Table 2 Study design, outcomes, and results of 11 trials evaluating gluten free diet in subjects with FGIDs
Author, Year, Country [ref.] | Type of Study, study population, intervention, evaluation scale | Inclusion Criteria | Outcomes/Endpoints | Results |
|---|---|---|---|---|
Adult studies | ||||
Wahnschaffe et al. 2007, Germany [15] | -Prospective −41 IBS-diarrhea (30–67 years); 102 controls (27–64 years) -GFD: 6 months − 5 GI symptoms graded with a 5-point Likert scale. | -IBS-diarrhea (Rome II) | -During the GFD, resolution of diarrhea and decrease in GI symptoms score below the mean + 2 standard deviations score of healthy controls, | - In 41 IBS-diarrhea patients the GI symptom score decreased from 14.5 ± 0.9 to 10.1 ± 0.9 (P < .01) - Decrease in stool frequency from 4.1 ± 0.2 to 2.0 ± 0.3 bowel movements/day (P < .01). - 15/41 (37%) had formed stools and normal frequency; 12/41 (29%) both GI symptoms and stool habits returned to normal. |
Biesiekierski et al. 2011, Australia [16] | -Double blind, placebo-controlled − 34 subjects (29–59 years) -GFD: at least 6 weeks before screening -Challenge: 6 weeks -Gluten containing muffin and bread (16 g/day) vs gluten free muffin and bread - Symptom questionnaire with 100-mm VAS. | -IBS (Rome III) | - Efficacy of the diet (gluten containing or GFD) in GI symptoms control. - Change in overall and individual GI symptoms. | - For more than half of the study duration, in 13/19 (68%) subjects in the gluten group the symptoms were not adequately controlled vs 6/15 (40%) in the placebo group, (P = .001) - The severity scores for pain, satisfaction with stool consistency, and tiredness were significantly higher for the gluten containing diet. - All patients experienced a worsening of symptoms in response to gluten by the first week of re-challenge, in contrast to the placebo group in which symptoms occurred more slowly and less severely. |
Carroccio et al. 2012, Italy [21] | -Double blind, placebo-controlled, crossover − 276 NCWS, 50 IBS, 100 CD (> 18 years) -Challenge: 2 weeks; Washout: 1 week -GFD: 4 weeks prior the challenge (also exclusion of cow’s milk, eggs, tomato, and chocolate) -Capsules containing wheat vs xylose -Symptoms with 100-mm VAS | -NCWS with IBS (Rome II) -IBS, no WS (negative at challenge) -CD | - Resolution of symptoms on elimination diets and recurrence after DBPC challenge. | - In the 276 NCWS patients the overall and the single symptom score for bloating, abdominal pain, and changes in stool consistency was significantly higher than baseline from the first week on the wheat containing diet (P < .0001) On placebo, there was no significant variation in score over baseline. |
Vazquez-Roche et al. 2013, USA [17] | - Single-blind, randomized, controlled − 45 subjects: 22 gluten group (43.4 ± 2.7 years); 23 gluten free group (41.8 ± 2.5 years) -Challenge: 4 weeks -Gluten vs rice starch -Daily bowel pattern diary | -IBS-diarrhea (Rome II) | -Effect of a gluten containing diet vs a GFD on bowel function | - Statistically significant decrease in the stool frequency of subjects on a GFD compared to a gluten containing diet (P = .04). - No effect on stool form. |
Biesiekierski et al. 2013, Australia [18] | -Double blind, randomized, crossover - 37 subjects (range 24–61 years) - 2 weeks run-in low FODMAPs diet, then GFD low in FODMAPs throughout. During the re-challenge, GFD, low FODMAPs, dairy free and low food chemicals. -Trial: 7 days; Washout: at least 2 weeks - Re-challenge: 3 days; Washout: at least 3 days -Trial: high gluten (16 g/day) vs low gluten (2 g gluten + 14 g whey/day) vs control (16 g whey/day) -Re-challenge: gluten (16 g/d) vs whey (16 g/d) vs placebo (no protein) -Symptoms with VAS | -IBS (Rome III) | -Change in overall symptoms score -Change in overall symptoms (> 20 mm VAS) from the run-in period (low FODMAPs) to the end of the study (gluten vs placebo). | - Reduced GI symptoms and fatigue in the run-in period (low FODMAPs diet) (P < .0001). - 22% had a mean VAS-improvement for overall abdominal symptoms of > 20 mm during the low FODMAPs diet. - During the re-challenge, no differences across the dietary treatment arms compared to the baseline (P > .209). -Specific and reproducible induction of symptoms with gluten was not demonstrated. |
Shahbazkhani et al. 2015, Iran [22] | -Double blind, placebo-controlled − 72 subjects: 35 gluten group (mean age 44.5 ± 10 years); 37 placebo group (mean age 43.2 ± 17 years) -Trial: 6 weeks -Gluten meal 100 g (free of FODMAPs and proteins, including 52% gluten or gliadin, 2.3% non-gluten and 27.7 g glucose) vs Placebo meal 100 g (gluten free powder, rice flour, corn starch and glucose) -Symptoms with a VAS (0–10) | -IBS (Rome III) | -Change in overall symptoms score | - Significant differences between the gluten-containing group and the placebo group symptoms control (P < .001). - After 6 weeks, symptoms were adequately controlled only in 9/35 (25.7%) of the gluten group vs 31/37 (83.8%) of the placebo group (P < .001). |
Aziz et al. 2016, UK [19] | - Prospective - 41 subjects (40.4 ± 14.9 years) - GFD: 6 weeks - Symptoms with IBS-SSS | - IBS-diarrhea (Rome III) | - Change in IBS symptom severity score. Clinical response with 50 points decrease. | - In 29/41 subjects (71%)., GFD reduced IBS-SSS of at least 50 points No differences between HLA-DQ groups. - The mean total IBS-SSS decreased from 286 to 131 points after 6 weeks on GFD (P < .001). |
Elli et al. 2016, Italy [23] | -Double blind, placebo-controlled gluten challenge, crossover − 98 subjects (mean age 38.9 ± 12.7 years) -Trial: 1 week; Washout: 1 week -GFD: 3 weeks before the trial - Capsules containing gluten 5.6 g/day vs rice starch -Symptoms with VAS 10 cm | -Functional GI symptoms (Rome III) | -Resolution of symptoms on elimination diet and recurrence after DBPC challenge | - More pronounced worsening of well-being with gluten than with placebo assumption (P = .05). - 28/98 (28.5%) relapsed during the gluten challenge, with 14/28 (50%) relapsing also during the placebo challenge. |
Zanwar et al. 2016, India [24] | -Double blind, placebo-controlled − 60 subjects: 30 gluten group (18–60 years); 30 placebo group (18–56 years) -Trial: 4 weeks - 2 slices of gluten containing bread vs 2 slices of gluten-free bread -Symptoms with 100-mm VAS | -IBS (Rome III) | -Change in overall symptoms score | - Worsening of overall symptoms in 55% of the gluten group vs 33% of the placebo group (P < .05). - Median VAS scores for abdominal pain, bloating, and tiredness significantly higher in the gluten group compared to the placebo group. |
Barmeyer et al. 2017, Germany [20] | - Prospective - 35 subjects - GFD: 4 months - Weekly Subject’s Global Assessment (SGA) - Symptoms with IBS-SSS | - IBS non-constipated (Rome III) | - Relief of IBS symptoms evaluated with the SGA on at least 75% of weeks over a 4-months period of GFD. - Clinical response with 50 points decrease. | - Considerably relief showed for 12/35 (34%) subjects. |
Paediatric studies | ||||
Francavilla et al. 2018, Italy [25] | -Double blind, placebo-controlled, crossover - 28 children (11.4 ± 4.3 years) - 2 weeks run-in open GFD - Trial: 2 weeks; Washout: 1 week; -Sachets of gluten (10 g/day) or placebo (rice starch) -Daily symptoms with VAS 10 cm - Weekly symptoms with IBS-SSS | -Functional GI symptoms (Rome III) | - Decrease of at least 30% of the global VAS from the gluten challenge to the placebo challenge - Prevalence of NCGS | - Decrease of all clinical scores (VAS, IBS-SSS) during the open GFD. - 11/28 (39.2%) patients had a global VAS variation > 30% between the gluten challenge group and the placebo challenge group. - No difference in the severity of the global VAS score during the gluten vs placebo challenge. - 4/28 (14.3%) large increase of symptoms with placebo |