy controls were screened for cognitive and depressive symptoms to the Montreal Cognitive Assessment (MoCA) and the 17-item Hamilton Depression Rating Scale (HDRS), respectively. TMS consisted of resting motor threshold, amplitude, latency, and duration of the motor evoked potentials, duration and latency of the contralateral silent period (cSP). Transcallosal inhibition was evaluated as duration and latency of the ipsilateral silent period (iSP). Results: MoCA and HDRS scored significantly worse in patients. The iSP and cSP were significantly shorter in duration in patients, with a positive correlation between the MoCA and iSP. Conclusions: An intracortical and interhemispheric motor disinhibition was observed in CD, suggesting the involvement of GABA-mediated cortical and callosal circuitries. Further studies correlating clinical, TMS, and neuroimaging data are needed. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Article
Stiff Person Syndrome and Gluten Sensitivity
Nutrients 2021, 13(4), 1373; https://doi.org/10.3390/nu13041373 - 20 Apr 2021
Viewed by 943
Abstract
Stiff person syndrome (SPS) is a rare autoimmune disease characterised by axial stiffness and episodic painful spasms. It is associated with additional autoimmune diseases and cerebellar ataxia. Most patients with SPS have high levels of glutamic acid decarboxylase (GAD) antibodies. The aetiology of [...] Read more.
Stiff person syndrome (SPS) is a rare autoimmune disease characterised by axial stiffness and episodic painful spasms. It is associated with additional autoimmune diseases and cerebellar ataxia. Most patients with SPS have high levels of glutamic acid decarboxylase (GAD) antibodies. The aetiology of SPS remains unclear but autoimmunity is thought to play a major part. We have previously demonstrated overlap between anti-GAD ataxia and gluten sensitivity. We have also demonstrated the beneficial effect of a gluten-free diet (GFD) in patients with anti-GAD ataxia. Here, we describe our experience in the management of 20 patients with SPS. The mean age at symptom onset was 52 years. Additional autoimmune diseases were seen in 15/20. Nineteen of the 20 patients had serological evidence of gluten sensitivity and 6 had coeliac disease. Fourteen of the 15 patients who had brain imaging had evidence of cerebellar involvement. Twelve patients improved on GFD and in seven GFD alone was the only treatment required long term. Twelve patients had immunosuppression but only three remained on such medication. Gluten sensitivity plays an important part in the pathogenesis of SPS and GFD is an effective therapeutic intervention. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Article
TG6 Auto-Antibodies in Dermatitis Herpetiformis
Nutrients 2020, 12(9), 2884; https://doi.org/10.3390/nu12092884 - 21 Sep 2020
Cited by 1 | Viewed by 1023
Abstract
Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen [...] Read more.
Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of gluten sensitivity. The interplay between B cell responses to these 3 transglutaminases in developing the clinical spectrum of disease manifestations is not completely understood. Also, the individual or combined diagnostic and predictive value of the respective autoantibodies is not fully explored. We examined the prevalence of TG6 antibodies in a cohort of patients with DH. TG6 positivity was found in 13/33 (39%), with IgA detected in 11 patients, IgG in 3, and both in 1. This was significantly higher compared to what is seen in the classic CD cases (14%) in a Finnish population. TG6 positive baseline samples constituted 60% of DH patients with no enteropathy (n = 10), as opposed to 17% positivity in those with overt enteropathy (n = 12; Marsh IIIB). Repeat testing after adherence to a gluten-free diet for 1 year showed reduced titers for TG6 antibodies in 11/13 (85%), whereby 7 patients were now TG6 antibody-negative. Four patients seroconverted and tested positive for TG6 antibodies at one year, due to the ongoing exposure to gluten. We report another patient who presented with neurological manifestations (encephalopathy) leading to the diagnosis of CD, who was intermittently adhering to a gluten-free diet. Serological testing at baseline showed him to be positive for antibodies to all 3 transglutaminases. Eleven years later, he developed DH. He also subsequently developed ataxia and peripheral neuropathy. Although TG3 and TG6 autoantibodies are linked to certain disease manifestations, TG2, TG3, and TG6 autoantibodies can be present across the spectrum of GRD patients and might develop years before onset of symptoms of extraintestinal manifestations. This is consistent with gluten-dependent adaptive immunity being a necessary but not sufficient pretext to organ-specific damage. TG6 antibodies appear to develop more frequently in patients where tolerance to gluten was broken but, either there was no development of the molecular state driving the tissue destruction at the level of the gut, or perhaps more likely, there was more resistance to developing this phenotype. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Article
Cognitive Impairment in Coeliac Disease with Respect to Disease Duration and Gluten-Free Diet Adherence: A Pilot Study
Nutrients 2020, 12(7), 2028; https://doi.org/10.3390/nu12072028 - 08 Jul 2020
Cited by 1 | Viewed by 966
Abstract
Cognitive deficit has been reported in coeliac disease (CD), but previous reports often study heterogenous samples of patients at multiple stages of the disease, or lack control data. Healthy controls (N = 21), newly diagnosed CD patients (NCD; N = 19) and [...] Read more.
Cognitive deficit has been reported in coeliac disease (CD), but previous reports often study heterogenous samples of patients at multiple stages of the disease, or lack control data. Healthy controls (N = 21), newly diagnosed CD patients (NCD; N = 19) and established CD patients (ECD; N = 35) were recruited from a specialist UK centre. Participants underwent a cognitive test battery that established seven overall domain scores. The SF-36 was administered as a quality of life (QoL) measure. Controlling for age, data were compared in between-group ANCOVAs with Tukey’s post-hoc test. Any significant outcome was compared in the ECD group only, between patients who were gluten-free diet adherent vs. non-adherent (defined via Biagi score and serology results). NCD and ECD groups underperformed relative to controls, by comparable degrees, in visual (overall model: p < 0.001) and verbal (p = 0.046) memory. The ECD group only underperformed in visuoconstructive abilities (p = 0.050). Regarding QoL, the NCD group reported lower vitality (p = 0.030), while the ECD group reported more bodily pain (p = 0.009). Comparisons based on dietary adherence were non-significant. These findings confirm cognitive deficit in CD. Dysfunction appears established at the point of diagnosis, after which it (predominantly) stabilises. While a beneficial effect of dietary treatment is therefore implied, future research is needed to establish to what extent any further decline is due to gluten exposure. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Article
Living with Gluten and Other Food Intolerances: Self-Reported Diagnoses and Management
Nutrients 2020, 12(6), 1892; https://doi.org/10.3390/nu12061892 - 26 Jun 2020
Cited by 6 | Viewed by 1312
Abstract
People suffering from a food intolerance (FI) tend to initiate restrictive diets such as a gluten-free diet (GFD), to alleviate their symptoms. To learn about how people live with these problems in daily life (independent of their medical diagnoses), 1203 participants answered a [...] Read more.
People suffering from a food intolerance (FI) tend to initiate restrictive diets such as a gluten-free diet (GFD), to alleviate their symptoms. To learn about how people live with these problems in daily life (independent of their medical diagnoses), 1203 participants answered a previously validated questionnaire and were divided into: G1 (those self-reporting symptoms after gluten consumption) and G2 (those informing no discomfort after gluten consumption). Self-reported clinical characteristics, diagnoses and diets followed were registered. Twenty nine percent referred some FI (8.5% in G1). In G1, self-reported diagnoses were more frequent (p < 0.0001), including a high proportion of eating and mood disorders. Diagnoses were reported to be given by a physician, but GFD was indicated by professional and nonprofessional persons. In G2, despite declaring no symptoms after gluten consumption, 11.1% followed a GFD. The most frequent answer in both groups was that GFD was followed “to care for my health”, suggesting that some celiac patients do not acknowledge it as treatment. Conclusion: close to one third of the population report suffering from some FI. Those perceiving themselves as gluten intolerant report more diseases (p < 0.0001). A GFD is followed by ~11% of those declaring no symptoms after gluten ingestion. This diet is perceived as a healthy eating option. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Review

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Review
Gluten and Autism Spectrum Disorder
Nutrients 2021, 13(2), 572; https://doi.org/10.3390/nu13020572 - 09 Feb 2021
Viewed by 1207
Abstract
An expanding body of literature is examining connections between Autism Spectrum Disorder (ASD) and dietary interventions. While a number of specialist diets have been suggested as beneficial in ASD, gluten has received particularly close attention as a potentially exacerbating factor. Reports exist suggesting [...] Read more.
An expanding body of literature is examining connections between Autism Spectrum Disorder (ASD) and dietary interventions. While a number of specialist diets have been suggested as beneficial in ASD, gluten has received particularly close attention as a potentially exacerbating factor. Reports exist suggesting a beneficial effect of the gluten-free diet (GFD) in ameliorating behavioural and intellectual problems associated with ASD, while epidemiological research has also shown a comorbidity between ASD and coeliac disease. However, both caregivers and clinicians have expressed an uncertainty of the value of people with ASD going gluten-free, and as the GFD otherwise receives considerable public attention a discussion which focuses specifically on the interaction between ASD and gluten is warranted. In this review we discuss the historical context of ASD and gluten-related studies, and expand this to include an overview of epidemiological links, hypotheses of shared pathological mechanisms, and ultimately the evidence around the use and adoption of the GFD in people with ASD. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Review
Current Evidence on the Efficacy of Gluten-Free Diets in Multiple Sclerosis, Psoriasis, Type 1 Diabetes and Autoimmune Thyroid Diseases
Nutrients 2020, 12(8), 2316; https://doi.org/10.3390/nu12082316 - 01 Aug 2020
Cited by 1 | Viewed by 2885
Abstract
In this review, we summarize the clinical data addressing a potential role for gluten in multiple sclerosis (MS), psoriasis, type 1 diabetes (T1D) and autoimmune thyroid diseases (ATDs). Furthermore, data on the prevalence of celiac disease (CD) and gluten-related antibodies in the above [...] Read more.
In this review, we summarize the clinical data addressing a potential role for gluten in multiple sclerosis (MS), psoriasis, type 1 diabetes (T1D) and autoimmune thyroid diseases (ATDs). Furthermore, data on the prevalence of celiac disease (CD) and gluten-related antibodies in the above patient groups are presented. Adequately powered and properly controlled intervention trials investigating the effects of a gluten-free diet (GFD) in non-celiac patients with MS, psoriasis, T1D or ATDs are lacking. Only one clinical trial has studied the effects of a GFD among patients with MS. The trial found significant results, but it is subject to major methodological limitations. A few publications have found beneficial effects of a GFD in a subgroup of patients with psoriasis that were seropositive for anti-gliadin or deamidated gliadin antibodies, but no effects were seen among seronegative patients. Studies on the role of gluten in T1D are contradictive, however, it seems likely that a GFD may contribute to normalizing metabolic control without affecting levels of islet autoantibodies. Lastly, the effects of a GFD in non-celiac patients with ATDs have not been studied yet, but some publications report that thyroid-related antibodies respond to a GFD in patients with concomitant CD and ATDs. Overall, there is currently not enough evidence to recommend a GFD to non-celiac patients with MS, psoriasis, ATDs or T1D. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
Review
The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review
Nutrients 2020, 12(3), 822; https://doi.org/10.3390/nu12030822 - 20 Mar 2020
Cited by 6 | Viewed by 1341
Abstract
Gluten-related neurological disorders (GRND) represent a spectrum of neurological manifestations that are triggered by gluten. In coeliac disease, a T-cell mediated enteropathy is triggered by gluten in genetically predisposed individuals. The underlying pathological mechanism of the neurological dysfunction is not yet clear. The [...] Read more.
Gluten-related neurological disorders (GRND) represent a spectrum of neurological manifestations that are triggered by gluten. In coeliac disease, a T-cell mediated enteropathy is triggered by gluten in genetically predisposed individuals. The underlying pathological mechanism of the neurological dysfunction is not yet clear. The aim of this review is to collate existing neuropathological findings in GRND as a means of aiding the understanding of the pathophysiology. A systematic search of the Pubmed Database yielded 188 articles, of which 32 were included, containing 98 eligible cases with a description of pathological findings in GRND. In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes. In patients with large-fiber neuropathy, nerve biopsies revealed axonopathy, loss of myelinated fibers and focal and perivascular infiltration by inflammatory cells. Inflammatory infiltrate was also observed in muscle in myopathy and in cerebrum of patients with encephalopathy and patients with epilepsy. Such changes were not seen in skin biopsies from patients with small fiber neuropathies. The findings from this systematic review suggest an immune mediated pathogenesis for GRND. Future research should focus on the characterization of the inflammatory cell infiltrates and identifying target epitopes. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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Review
Psychiatric Manifestations of Coeliac Disease, a Systematic Review and Meta-Analysis
Nutrients 2020, 12(1), 142; https://doi.org/10.3390/nu12010142 - 04 Jan 2020
Cited by 11 | Viewed by 2497
Abstract
Background: Coeliac disease (CD) is increasingly prevalent and is associated with both gastrointestinal (GI) and extra-intestinal manifestations. Psychiatric disorders are amongst extra-intestinal manifestations proposed. The relationship between CD and such psychiatric disorders is not well recognised or understood. Aim: The aim of this [...] Read more.
Background: Coeliac disease (CD) is increasingly prevalent and is associated with both gastrointestinal (GI) and extra-intestinal manifestations. Psychiatric disorders are amongst extra-intestinal manifestations proposed. The relationship between CD and such psychiatric disorders is not well recognised or understood. Aim: The aim of this systematic review and meta-analysis was to provide a greater understanding of the existing evidence and theories surrounding psychiatric manifestations of CD. Methodology: An online literature search using PubMed was conducted, the prevalence data for both CD and psychiatric disorders was extracted from eligible articles. Meta analyses on odds ratios were also performed. Results: A total of 37 articles were included in this review. A significant increase in risk was detected for autistic spectrum disorder (OR 1.53, 95% CI 1.24–1.88, p < 0.0001), attention deficit hyperactivity disorder (OR 1.39, 95% CI 1.18–1.63, p < 0.0001), depression (OR 2.17, 95% CI 2.17–11.15, p < 0.0001), anxiety (OR 6.03, 95% CI 2.22–16.35, p < 0.0001), and eating disorders (OR 1.62, 95% CI 1.37–1.91, p < 0.00001) amongst the CD population compared to healthy controls. No significant differences were found for bipolar disorder (OR 2.35, 95% CI 2.29–19.21, p = 0.43) or schizophrenia (OR 0.46, 95% CI 0.02–10.18, p = 0.62). Conclusion: CD is associated with an increased risk of depression, anxiety, eating disorders as well as ASD and ADHD. More research is required to investigate specific biological explanations as well as any effect of gluten free diet. Full article
(This article belongs to the Special Issue Gluten-Related Disorders: Time to Move from Gut to Brain)
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