Efficacy of a gluten-free diet in subjects with irritable bowel syndrome- diarrhea unaware of their HLA-DQ2/8 genotype
Aziz I, Trott N, Briggs R et al
Clinical Gastroenterolgy and Hepatology 2016, Article in Press
IBS-D accounts for almost one third of IBS patients and is the predominant subtype of IBS encountered in clinical practice. Research suggests that 84% of patients with IBS believe that food triggers their gastrointestinal symptoms and of these, gluten-based products are cited by approximately 1 in 4 patients as a common trigger. These observations have given rise to the clinical entity known as ‘non-celiac gluten sensitivity’ (NCGS). However, NCGS remains a controversial condition due to the existence of co-existing non-gluten components (including FODMAPs) that have also been demonstrated to induce IBS symptoms.
Clinical Gastroenterolgy and Hepatology 2016, Article in Press
IBS-D accounts for almost one third of IBS patients and is the predominant subtype of IBS encountered in clinical practice. Research suggests that 84% of patients with IBS believe that food triggers their gastrointestinal symptoms and of these, gluten-based products are cited by approximately 1 in 4 patients as a common trigger. These observations have given rise to the clinical entity known as ‘non-celiac gluten sensitivity’ (NCGS). However, NCGS remains a controversial condition due to the existence of co-existing non-gluten components (including FODMAPs) that have also been demonstrated to induce IBS symptoms.
The purpose of this prospective study was to evaluate the clinical response to a gluten free diet (GFD) in a cohort of patients with IBS-D blinded to their HLA-DQ status. The long-term benefit and sustainability of a gluten free diet was also assessed.
The study was conducted at the Royal Hallamshire Hospital in Sheffield between Sept 2012 and July 2015. Patients attending the gastroenterology out-patient clinic who fulfilled the Rome II criteria for IBS-D were eligible for inclusion. Celiac disease was excluded based on negative serology and normal duodenal biopsy. Individuals with self-reported gluten sensitivity; those already on a GFD; and those with other medical conditions known to mimic IBS-D were also excluded. Seventy eight participants were selected as eligible to take part in the study, of these 48 patients agreed to enrol (24 HLA-DQ2/8+ve and 24 HLA- DQ2/8-ve). Subjects were referred to 1 of 2 senior dietitians who provided uniform information on how to undertake a GFD. Subjects were also given validated questionnaires to self-complete the day before commencing a GFD and during the GFD period, these included the IBS Symptom Severity Score (IBS-SSS), Hospital Anxiety and Depression Scale (HADS), Fatigue Impact Score (FIS), and Short-form 36 (SF-36) quality of life questionnaire. Seven subjects dropped out of the study (4 did not attend their initial dietitian appointment; 1 became pregnant; 1 started an additional diet; and 1 felt the GFD was too expensive). Those subjects remaining (21 HLA-DQ –ve; 20 HLA DQ +ve) were instructed to follow a GFD for 6 weeks, after which they returned for a follow-up appointment with the dietitians and returned their questionnaires. Dietary adherence was evaluated using a simple, validated tool. Patients were also asked if they intended to continue with a GFD for the foreseeable future. For those that answered yes, a follow-up dietitian appointment was arranged for approximately 18 months time. Importantly, both dietitians and patients were blinded to the fact that HLA-DQ2/8 status was being used as a comparative factor within the study.
Following the 6-week GFD, a reduction of IBS-SSS of ≥50 points (indicating clinical benefit) was seen in 71% of patients, there was no difference between HLA-DQ groups. A significant symptom reduction was seen as early as week 2 and this continued to drop between each interval at week 4 and week 6. The greatest improvements were seen in those who had the severest IBS scores at baseline. In terms of IBS subscales, a significant mean reduction in abdominal pain, pain frequency, stool dissatisfaction and life interferences was observed in both HLA-DQ subgroups, with no difference between groups. However HLA-DQDQ2/8-ve subjects showed a greater reduction in abdominal distension compared with HLA-DQ2/8+ve subjects (p=0.04). A significant improvement in HADS, FIS and SF-36 quality of life was also observed following a GFD, seen across both groups. However HLA-DQ2/8+ve patients experienced a significantly greater improvement in depression (p=0.02) and vitality (p=0.03) compared with the HLA-DQ2/8-ve group. At the end of the 6-week intervention, 72% of IBS-SS responders planned to continue to follow a GFD for the foreseeable future (11 HLA-DQ2/8+ve and 10 HLA-DQ2/8-ve). When these patients were contacted on average 18 months later, all were still following a GFD with a good level of adherence and reported ongoing symptom improvement without any alterations in body mass index or biochemical status (compared to baseline).
The results of this study demonstrate that a dietitian-led GFD should be considered as a therapeutic option for the management of patients with IBS-D who are previously naïve to the effects of gluten. The strengths of this study lie in it’s rigorously defined cohort, in which CD was excluded and patients and dietitians were blinded to the fact that HLA-DQ2/8 status was being used as a comparative factor. This study also demonstrates a real-life situation in which patients were provided with a single dietetic consultation and then left to follow the GFD themselves, rather than being provided with all meals in a heavily controlled research environment. The limitations of the study include the placebo-effect of undertaking a dietary trial, however this is unlikely to account fully for the 71% response rate observed, particularly in view of the fact that well-being was maintained at 18 months. The authors of this study speculate that the patho-physiological mechanisms resulting in symptom reduction for IBS-D patients treated with a GFD may differ according to HLA-DQ status, and this is worthy of further mechanistic exploration.
The study was conducted at the Royal Hallamshire Hospital in Sheffield between Sept 2012 and July 2015. Patients attending the gastroenterology out-patient clinic who fulfilled the Rome II criteria for IBS-D were eligible for inclusion. Celiac disease was excluded based on negative serology and normal duodenal biopsy. Individuals with self-reported gluten sensitivity; those already on a GFD; and those with other medical conditions known to mimic IBS-D were also excluded. Seventy eight participants were selected as eligible to take part in the study, of these 48 patients agreed to enrol (24 HLA-DQ2/8+ve and 24 HLA- DQ2/8-ve). Subjects were referred to 1 of 2 senior dietitians who provided uniform information on how to undertake a GFD. Subjects were also given validated questionnaires to self-complete the day before commencing a GFD and during the GFD period, these included the IBS Symptom Severity Score (IBS-SSS), Hospital Anxiety and Depression Scale (HADS), Fatigue Impact Score (FIS), and Short-form 36 (SF-36) quality of life questionnaire. Seven subjects dropped out of the study (4 did not attend their initial dietitian appointment; 1 became pregnant; 1 started an additional diet; and 1 felt the GFD was too expensive). Those subjects remaining (21 HLA-DQ –ve; 20 HLA DQ +ve) were instructed to follow a GFD for 6 weeks, after which they returned for a follow-up appointment with the dietitians and returned their questionnaires. Dietary adherence was evaluated using a simple, validated tool. Patients were also asked if they intended to continue with a GFD for the foreseeable future. For those that answered yes, a follow-up dietitian appointment was arranged for approximately 18 months time. Importantly, both dietitians and patients were blinded to the fact that HLA-DQ2/8 status was being used as a comparative factor within the study.
Following the 6-week GFD, a reduction of IBS-SSS of ≥50 points (indicating clinical benefit) was seen in 71% of patients, there was no difference between HLA-DQ groups. A significant symptom reduction was seen as early as week 2 and this continued to drop between each interval at week 4 and week 6. The greatest improvements were seen in those who had the severest IBS scores at baseline. In terms of IBS subscales, a significant mean reduction in abdominal pain, pain frequency, stool dissatisfaction and life interferences was observed in both HLA-DQ subgroups, with no difference between groups. However HLA-DQDQ2/8-ve subjects showed a greater reduction in abdominal distension compared with HLA-DQ2/8+ve subjects (p=0.04). A significant improvement in HADS, FIS and SF-36 quality of life was also observed following a GFD, seen across both groups. However HLA-DQ2/8+ve patients experienced a significantly greater improvement in depression (p=0.02) and vitality (p=0.03) compared with the HLA-DQ2/8-ve group. At the end of the 6-week intervention, 72% of IBS-SS responders planned to continue to follow a GFD for the foreseeable future (11 HLA-DQ2/8+ve and 10 HLA-DQ2/8-ve). When these patients were contacted on average 18 months later, all were still following a GFD with a good level of adherence and reported ongoing symptom improvement without any alterations in body mass index or biochemical status (compared to baseline).
The results of this study demonstrate that a dietitian-led GFD should be considered as a therapeutic option for the management of patients with IBS-D who are previously naïve to the effects of gluten. The strengths of this study lie in it’s rigorously defined cohort, in which CD was excluded and patients and dietitians were blinded to the fact that HLA-DQ2/8 status was being used as a comparative factor. This study also demonstrates a real-life situation in which patients were provided with a single dietetic consultation and then left to follow the GFD themselves, rather than being provided with all meals in a heavily controlled research environment. The limitations of the study include the placebo-effect of undertaking a dietary trial, however this is unlikely to account fully for the 71% response rate observed, particularly in view of the fact that well-being was maintained at 18 months. The authors of this study speculate that the patho-physiological mechanisms resulting in symptom reduction for IBS-D patients treated with a GFD may differ according to HLA-DQ status, and this is worthy of further mechanistic exploration.
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