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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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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.