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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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Exposure to Different Amounts of Dietary Gluten in Patients with Non-Celiac Gluten Sensitivity (NCGS): An Exploratory Study.
Roncoroni, L, Bascuñán, KA, Vecchi, M, Doneda, L, Bardella, MT, Lombardo, V, Scricciolo, A, Branchi, F, Elli, L
Nutrients. 2019;11(1)
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Non-coeliac gluten sensitivity (NCGS) is characterised by adverse gastrointestinal symptoms related to ingestion of gluten-containing foods and amelioration of symptoms when gluten is removed from the diet. It is currently unclear whether gluten sensitivity is a permanent condition. The aim of this exploratory study was to evaluate the effects of gluten re-introduction in 22 NCGS patients who have been on a strict gluten-free diet for three weeks. Working with a qualified nutritionist, participants began incrementally introducing gluten each week for three weeks. Gastrointestinal symptoms and quality of life were assessed at baseline and post-intervention. When adverse symptomology was reported, participants returned to the gluten-level before symptoms started. This study found mixed results with gluten reintroduction. Of the 22 participants, 8 were able to return to a normal gluten-containing diet, and the remaining participants had differing levels of tolerance for gluten consumption. Based on these results, the authors conclude further controlled studies are required to assess the clinical response of reintroducing dietary gluten in patients with NCGS.
Abstract
It is unclear whether patients with non-celiac gluten sensitivity (NCGS) can tolerate gluten. We have evaluated the changes of both gastrointestinal symptoms and quality of life for NCGS patients after the re-introduction of dietary gluten. Twenty-two NCGS patients reporting functional gastroenterological symptoms and on gluten-free diet (GFD) for the previous three weeks were exposed to incremental gluten-containing diets. Three groups were compared at baseline (immediately after 3-weeks on GFD) and immediately after the return of symptomatology: (i) a group tolerating a low-gluten diet (3.5 g gluten/day, week 1, n = 8), (ii) a group tolerating a mid-gluten diet (8 g gluten/day, week 2, n = 6), and (iii) a group tolerating a high-gluten diet (13 g gluten/day, week 3, n = 8). Their gastrointestinal symptoms and quality of life were assessed at baseline and post-intervention. The most common symptoms were: constipation (46%), abdominal pain (50%) and dyspepsia (38%). A decrease in several short form health survey (SF-36) sub-scores (all p < 0.03) after gluten re-introduction was only observed in the group tolerating the low-gluten diet; the same group showed a lower post-intervention role-emotional SF-36 score (p = 0.01). Most gastrointestinal symptoms remained similar after gluten re-introduction. However, a decrease in the general perception of well-being was only found after gluten re-introduction in the group tolerating a low-gluten diet (p = 0.01); the same was true when comparing the post-intervention general well-being perception among the three groups (p = 0.050). In conclusion, dissimilar responses from patients with NCGS were observed after the re-introduction of gluten, with gluten at a low dosage affecting the quality of life and general well-being of a group of patients, whereas others tolerate even higher doses of dietary gluten.
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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.
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Search for atoxic cereals: a single blind, cross-over study on the safety of a single dose of Triticum monococcum, in patients with celiac disease.
Zanini, B, Petroboni, B, Not, T, Di Toro, N, Villanacci, V, Lanzarotto, F, Pogna, N, Ricci, C, Lanzini, A
BMC gastroenterology. 2013;13:92
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The only current treatment for coeliac disease (CD) is lifelong adherence to a gluten free diet (GFD). As many CD patients report this to be difficult, alternatives for a baking-quality wheat that does not contain gluten are sought. Triticum monococcum (TM) is an ancient wheat that has shown potential to be a non-toxic gluten alternative for patients with CD. The aim of this study was to assess the safety of TM administration in patients with CD. 12 CD patients who have followed a gluten free diet for at least one year and were challenged with rice, gluten or TM, and followed for four weeks. The findings of this study showed that the safety of TM administration is inconclusive, though well tolerated by all patients. The authors encourage further investigation on this cereal as a harmless gluten alternative for CD patients.
Abstract
BACKGROUND Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and ex-vivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD. METHODS We performed a single blind, cross-over study involving 12 CD patients who had been on a GFD for at least 12 months, challenged on day 0, 14 and 28 with a single fixed dose of 2.5 grams of the following (random order): Tm, rice (as reference atoxic protein) and Amygluten (as reference toxic protein) dispersed in a gluten-free pudding. The primary end-point of the study was the change in intestinal permeability, as assessed by changes in the urinary lactulose/rhamnose ratio (L/R ratio) measured by High Pressure Liquid Chromatography. We also assessed the occurrence of adverse gastrointestinal events, graded for intensity and duration according to the WHO scale. Variables were expressed as mean ± SD; paired t-test and χ² test were used as appropriate. RESULTS The urinary L/R ratio did not change significantly upon challenge with the 3 cereals, and was 0.055 ± 0.026 for Tm Vs 0.058 ± 0.035 for rice (p = 0.6736) and Vs 0.063 ± 0.054 with Amygluten (p = 0.6071). Adverse gastrointestinal events were 8 for Tm, Vs 11 for rice (p = 0.6321) and Vs 31 for Amygluten p = 0.0016), and, in all cases events were graded as "mild" or "moderate" with TM and rice, and as "severe" or "disabling" in 4 cases during Amygluten. CONCLUSIONS No definite conclusion can be drawn on the safety of Tm, based on no change in urinary L/R because even Amygluten, a toxic wheat protein, did not cause a significant change in urinary L/R indicating low sensitivity of this methodology in studies on acute toxicity. Tm was, however, well tolerated by all patients providing the rationale for further investigation on the safety of this cereal for CD patients. TRIAL REGISTRATION EudraCT-AIFA n2008-000697-20.
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Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study.
Kelly, CP, Green, PH, Murray, JA, Dimarino, A, Colatrella, A, Leffler, DA, Alexander, T, Arsenescu, R, Leon, F, Jiang, JG, et al
Alimentary pharmacology & therapeutics. 2013;37(2):252-62
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Coeliac disease (CD) is an autoimmune disorder triggered by ingestion of gluten in genetically susceptible individuals. CD can cause inflammation and histological changes including villous atrophy and increased intestinal permeability. Larazotide acetate is a peptide that has been shown to block the gluten-induced increase in intestinal permeability, therefore improving gastrointestinal symptoms in CD patients. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate during a gluten challenge in patients with CD. The study included 184 adults diagnosed with CD, adhering to a gluten-free diet for at least six months. For six weeks, participants received 2.7 grams of gluten daily and were randomised to receive larazotide acetate three times daily. The findings of this study showed that larazotide acetate reduced gluten-induced immune activation, alleviated gastrointestinal symptoms and was well tolerated. While there was a reduction in the biomarker for intestinal permeability, there was no significant difference found compared with placebo. The authors conclude that the design and results of this study can be used for future pharmacological studies for CD.
Abstract
BACKGROUND Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. AIM: To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. METHODS This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. RESULTS No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. CONCLUSIONS Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.
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[Nursing and organizational development].
Donnenberg, OH, Locher, K
Tijdschrift voor ziekenverpleging. 1986;39(1):18-22
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The relationship between gluten exposure and diarrhoea-predominant irritable bowel syndrome (IBS-D) is not well understood. Non-celiac IBS-D patients who are positive for HLA-DQ2/8 genes associated with CD can show symptom improvement on a gluten-free diet (GFD). The aim of this 4-week parallel randomized controlled clinical trial in HLA-DQ2/8 positive and negative patients with IBS-D was to assess the effects of a gluten-containing diet (GCD) compared to a GFD on bowel function, gut transit, small bowel and colonic barrier functions. 45 patients were recruited from the Mayo clinic’s database of IBS suffers, and invited to participate. Patients with diagnosed CD were excluded. 22 patients were placed on the GCD (11 HLA-DQ2/8–negative and 11 HLA-DQ2/8–positive) and 23 on the GFD (12 HLA-DQ2/8−negative and 11 HLA-DQ2/8–positive). All meals and snacks were ingested or prepared in the Mayo Clinic. Patients were advised to eat only the foods provided by the study dieticians. Gluten-free and gluten-containing meals were prepared using the same macronutrient content (20% protein, 30% fat, 50% carb). Compliance to the diet was assessed by direct questioning by the dietitians and reported to be excellent. All patients were ingesting gluten in their diet prior to starting the study. At 4-weeks, a statistically significant decrease in stool frequency of subjects on GFD compared to subjects on GCD was seen. This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive. There was no significant dietary effect on daily stool form, ease of passage or gastric emptying. The GCD was associated with higher small bowel permeability and lactulose:mannitol ratio. Small bowel permeability was greater in HLA-DQ2/8–positive than negative patients. No significant differences in colonic permeability were observed. The author concludes that this study provides mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS. The data also partially explains that the biological effects of gluten were associated with HLA-DQ2 or 8 genotype. The relationship of dietary factors, innate and adaptive immune responses and mucosal interactions in IBS-D deserve further study. Further clinical studies evaluating the effects of gluten withdrawal in patients with IBS-D are needed.