1.
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
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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.
2.
The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study.
Paterson, BM, Lammers, KM, Arrieta, MC, Fasano, A, Meddings, JB
Alimentary pharmacology & therapeutics. 2007;26(5):757-66
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In a healthy gut, intestinal epithelial cells, with their tight junctions, allow controlled passage of gluten and other fragments. When integrity of this system is compromised, as in celiac disease (CD), an inappropriate immune response to environmental antigens (i.e. gluten) develops. This is called hyper-intestinal permeability or 'leaky gut'. AT-1001 is a protein derived from a Gram-negative bacteria called Vibrio cholera. AT-1001 inhibits leaky gut and appears to have an impact on autoimmunity, making it a potential candidate for the treatment of CD. This double-blind, randomised placebo controlled study aims to determine the safety and tolerability of 12 mg doses of AT-1001 in CD subjects challenged with gluten. Intestinal permeability (IP) (measured urinary lactulose-to-mannitol) is used as a measure of drug efficacy. Male and female in-patients (n=20) aged 18-59y with diagnosed CD, on gluten-free diets for 6 months+ were, on days 1 and 3, treated with 12mg AT-1001 or placebo, followed by a sham gluten challenge, followed by the intestinal permeability measure. On day 2 the sham gluten was replaced by gluten. Puddings (containing sham or gluten) were served to all participants by kitchen staff in singe-blind fashion. For day 2 to day 1 IP change, there was a 70% increase in IP in the placebo group (P = 0.041) and no increase in the drug group, confirming the effects of gluten exposure on IP and the protective effects of AT-1001. Adverse events were mild (n=49) or moderate (n=3). Both groups experienced diarrhoea (an expected symptom in CD patients after exposure to gluten) but the AT-1001 treated volunteers reported less diarrhoea than placebo (P=0.017) suggesting a protective effect for AT-1001. This data demonstrate that 12 mg AT-1001 was generally safe, well tolerated and effectively mitigated gluten-induced GI adverse effects in coeliac patients when compared to placebo. Interferon (IFN)-γ (a marker of immune activity after acute dietary gluten) increased on day 3 in both the placebo group and AT-1001 group, but less so in the AT-1001 group though the difference was not statistically significant (likely due to small sample size). AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure. Larger studies are required to further elucidate the effects of AT-1001.
Abstract
BACKGROUND Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae. AIM: To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten. METHODS An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy. RESULTS Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018). CONCLUSIONS AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.
3.
Insulin-like growth factor I response during nutritional rehabilitation of persistent diarrhoea.
Bhutta, ZA, Bang, P, Karlsson, E, Hagenäs, L, Nizami, SQ, Söder, O
Archives of disease in childhood. 1999;80(5):438-42
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Persistent diarrhoea in childhood causes severe malnutrition, and morbidity in 15%+ cases. Treatment includes nutritional rehabilitation for weight gain and diarrheal recovery. This study evaluates nutritional recovery (defined as weight gain (> 5 g/kg/day) with a resolution of diarrhea by day 7 of treatment), intestinal permeability and insulin-like growth factor I (IGF-I) response in malnourished children with faltering growth (aged 6-36 months) with persistent diarrhoea ((>/= 14 days) and their relation to concomitant systemic infection(s) (as indicated by serum C reactive protein (CRP)). For a minimum of 7 days, 63 children were fed a previously validated dietary regimen (data not available) of rice–lentil (khitchri) and yogurt aimed at providing at least 100 kcal/kg/day by day 3, with ad libitum feeds thereafter. Children were nursed on a research ward throughout. 49 children were treatment successes. They had a significant increase in serum IGF-I and IGF-I% correlated with weight gain. 14 children did not meet the criteria for nutritional recovery. They had higher serum CRP concentrations and sepsis at admission. They had lower mean (SD) weight gain in spite of overall mean energy intake being comparable with treatment successes. This may indicate malabsoption. Admission CRP concentration and IGF-I were negatively correlated. CRP concentrations at admission and corresponding individual IGF-I values over the 7 days treatment were significantly correlated. Significantly raised CRP concentrations in children with a correspondingly low IGF-I response may indicate a continued inflammatory or infected state in these children. Small but opposing trends of urinary excretion of the oral lactulose dose were seen in both groups over the seven days of treatment, indicating worsening enteropathy (mucosal injury) among treatment failures. None of the permeability parameters correlated with IGF-I at baseline or recovery. The study confirms that a traditional rice–lentil (khitchri) and yogurt diet can be used successfully for enteral nutritional rehabilitation in malnourished children with persistent diarrhoea and leads to adequate weight gain; Serum IGF-I levels correlates closely with weight gain and reduction in stool output; recovery is delayed with sepsis and raised blood CRP concentrations at admission; IGF-I is depressed at admission in children with persistent diarrhoea. The data provide evidence that serum IGF-I response in recovering malnourished children with persistent diarrhoea may provide a sensitive measure of nutritional and diarrhoeal recovery. Further studies are needed to evaluate factors regulating the IGF-I response in such children, especially the effect of intercurrent infections. Arbitrary definition of treatment failure is a study limitation.
Abstract
OBJECTIVE Evaluation of nutritional recovery, intestinal permeability, and insulin-like growth factor I (IGF-I) response in malnourished children with persistent diarrhoea and their relation to concomitant systemic infection(s). STUDY DESIGN Open study of severely malnourished children (aged 6-36 months) with persistent diarrhoea (≥ 14 days) admitted for nutritional rehabilitation with a standardised rice-lentil and yogurt diet. Successful recovery was defined prospectively as overall weight gain (> 5 g/kg/day) with a reduction in stool output by day 7 of treatment. Data on coexisting infections and serum C reactive protein (CRP) were collected at admission. RESULTS Of 63 children, 48 (group A) recovered within seven days of dietary treatment. These children had a significant increase in serum IGF-I (DeltaIGF-I%) and, in contrast to serum prealbumin and retinol binding protein, DeltaIGF-I% correlated with weight gain (r = 0.41). There was no correlation between the IGF-I response and intestinal permeability as assessed by urinary lactulose/rhamnose excretion. Treatment failures (group B) included more children with clinical (relative risk, 4.8; 95% confidence interval, 1.2 to 19.7) and culture proven sepsis at admission and higher concentrations of serum CRP (median (range), 36 (0-182) v 10 (0-240) mg/l) at admission. There was a negative correlation between admission CRP concentration and DeltaIGF-I% (r = -0.45). CONCLUSIONS In comparison with serum albumin, prealbumin, and retinol binding protein, serum IGF-I increment is a better marker of nutritional recovery in malnourished children with persistent diarrhoea. The possible association of systemic infections, serum IGF-I response, and mucosal recovery needs evaluation in future studies.
4.
[Nursing and organizational development].
Donnenberg, OH, Locher, K
Tijdschrift voor ziekenverpleging. 1986;39(1):18-22
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 and colonic barrier functions. 45 patients were recruited from the Mayo clinic’s database of IBS suffers, and invited to participate. Patients with diagnosed CD were excluded. 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 was seen. This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive. There was no significant dietary effect on daily stool form, ease of passage or gastric emptying. The GCD was associated with higher small bowel permeability and lactulose:mannitol ratio. Small bowel permeability was greater in HLA-DQ2/8–positive than negative patients. No significant differences in colonic permeability were observed. The author concludes that this study provides 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.