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The effect of gluten in adolescents and young adults with gastrointestinal symptoms: a blinded randomised cross-over trial.
Crawley, C, Savino, N, Halby, C, Sander, SD, Andersen, AN, Arumugam, M, Murray, J, Christensen, R, Husby, S
Alimentary pharmacology & therapeutics. 2022;55(9):1116-1127
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The gluten-free diet (GFD) has gained increasing popularity among healthy people without coeliac disease or wheat allergy. The main reasons for following a GFD are weight control, the perception that a GFD is healthier, and the presence of symptoms after gluten ingestion. The aim of this study was to address the hypothesis that adding gluten to the diet results in a self-reported worsening of gastrointestinal symptoms (primary outcome) and mental health (key secondary outcomes) in a well-characterised group of adolescents. This study was arranged in two phases; the first phase began with 2 weeks of a GFD, and if the participants responded to the GFD, they proceeded to phase 2. Phase 2 was a double-blinded randomised trial with cross-over and consisted of three periods, each lasting 7 days: (1) a challenge with gluten/placebo, (2) wash-out phase, and (3) the second challenge with placebo/gluten. Results show that it was not possible to detect a difference in symptoms between gluten and placebo at a group level. Furthermore, on an individual level, there was a comparable number of gluten responders and placebo responders, underscoring the insignificant difference between gluten and placebo. Authors conclude that adding gluten to the diet does not induce gastrointestinal symptoms or worsened mental health in adolescents.
Abstract
BACKGROUND The popularity of the gluten-free diet and sales of gluten-free products have increased immensely. AIMS To investigate whether gluten induces gastrointestinal symptoms, measured by self-reported questionnaires, as well as mental health symptoms in adolescents from a population-based cohort. METHODS The eligible participants (n = 273) were recruited from a population-based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run-in phase where the participants lived gluten-free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross-over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7-day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed. RESULTS In total, 54/273 participants entered the run-in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2-20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was -0.01 (95% confidence interval -2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health. CONCLUSION Compared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population-based cohort. The trial registration number is NCT04639921.
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The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review.
Rouvroye, MD, Zis, P, Van Dam, AM, Rozemuller, AJM, Bouma, G, Hadjivassiliou, M
Nutrients. 2020;12(3)
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Coeliac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten in genetically susceptible individuals. A wide range of extraintestinal manifestations has been attributed to CD, changing the classic perception of a disease limited to the intestine, to a multisystem disorder. The aim of this study was to analyse the published neuropathology of confirmed cases of gluten-related neurological dysfunction to aid our understanding of the pathogenesis. CD can therefore manifest with dental problems, consequences of malabsorption, skin and neurological disorders. This study is a systematic review of thirty-two neurological disorder focused studies. Results show that: - the neuropathological findings in gluten-related neurological disorders are widespread and not limited to the cerebellum. - the pathology is immune mediated and not related to vitamin or trace elements deficiencies. - the pathophysiology of neurological damage in the context of gluten sensitivity has an immune mediated basis. - more gluten-related neurological disorders affected men (57%), which was even higher in the ataxia group (76%). - transglutaminase 6 antibodies might be helpful in the diagnostic workup of gluten-related neurological disorders. Authors conclude that the current evidence is suggestive of both humoral and cell-mediated immunological responses. Further research is required to investigate the underlying neuropathological mechanism by characterisation of the inflammatory cell infiltrate and identification of target epitopes.
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 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.
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Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review.
Mearns, ES, Taylor, A, Thomas Craig, KJ, Puglielli, S, Leffler, DA, Sanders, DS, Lebwohl, B, Hadjivassiliou, M
Nutrients. 2019;11(2)
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Coeliac disease (CD) is a chronic, immune-mediated enteropathy in which dietary gluten triggers an inflammatory reaction of the small intestine in genetically predisposed individuals. The clinical presentation of the disease varies broadly and may include both intestinal symptoms and extra-intestinal manifestations, including iron-deficiency anaemia, osteoporosis, dermatitis herpetiformis, and neurological disorders, such as peripheral neuropathies and ataxia (a condition that affects co-ordination, balance and speech). Many patients who present with neurological manifestations of CD have no gastrointestinal symptoms, commonly leading to a delay in diagnosis. The aim of this systematic review was to assess the prevalence of peripheral neuropathies and gluten ataxia. Nine studies on gluten ataxia and 13 on gluten neuropathy were included in this review. The prevalence of both, neuropathy and ataxia, in the general population is very low, but this risk is increased in patients with CD. Estimates of the prevalence of neuropathy in CD patients ranged from 0% to 39%, with an increased risk in older and female patients. Prevalence of gluten ataxia varied from 0% to 6%. Symptoms of gluten neuropathy improve when patients with CD follow a gluten free diet (GFD), whilst the benefits of a GFD for ataxia vary between studies, possibly due to differences in study design. The authors note that this review primarily concentrated on patients with CD (i.e. those with evidence of enteropathy). However, neurological manifestations may exist in the presence of anti-gliadin antibodies alone (gluten sensitivity without evidence of enteropathy), and such patients benefit equally from a GFD. The authors conclude that patients with CD have an increased risk of gluten ataxia and gluten neuropathy, and that clinicians should check for gluten sensitivity in patients with ataxia and neuropathy of unknown origin.
Abstract
Celiac disease (CD) is an immune-mediated gastrointestinal disorder driven by innate and adaptive immune responses to gluten. Patients with CD are at an increased risk of several neurological manifestations, frequently peripheral neuropathy and gluten ataxia. A systematic literature review of the most commonly reported neurological manifestations (neuropathy and ataxia) associated with CD was performed. MEDLINE, Embase, the Cochrane Library, and conference proceedings were systematically searched from January 2007 through September 2018. Included studies evaluated patients with CD with at least one neurological manifestation of interest and reported prevalence, and/or incidence, and/or clinical outcomes. Sixteen studies were included describing the risk of gluten neuropathy and/or gluten ataxia in patients with CD. Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies. Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%⁻6%. Adherence to a gluten-free diet appeared to improve symptoms of both neuropathy and ataxia. The prevalence of gluten neuropathy and gluten ataxia in patients with CD varied in reported studies, but the increased risk supports the need for physicians to consider CD in patients with ataxia and neurological manifestations of unknown etiology.
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Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity.
Lichtwark, IT, Newnham, ED, Robinson, SR, Shepherd, SJ, Hosking, P, Gibson, PR, Yelland, GW
Alimentary pharmacology & therapeutics. 2014;40(2):160-70
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Coeliac disease (CD) is an inflammatory autoimmune disorder caused by the ingestion of gluten. While CD is known to primarily affect the bowel, there is reported evidence of potential neurological side effects. Cognition may be impaired in undiagnosed CD patients because of nutrient deficiencies, systemic inflammation and changes in the gut microbiome. CD patients often report a mild cognitive impairment, brain fog, characterised by difficulty concentrating, short-term memory and confusion. The aim of this study was to investigate the relationship between gut mucosal healing and cognitive function in eleven patients recently diagnosed with CD commencing a strict gluten-free diet. The findings of this study showed that in newly diagnosed CD patients, cognitive functioning improved with a gluten-free diet and was correlated with mucosal healing. Based on this study, the authors conclude that cognition is impaired in people with untreated coeliac disease and may affect the performance of everyday tasks. This finding also introduces the possibility of using cognitive tests to provide a marker of intestinal healing.
Abstract
BACKGROUND Mild impairments of cognition or 'Brain fog' are often reported by patients with coeliac disease but the nature of these impairments has not been systematically investigated. AIM: This longitudinal pilot study investigated relationships between cognitive function and mucosal healing in people with newly diagnosed coeliac disease commencing a gluten-free diet. METHODS Eleven patients (8 females, 3 males), mean age 30 (range 22-39) years, were tested with a battery of cognitive tests at weeks 0, 12 and 52. Information processing efficacy, memory, visuospatial ability, motoric function and attention were tested. Small bowel biopsies were collected via routine gastroscopy at weeks 12 and 52 and were compared to baseline Marsh scores. Cognitive performance was compared to serum concentrations of tissue transglutaminase antibodies, biopsy outcomes and other biological markers. RESULTS All patients had excellent adherence to the diet. Marsh scores improved significantly (P = 0.001, Friedman's test) and tissue transglutaminase antibody concentrations decreased from a mean of 58.4 at baseline to 16.8 U/mL at week 52 (P = 0.025). Four of the cognitive tests assessing verbal fluency, attention and motoric function showed significant improvement over the 12 months and strongly correlated with the Marsh scores and tissue transglutaminase antibody levels (r = 0.377-0.735; all P < 0.05). However, no meaningful patterns of correlations were found for nutritional or biochemical markers, or markers of intestinal permeability. CONCLUSIONS In newly diagnosed coeliac disease, cognitive performance improves with adherence to the gluten-free diet in parallel to mucosal healing. Suboptimal levels of cognition in untreated coeliac disease may affect the performance of everyday tasks.