-
1.
Randomised clinical trial: pregabalin vs placebo for irritable bowel syndrome.
Saito, YA, Almazar, AE, Tilkes, KE, Choung, RS, Van Norstrand, MD, Schleck, CD, Zinsmeister, AR, Talley, NJ
Alimentary pharmacology & therapeutics. 2019;(4):389-397
-
-
Free full text
-
Abstract
BACKGROUND Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. AIM: To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. METHODS A double-blind, placebo-controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9-12. An intention-to-treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi-squared test. RESULTS Eighty-five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS-D, 29 (35%) IBS-M, 18 (21%) IBS-C. The pregabalin arm had lower average pain-BSS scores weeks 9-12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea-BSS and bloating-BSS scores (P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation-BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline (P = 0.10). Post-treatment IBS-QoL scores did not differ between groups. CONCLUSION This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.
-
2.
Effects of Antidepressants on Gastric Function in Patients with Functional Dyspepsia.
Lacy, BE, Saito, YA, Camilleri, M, Bouras, E, DiBaise, JK, Herrick, LM, Szarka, LA, Tilkes, K, Zinsmeister, AR, Talley, NJ
The American journal of gastroenterology. 2018;(2):216-224
Abstract
BACKGROUND Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood. AIMS Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology. METHODS This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS). RESULTS In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02). CONCLUSIONS Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.
-
3.
Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial.
Halawi, H, Khemani, D, Eckert, D, O'Neill, J, Kadouh, H, Grothe, K, Clark, MM, Burton, DD, Vella, A, Acosta, A, et al
The lancet. Gastroenterology & hepatology. 2017;(12):890-899
Abstract
BACKGROUND Liraglutide, a long-acting GLP-1 receptor agonist, is approved for treatment of obesity; however, the mechanisms of action of liraglutide are incompletely understood. We compared effects of liraglutide versus placebo on gastric motor functions, satiation, satiety, and weight in obese individuals over 16 weeks. METHODS We did a randomised, double-blind, placebo-controlled pilot trial at a single centre (Mayo Clinic, Rochester, MN, USA). Participants were randomly allocated (1:1) by a computer generated randomisation schedule with no stratification to receive subcutaneous liraglutide (3·0 mg) or placebo, with standardised nutritional and behavioural counselling. Allocation was concealed from participants and study investigators. Otherwise healthy, local residents aged 18-65 years with body-mass index (BMI) 30 kg/m2 or higher were included. Liraglutide or placebo was escalated by 0·6 mg/day each week for 5 weeks and continued until week 16. The primary outcome was change in gastric emptying (delay relative to baseline) of solids T1/2 (time taken for half the radiolabelled meal to empty from the stomach), measured at 5 weeks and 16 weeks in all patients who received at least one dose of study drug, with missing data imputed. Secondary outcomes included weight loss at weeks 5 and 16, satiation (volume to fullness and maximum tolerated volume), satiety, and fasting and postprandial gastric volumes at 16 weeks. This trial is registered with ClinicalTrials.gov, number NCT02647944, and is closed to new participants. FINDINGS Between Dec 18, 2015, and Sept 1, 2016, 40 adults were enrolled and randomly allocated (19 to the liraglutide group; 21 to the placebo group). Compared with placebo, liraglutide delayed gastric emptying of solids at 5 weeks (median 70 min [IQR 32 to 151] vs 4 min [-21 to 18]; p<0·0001) and 16 weeks (30·5 min [-11 to 54] vs -1 min [-19 to 7]; p=0·025). There was also significantly greater weight loss in the liraglutide group than in the placebo group (at 5 weeks: median 3·7 kg [IQR 2·8 to 4·8] vs 0·6 kg [-0·3 to 1·4], p<0·0001; at 16 weeks: 5·3 kg [5·2 to 6·8] vs 2·5 kg [0·1 to 4·2], p=0·0009). Satiation, as assessed by maximum tolerated volume at 16 weeks, was lower in the liraglutide group (median 750 mL [IQR 651 to 908]) compared with the placebo group (1126 mL [944-1185]; p=0·054). No significant differences were noted between groups in terms of volume to fullness, satiety, or fasting and postprandial gastric volumes at week 16. Post-hoc analysis showed that the T1/2 of gastric emptying of solids at 5 weeks correlated with change in weight loss at week 16 with liraglutide (Rs 0·567, p=0·018). Nausea was the most common adverse event in the liraglutide group (12 of 19) compared with placebo (four of 21). INTERPRETATION Effects of liraglutide on weight loss are associated with delay in gastric emptying of solids; measurement of gastric emptying (eg, at 5 weeks of treatment) may be a biomarker of responsiveness and may help to select individuals for prolonged treatment with this class of drug. FUNDING US National Institutes of Health grant R56-DK67071.
-
4.
Polymorphisms of 5-HTT LPR and GNβ3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.
Saito, YA, Locke, GR, Almazar, AE, Bouras, EP, Howden, CW, Lacy, BE, DiBaise, JK, Prather, CM, Abraham, BP, El-Serag, HB, et al
The American journal of gastroenterology. 2017;(6):903-909
Abstract
OBJECTIVES The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNβ3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNβ3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. METHODS Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNβ3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. RESULTS GNβ3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNβ3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). CONCLUSIONS GNβ3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.
-
5.
Acute Effects of a Glucagon-Like Peptide 2 Analogue, Teduglutide, on Gastrointestinal Motor Function and Permeability in Adult Patients With Short Bowel Syndrome on Home Parenteral Nutrition.
Iturrino, J, Camilleri, M, Acosta, A, O'Neill, J, Burton, D, Edakkanambeth Varayil, J, Carlson, PJ, Zinsmeister, AR, Hurt, R
JPEN. Journal of parenteral and enteral nutrition. 2016;(8):1089-1095
Abstract
BACKGROUND Glucagon-like peptide 2 (GLP-2) agonists decrease the need for parenteral nutrition (PN) in short bowel syndrome (SBS); mechanisms evaluated to date have focused on the intestinotrophic effect of GLP-2 agonists such as increased absorptive capacity of the remnant intestine and increased citrulline levels. Other mechanisms may also play a role in effects of GLP-2 agonists. AIM: To measure effects of a GLP-2 agonist, teduglutide (TED), compared with placebo (PLA) on gastric emptying (GE), overall gut transit, fluid balance, intestinal monosaccharide absorption, and permeability in patients with SBS on home PN (HPN). MATERIALS AND METHODS In 8 adults with SBS on HPN, we compared daily subcutaneous TED (0.05 mg/kg) and PLA (crossover design, each treatment 7 days with a 14-day washout) on gut transit, intestinal absorption, and permeability after oral mannitol (200 mg) and lactulose (1 g), as well as stool weight and urine volume over 8 hours. Analysis used the paired t test. RESULTS Of 8 patients, 4 were men, with a mean ± SD age of 54 ± 1 years, body mass index of 25 ± 4 kg/m2, residual small intestine of 63 ± 12 cm, and 25% ± 15% of residual colon. The overall gut transit (% emptied at 6 hours) was 53.4% ± 15% for TED vs 62.4% ± 15.2% for PLA (P = .075), with no effect on GE (P = .74). TED increased urine mannitol excretion at 0-2 hours (16.2 ± 3.6 mg TED vs 11.3 ± 2.2 mg PLA, P = .20) and 0-8 hours (32.7 ± 5.9 mg PLA vs 48.8 ± 8.9 mg TED, P = .17). There were no differences in urine lactulose excretion or lactulose/mannitol ratio (0.024 ± 0.005 TED vs 0.021 ± 0.005 PLA). Over 8 hours, TED (vs PLA) numerically reduced stool weight (mean ± SEM, 77 ± 18 g TED vs 106 ± 43 g PLA, P = .42) and increased urine volume (408.9 ± 52.2 mL TED vs 365.7 ± 57.3 mL PLA, P = .34). CONCLUSION Seven-day TED treatment in 8 participants suggests beneficial effects on fluid balance and monosaccharide absorption, and it retarded overall gut transit with no effects on GE or mucosal permeability. Larger, longer, mechanistic studies of TED in SBS are warranted. This trial was registered at clinicaltrials.gov as NCT02099084.
-
6.
Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study.
Talley, NJ, Locke, GR, Saito, YA, Almazar, AE, Bouras, EP, Howden, CW, Lacy, BE, DiBaise, JK, Prather, CM, Abraham, BP, et al
Gastroenterology. 2015;(2):340-9.e2
-
-
Free full text
-
Abstract
BACKGROUND & AIMS Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 ± 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651.
-
7.
Delayed Gastric Emptying Is Associated With Early and Long-term Hyperglycemia in Type 1 Diabetes Mellitus.
Bharucha, AE, Batey-Schaefer, B, Cleary, PA, Murray, JA, Cowie, C, Lorenzi, G, Driscoll, M, Harth, J, Larkin, M, Christofi, M, et al
Gastroenterology. 2015;(2):330-9
-
-
Free full text
-
Abstract
BACKGROUND & AIMS After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to show persistent benefit of prior intensive therapy on neuropathy, retinopathy, and nephropathy in type 1 diabetes mellitus (DM). The relationship between control of glycemia and gastric emptying (GE) is unclear. METHODS We assessed GE with a (13)C-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and glycated hemoglobin (HbA1c), complications of DM, and gastrointestinal symptoms were evaluated. RESULTS GE was normal (37 participants; 50%), delayed (35 participants; 47%), or rapid (2 participants; 3%). The latest mean HbA1c was 7.7%. In univariate analyses, delayed GE was associated with greater DCCT baseline HbA1c and duration of DM before DCCT (P ≤ .04), greater mean HbA1c over an average of 27 years of follow-up evaluation (during DCCT-EDIC, P = .01), lower R-R variability during deep breathing (P = .03) and severe nephropathy (P = .05), and a greater composite upper gastrointestinal symptom score (P < .05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3) and duration of DM (OR, 1.2; 95% CI, 1.01-1.3) before DCCT entry and mean HbA1c during DCCT-EDIC (OR, 2.2; 95% CI, 1.04-4.5) were associated independently with delayed GE. CONCLUSIONS In the DCCT/EDIC study, delayed GE was remarkably common and associated with gastrointestinal symptoms and with measures of early and long-term hyperglycemia. ClinicalTrials.gov numbers NCT00360815 and NCT00360893.
-
8.
Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy.
Acosta, A, Camilleri, M, Shin, A, Vazquez-Roque, MI, Iturrino, J, Burton, D, O'Neill, J, Eckert, D, Zinsmeister, AR
Gastroenterology. 2015;(3):537-546.e4
-
-
Free full text
-
Abstract
BACKGROUND & AIMS Weight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy. METHODS In a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations betwecen a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof of concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients to validate associations between quantitative traits and response to weight-loss therapy. RESULTS In the prospective study, obesity was associated with fasting gastric volume (P = .03), accelerated gastric emptying (P < .001 for solids and P = .011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P = .003), and higher postprandial levels of glucagon-like peptide 1 (P < .001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n = 509; P = .038) and satiety with abnormal waist circumference (n = 271; P = .016). Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed gastric emptying, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test. CONCLUSIONS Quantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof of concept clinical trial, predicted response to pharmacotherapy for obesity. ClinicalTrials.gov Number: NCT01834404.
-
9.
A randomised controlled study of the effect of cholinesterase inhibition on colon function in patients with diabetes mellitus and constipation.
Bharucha, AE, Low, P, Camilleri, M, Veil, E, Burton, D, Kudva, Y, Shah, P, Gehrking, T, Zinsmeister, AR
Gut. 2013;(5):708-15
-
-
Free full text
-
Abstract
OBJECTIVES Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. This study evaluated the effects of a cholinesterase inhibitor on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. DESIGN After a 9-day baseline period, 30 patients (mean ± SEM age 50 ± 2 years) with diabetes mellitus (18 type 1, 12 type 2) and chronic constipation without defaecatory disorder were randomised to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose or 120 mg three times a day; this dose was maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function were evaluated at baseline and the final 3 and 7 days of treatment, respectively. Treatment effects were compared using analysis of covariance, with gender, body mass index and baseline colonic transit as covariates. RESULTS 19 patients (63%) had moderate or severe autonomic dysfunction; 16 (53%) had diabetic retinopathy. 14 of 16 patients randomised to pyridostigmine tolerated 360 mg daily; two patients took 180 mg daily. Compared with placebo (mean ± SEM 1.98 ± 0.17 (baseline), 1.84 ± 0.16 (treatment)), pyridostigmine accelerated (1.96 ± 0.18 (baseline), 2.45 ± 0.2 units (treatment), p<0.01) overall colonic transit at 24 h, but not gastric emptying or small-intestinal transit. Treatment effects on stool frequency, consistency and ease of passage were significant (p ≤ 0.04). Cholinergic side effects were somewhat more common with pyridostigmine (p=0.14) than with placebo. CONCLUSIONS Cholinesterase inhibition with oral pyridostigmine accelerates colonic transit and improves bowel function in diabetic patients with chronic constipation.
-
10.
A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
Vazquez-Roque, MI, Camilleri, M, Smyrk, T, Murray, JA, Marietta, E, O'Neill, J, Carlson, P, Lamsam, J, Janzow, D, Eckert, D, et al
Gastroenterology. 2013;144(5):903-911.e3
-
-
-
Free full text
-
Plain language summary
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 (SB) and colonic barrier functions as measured by two-sugar excretion permeability test and mRNA expression of TJ proteins in mucosa of the small bowel (SB) and rectosigmoid (RS) derived by biopsy. Immune response to diets was also measured as cytokine production from peripheral blood mononuclear cells (PBMCs). Patient were recruited from the Mayo clinic’s database of IBS suffers, and invited to participate. Patients with diagnosed CD were excluded. Genotype analysis was performed for HLA-DQ2 and HLA-DQ8. 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 (p=0.04) was seen. This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive (p=0.019) There was no significant diet effect (GFD vs. GCD) on, daily stool form, ease of passage or gastric emptying. The GCD was associated with higher small bowel (SB) permeability (based on 0–2 hr levels of mannitol (p=0.028) and lactulose:mannitol ratio (P=0.0012)). SB permeability was greater in HLA-DQ2/8–positive than −negative patients (P=.018). No significant differences in colonic permeability were observed. Significant diet-associated changes in occludin expression in SB mucosa in the HLA-DQ2 or 8 positive group were seen (p=0.017). Expressions of tight junction proteins (zonulin (ZO-1), occludin, and claudin-1 mRNA) in colonic mucosa were significantly lower in GCD relative to GFD in the overall groups, particularly in subjects with HLA-DQ2 or 8 positive status. Cytokine response was higher (interleukin-10) in response to GCD than GFD (unrelated to HLA genotype). A limitation in the quantification of TJ protein expression is that it was solely based on PCR (mRNA expression). In future, other methods should be included to directly identify these proteins and their distribution. The inability to document alterations in colonic permeability using the 2-sugar excretion profile from 8 to 24 hours is a limitation. This may be due to lack of sensitivity of the lactulose and mannitol excretion test, for example, due to the metabolism of both sugars by colonic bacteria. Another limitation is that the mechanism for improvement in stool frequency on a GFD in the absence of changes in colonic transit was not elucidated by our studies. This study does not specifically address the effects of gluten protein per se, and it is possible that other proteins in wheat flour may be responsible for the changes observed. The author concludes that this study provide 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.
Abstract
BACKGROUND & AIMS Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). METHODS We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups. RESULTS Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0-2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8-positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype). CONCLUSIONS Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8-positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.govNCT01094041.