Effects of a low FODMAP diet on gut microbiota in individuals with treated coeliac disease having persistent gastrointestinal symptoms - a randomised controlled trial.

Individuals with coeliac disease (CeD) often experience gastrointestinal symptoms despite adherence to a gluten-free diet (GFD). While we recently showed that a diet low in fermentable oligo-, di-, monosaccharides and polyols (FODMAP) successfully provided symptom relief in GFD-treated CeD patients, there have been concerns that the low FODMAP diet (LFD) could adversely affect the gut microbiota. Our main objective was therefore to investigate whether the LFD affects the faecal microbiota and related variables of gut health. In a randomised controlled trial GFD-treated CeD adults, having persistent gastrointestinal symptoms, were randomised to either consume a combined LFD and GFD (n 39) for 4 weeks or continue with GFD (controls, n 36). Compared with the control group, the LFD group displayed greater changes in the overall faecal microbiota profile (16S rRNA gene sequencing) from baseline to follow-up (within-subject ß-diversity, P < 0·001), characterised by lower and higher follow-up abundances (%) of genus Anaerostipes (Pgroup < 0·001) and class Erysipelotrichia (Pgroup = 0·02), respectively. Compared with the control group, the LFD led to lower follow-up concentrations of faecal propionic and valeric acid (GC-FID) in participants with high concentrations at baseline (Pinteraction ≤ 0·009). No differences were found in faecal bacterial α-diversity (Pgroup ≥ 0·20) or in faecal neutrophil gelatinase-associated lipocalin (ELISA), a biomarker of gut integrity and inflammation (Pgroup = 0·74), between the groups at follow-up. The modest effects of the LFD on the gut microbiota and related variables in the CeD patients of the present study are encouraging given the beneficial effects of the LFD strategy to treat functional GI symptoms (Registered at clinicaltrials.gov as NCT03678935).

Nutritional assessment of women with celiac disease compared to the general population.

BACKGROUND & AIMS: The nutritional quality of a gluten-free diet is debated because of the elimination of grains that are important sources of nutrients. The aim of this cross-sectional study was to perform a nutritional assessment in treated women with celiac disease and ongoing symptoms, and compare dietary intake with a healthy reference group (Norkost 3). METHODS: Celiac disease patients with biopsy confirmed mucosal healing, but persistent gastrointestinal symptoms, were included from an ongoing clinical trial. Nutritional assessment included anthropometrics, blood samples and dietary intake obtained by two 24 h recalls. Dietary intake in celiac women was compared with dietary intake in healthy women (Norkost 3). Two sample t-test was used for comparison of CeD and Norkost 3 women. Adjustment for age, BMI, education and smoking, by use of multiple linear regression analysis, did not change the results. RESULTS: In total, 59 women with celiac disease and 925 women that participated in Norkost 3 were included, with a mean age of 45 years in both groups. Women with celiac disease had a higher proportion of energy (E%) from fat (39 vs 34%, P < 0.001) and saturated fat (15 vs 13%, P = 0.01), a lower E% from protein (16 vs 18%, P = 0.01) and a lower intake of dietary fiber (19 vs 22 g, P = 0.002) compared to Norkost 3 women. Women with celiac disease had a lower intake of bread, fruit and milk, and a higher intake of cereals and cheese compared to Norkost 3 women. The average requirement was not met for several micronutrients, but blood analysis revealed few nutritional deficiencies: two women with insufficient vitamin D status and one with insufficient folic acid status. CONCLUSION: The women with celiac disease had an unbalanced diet with a higher intake of total- and saturated fatty acids and a lower intake of fiber compared to the general population. These findings emphasizes the need for nutritional follow-up of celiac patients and development of nutrient dense gluten-free products.

A Low FODMAP Diet Reduces Symptoms in Treated Celiac Patients With Ongoing Symptoms-A Randomized Controlled Trial.

BACKGROUND & AIMS: A gluten-free diet usually leads to mucosal remission in celiac disease, but persistent symptoms are common. A low fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet is an established treatment for irritable bowel syndrome (IBS). We have assessed the efficacy of a moderately low FODMAP diet on persistent symptoms in treated celiac patients. METHODS: A randomized controlled trial was performed from 2018 to 2019 in 70 adults with biopsy-proven celiac disease. Inclusion criteria were as follows: persistent gastrointestinal symptoms defined by a Gastrointestinal Symptom Rating Scale (GSRS)-IBS version score of 30 or higher, gluten-free diet adherence for 12 months or longer, and serologic and mucosal remission. Participants were randomized to a low FODMAP-gluten-free diet (intervention) or usual gluten-free diet (control). The GSRS-IBS score was recorded at baseline and at weeks 1 to 4, and the Celiac Symptom Index at baseline and at week 4. Statistics included marginal models for repeated data and analyses of covariance. RESULTS: We included 34 participants in the intervention group and 36 in the control group. Time development of GSRS-IBS total scores differed significantly between the groups (Pinteraction < .001), evident after 1 week (mean difference in intervention vs control, -8.2; 95% CI, -11.5 to -5.0) and persisting through week 4 (mean difference in intervention vs control, -10.8; 95% CI, -14.8 to -6.8). Moreover, significantly lower scores were found for the dimensions of pain, bloating, diarrhea, and satiety (Pinteraction ≤ .04), but not constipation (Pinteraction = .43). FODMAP intake during the intervention was moderately low (mean, 8.1 g/d; 95% CI, 6.7-9.3 g/d). The Celiac Symptom Index was significantly lower in the intervention group at week 4 (mean difference, -5.8; 95% CI, -9.6 to -2.0). CONCLUSIONS: A short-term moderately low FODMAP diet significantly reduced gastrointestinal symptoms and increased celiac disease-specific health, and should be considered for the management of persistent symptoms in celiac disease. CLINICALTRIALS: gov: NCT03678935.

High disease burden in treated celiac patients - a web-based survey.

BACKGROUND: Strict adherence to a gluten-free diet usually leads to clinical and histological remission in celiac disease. Few studies have investigated the prevalence of persistent symptoms in a celiac population. We aimed to study the impact of gastrointestinal symptoms on general health in a large number of treated celiac patients, and describe the prevalence of persistent gastrointestinal symptoms and investigate associated factors. METHODS: Adults with celiac disease filled out background questions, the Celiac Symptom Index (CSI) and the celiac disease adherence test (CDAT) in a web-based national survey. Participants who reported gastrointestinal symptoms during the previous week also recorded the gastrointestinal symptom rating scale-irritable bowel syndrome version (GSRS-IBS). Statistical analysis included chi-squared test, t-test, correlation, and linear regression. RESULTS: Of 3834 participants (82% women; mean age 47 years), 54% reported gastrointestinal symptoms the previous week, and 30% of these had CSI score ≥45, indicative of the relatively poor quality of life (vs. 5% among those without gastrointestinal symptoms). The prevalence of persistent gastrointestinal symptoms (GSRS-IBS ≥30) was 40% and the most prominent symptoms were bloating (44%) and pain (37%). Age, sex, symptoms at the time of diagnosis, comorbidity, dietary adherence and CeD-specific health were significantly associated with gastrointestinal symptoms (p < .001). CONCLUSION: In this national cross-sectional study among participants with celiac disease, persistent gastrointestinal symptoms were frequent, and were associated with a high symptom burden and reduced CeD-specific health. Several factors were associated with gastrointestinal symptoms, but more research is needed to find the cause of persistent symptoms in patients with celiac disease.

Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity.

BACKGROUND: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD. OBJECTIVE: We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS: Australian patients with CD (n = 26) and SR-GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS: Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52-24.0; P < 0.0001, Wilcoxon test). The two SR-GS cohorts included only one (1.5%) confirmed IL-2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CD participants, but 2 of the 4 non-responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 'verified' CD participants. CONCLUSIONS: Gluten challenge with high-sensitivity cytokine assessment differentiates CD from SR-GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR-GS individuals.

Dietary and symptom assessment in adults with self-reported non-coeliac gluten sensitivity.

BACKGROUND & AIMS: The mechanisms behind non-coeliac gluten sensitivity (NCGS) are not fully understood although clinical symptoms have shown to subside after wheat withdrawal. Self-prescription of a gluten-free diet (GFD) without medical supervision is common in NCGS subjects, resulting in dietary restrictions that can cause macro- and micronutrient deficiencies. The primary aim was to describe dietary intake, including FODMAP, in subjects with self-reported gluten sensitivity on GFD in whom coeliac disease (CD) and wheat allergy were excluded. Secondary, clinical symptoms and health-related quality of life (HR-QoL) were examined. METHODS: Baseline characteristics were obtained from 65 adults with self-reported NCGS on GFD recruited to a randomised placebo-controlled challenge trial at Oslo University Hospital. Dietary intake was obtained by a seven-day food record and symptoms recorded by questionnaires. RESULTS: Mean proportions of energy were 43 E% from fat, 40 E% from carbohydrate and 17 E% from protein. Intakes of vitamin D, folic acid, calcium, iodine and iron were lower than recommended, mean (SD) 7.3 (5.8) µg, 235 (105) µg, 695 (309) mg, 81 (52) µg and 9.6 (7.5) mg, respectively. Mean (SD) intake of FODMAP was 11.6 g (8.7). Gastrointestinal symptoms as scored by 100 mm visual analogue scale (VAS) were all below 15 mm of which wind and bloating were the most expressed. Tiredness, concentration difficulties, fatigue and muscle/joint pain were scored highest among extra-intestinal symptoms. Gastrointestinal symptoms as scored by gastrointestinal symptom rating scale - irritable bowel syndrome version (GSRS-IBS) were correlated with mild depression (r = 0.43) and inversely correlated with five sub-domains of HR-QoL (-0.29 < r < -0.26). CONCLUSION: Subjects with self-reported NCGS on GFD had high proportion of energy from fat and sub-optimal intakes of vitamin D, folic acid, calcium, iodine and iron. Despite GFD and moderate intake of FODMAP, the subjects reported various gastro- and extra-intestinal symptoms and reduced HR-QoL. The findings highlight the importance of dietary education and nutritional follow-up of subjects on GFD.

HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge.

OBJECTIVE: Initiation of a gluten-free diet without proper diagnostic work-up of coeliac disease is a frequent and demanding problem. Recent diagnostic guidelines suggest a gluten challenge of at least 14 days followed by duodenal biopsy in such patients. The rate of false-negative outcome of this approach remains unclear. We studied responses to 14-day gluten challenge in subjects with treated coeliac disease. DESIGN: We challenged 20 subjects with biopsy-verified coeliac disease, all in confirmed mucosal remission, for 14 days with 5.7 grams per oral gluten daily. Duodenal biopsies were collected. Blood was analysed by multiplex assay for cytokine detection, and by flow cytometry using HLA-DQ:gluten tetramers. RESULTS: Nineteen participants completed the challenge. Villous blunting appeared at end of challenge in 5 of 19 subjects. Villous height to crypt depth ratio reduced with at least 0.4 concomitantly with an increase in intraepithelial lymphocyte count of at least 50% in 9 of 19 subjects. Interleukin-8 plasma concentration increased by more than 100% after 4 hours in 7 of 19 subjects. Frequency of blood CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells increased by more than 100% on day 6 in 12 of 15 evaluated participants. CONCLUSION: A 14-day gluten challenge was not enough to establish significant mucosal architectural changes in majority of patients with coeliac disease (sensitivity ≈25%-50%). Increase in CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells in blood 6 days after gluten challenge is a more sensitive and less invasive biomarker that should be validated in a larger study. TRIAL REGISTRATION NUMBER: NCT02464150.

Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity.

BACKGROUND & AIMS: Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity. METHODS: We performed a double-blind crossover challenge of 59 individuals on a self-instituted gluten-free diet, for whom celiac disease had been excluded. The study was performed at Oslo University Hospital in Norway from October 2014 through May 2016. Participants were randomly assigned to groups placed on diets containing gluten (5.7 g), fructans (2.1 g), or placebo, concealed in muesli bars, for 7 days. Following a minimum 7-day washout period (until the symptoms induced by the previous challenge were resolved), participants crossed over into a different group, until they completed all 3 challenges (gluten, fructan, and placebo). Symptoms were measured by Gastrointestinal Symptom Rating Scale Irritable Bowel Syndrome (GSRS-IBS) version. A linear mixed model for analysis was used. RESULTS: Overall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1 ± 13.3, 38.6 ± 12.3, and 34.3 ± 13.9, respectively (P = .04). Mean scores for GSRS-IBS bloating were 9.3 ± 3.5, 11.6 ± 3.5, and 10.1 ± 3.7, respectively, during the gluten, fructan, and placebo challenges (P = .004). The overall GSRS-IBS score for participants consuming fructans was significantly higher than for participants consuming gluten (P = .049), as was the GSRS bloating score (P = .003). Thirteen participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and 22 had the highest score after consuming placebo. There was no difference in GSRS-IBS scores between gluten and placebo groups. CONCLUSIONS: In a randomized, double-blind, placebo-controlled crossover study of individuals with self-reported non-celiac gluten sensitivity, we found fructans to induce symptoms, measured by the GSRS-IBS. Clinicaltrials.gov no: NCT02464150.

Non-coeliac gluten sensitivity.

Irritable bowel syndrome-like symptoms in response to wheat ingestion is common and well described, but whether the reaction is due to gluten (i.e., non-coeliac gluten sensitivity), other wheat proteins, or FODMAPs (mostly fructans) alone or in combinations has not been clearly defined. Exclusion of coeliac disease in the presence of negative serology, and normal villous architecture but increased density of intraepithelial lymphocytes on duodenal biopsies, is difficult. Furthermore, the confidence by which a positive diagnosis is made or non-coeliac gluten sensitivity is excluded by blinded placebo-controlled rechallenge with wheat protein is reduced by strong nocebo responses generally found in patients with self-reported non-coeliac gluten sensitivity. The absence of a clear biological mechanism of action and difficulties with the design and interpretation of research studies have plunged this entity into even deeper controversy. In the absence of clarity in its diagnosis, the epidemiology, prognosis, and therapeutic approaches to a patient who may be gluten sensitive remain to be determined. Adequate understanding of the issues surrounding the controversy and further research will slowly unravel the truth behind the problem.

Wheat challenge in self-reported gluten sensitivity: a comparison of scoring methods.

BACKGROUND: The condition non-coeliac gluten sensitivity (NCGS) is clinically similar to coeliac disease, but lack objective diagnostic criteria. Symptom relief on gluten-free diet followed by gluten containing food challenge may confirm the condition in clinical settings. AIM: To describe the results of an open bread challenge in patients with suspected NCGS, and to compare the results with recently suggested cut-offs for symptom change. MATERIAL AND METHODS: Fifty-six patients (12 males) self-instituted on gluten-free diet with negative coeliac disease diagnostics were examined for NCGS by an open bread challenge. Symptoms were reported by Gastrointestinal Symptom Rating Scale, IBS-version (GSRS-IBS) and visual analogue scale (VAS). Results were retrospectively compared to the Salerno and Monash cut-offs for symptom change. RESULTS: Forty-seven patients were diagnosed with NCGS. Total GSRS-IBS score and overall symptoms by VAS increased significantly in NCGS (p < .001), but not in non-NCGS patients (p < .12 and p = .08, respectively). Total GSRS-IBS challenge score and overall symptoms by VAS were significantly higher in NCGS than in non-NCGS patients (53 vs. 37, p = .004 and 76 vs. 39 mm, p = .02, respectively). Applying the Salerno and Monash cut-offs, 63 and 75% would be classified with NCGS, respectively. According to total GSRS-IBS absolute agreement was lowest between clinician's diagnosis and Salerno cut-off (63%) and highest between Salerno and Monash cut-offs (88%). CONCLUSION: Clinician diagnosed 85% with NCGS. The proportion of NCGS was lower according to the Salerno and Monash cut-offs. The Salerno cut-off should be the starting point for a common definition of symptom change.