Irritable bowel syndrome-diarrhea: the role of gluten intolerance and HLA-DQ2

Summary

Principal Investigator: MICHAEL L CAMILLERI
Abstract: DESCRIPTION (provided by applicant): This application addresses broad Challenge Area CLINICAL RESEARCH and specific Challenge Topic, 04-DK-103: Develop Novel Approaches to Understand and Treat Functional Disorders. In this application, we plan to determine the role of diet in the development of functional GI and motility disorders and how genotype contributes to the development of functional GI and motility disorders. The genotype of interest is the mixed histocompatibility complex, HLA. There is epidemiological evidence of significant overlap between irritable bowel syndrome (IBS) and functional chronic diarrhea [FD (Locke et al 2005)]. The relationship of celiac disease and IBS is complex;while guidelines suggest screening for celiac disease in patients with FD or IBS with diarrhea (IBS-D), there is a paucity of evidence to support that recommendation. In Olmsted Co., MN, overall prevalence of positive tissue transglutaminase serology was 4%, and celiac disease did not explain the presence of either IBS or dyspepsia (Locke et al 2004). In a cost effectiveness analysis, testing for celiac disease became the dominant strategy when prevalence was >8%, specificity of the test for celiac disease was >98%, or the cost of IBS treatment exceeded $130/month (Spiegel BM, et al 2004). In fact, the incremental cost of testing for celiac disease exceeded $50,000 when the prevalence fell below 1%. Community studies suggest that celiac disease affects 0.5 to 1.0% of people in the USA. On the other hand, there is increasing recognition of a potential role of intolerance to gluten in patients with IBS-D or FD. Gluten intolerance without celiac disease was first popularized as a clinical entity in 1981 (Cooper BT et al 1981). However, until recently, there have been very limited investigations of the role of gluten intolerance as a factor contributing to IBS-D or FD. Wahnschaffe et al demonstrated that, among patients with IBS-D or FD, response of diarrhea to GFD was influenced by the HLA type and the presence of IgG tissue transglutaminase antibody: for HLA DQ 2 +ve, IgG TGA +ve, the response to gluten withdrawal occurred in 62%;conversely, in those DQ 2 -ve and IgG TGA -ve, 12% responded (Wahnschaffe et al 2007). This suggests that there is an immunogenetic predisposition to gluten intolerance among patients with IBS-D or FD in the absence of celiac disease. The mechanisms underlying this intolerance of gluten in humans with IBS are unclear. In HLA-D8 transgenic mice sensitized to gluten, gliadin exposure (in contrast to negative and positive controls) results in CD3, CD4 lymphocyte and macrophage infiltration of villi, and increased contractile responses of smooth muscle to electrical field stimulation and carbachol (Verdu et al 2008). This contractile activity may be a mechanism for the development of diarrhea. The link between gluten or gliadin and inflammation may be the increase in intestinal permeability, which is well established in celiac disease and involves binding to the chemokine receptor, CXCR3, leading to MyD88-dependent zonulin release (Lammers et al 2008). It is still unclear whether gluten alters permeability in the absence of celiac disease. On the other hand, there are reports of increased mucosal permeability in IBS, both non-infectious and post-infectious varieties, that typically causes IBS-D (Dunlop et al 2006). Our overall hypothesis is that gluten intake increases intestinal permeability in susceptible patients and leads to alterations in gastrointestinal function that manifest as IBS-D or chronic diarrhea. Our overall aim is to understand the mechanism of gluten-induced symptoms in patients with symptoms suggestive of IBS-D or FD, and optimize treatment of these patients. We propose to test the following: Specific hypotheses: 1. IBS-D or FD patients who are HLA-DQ2 positive have higher small intestinal and colonic permeability than HLA-DQ2 negative patients. 2. Gluten supplementation for four weeks increases small intestinal permeability and accelerates colonic transit in patients with IBS-D or FD who are HLA-DQ2 positive. Specific aims: 1. To compare small intestinal and colonic permeability in patients with IBS-D or FD who are positive or negative for HLA-DQ2. 2. To compare in a parallel-group, randomized, controlled trial, the effect of gluten-rich versus gluten-free diet on small intestinal and colonic permeability, small bowel and colonic mucosal morphology, and gastrointestinal and colonic transit in HLA-DQ2 positive and HLA-DQ2 negative patients with IBS-D or FD. PUBLIC HEALTH RELEVANCE: This application addresses the Challenge Area of Clinical Research in Digestive Diseases and the development of novel approaches to understand and treat functional GI and motility disorders. The application focuses specifically on the role of gluten (a protein in flour) diet and patients'genetic make-up in the development of chronic diarrhea and irritable bowel syndrome (IBS) with diarrhea, and how gluten free diet normalizes intestinal functions and bowel movements.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Genetics of human gastrointestinal sensation
    M Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research C E N T E R, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 25:458-66. 2013
  2. pmc A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function
    Maria I Vazquez-Roque
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, USA
    Gastroenterology 144:903-911.e3. 2013
  3. pmc Functions and imaging of mast cell and neural axis of the gut
    Michael Schemann
    Human Biology, Technische Universitat Munchen, Freising, Germany
    Gastroenterology 144:698-704.e4. 2013
  4. pmc Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea
    Maria I Vazquez-Roque
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Charlton 8 110, 200 First St SW, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 303:G1262-9. 2012
  5. pmc Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea
    Banny S Wong
    Clinical Enteric Neuroscience Translational and Epidemiological Research C E N T E R, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Clin Gastroenterol Hepatol 10:1009-15.e3. 2012
  6. pmc Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation
    Sara Nullens
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Gut 61:1132-9. 2012
  7. pmc Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls
    Archana S Rao
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Am J Physiol Gastrointest Liver Physiol 301:G919-28. 2011
  8. pmc Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders
    M Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Neurogastroenterol Motil 23:995-9, e458. 2011
  9. pmc Brain-gut axis: from basic understanding to treatment of IBS and related disorders
    Michael Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    J Pediatr Gastroenterol Nutr 54:446-53. 2012
  10. pmc Methods for the assessment of small-bowel and colonic transit
    Lawrence A Szarka
    Clinical Enteric Neuroscience Translational and Epidemiological Research CENTER, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Semin Nucl Med 42:113-23. 2012

Scientific Experts

  • MICHAEL L CAMILLERI
  • Alan R Zinsmeister
  • Maria I Vazquez-Roque
  • Duane Burton
  • Paula Carlson
  • Banny S Wong
  • Jesse Lamsam
  • Archana S Rao
  • Sanna McKinzie
  • Deborah Eckert
  • Joseph A Murray
  • Johanna Iturrino
  • Irene Busciglio
  • Michael Ryks
  • Michael Schemann
  • Jessica O'Neill
  • Denise Janzow
  • Thomas Smyrk
  • Sara Nullens
  • Lawrence A Szarka
  • J Iturrino
  • A R Zinsmeister
  • D Burton
  • M Breen
  • Marco Zucchelli
  • Duane D Burton
  • Ravinder Singh
  • Eric Marietta
  • Tyler Nelsen
  • Maria Vazquez-Roque
  • Olga Bondar
  • I Busciglio
  • Roy B Dyer
  • Deborah Rhoten
  • Richard H Duerr
  • Deborah J Eckert
  • Tricia L Brantner
  • Leif Torkvist
  • Pontus Karling
  • Francesca Bresso
  • Gregory J Gores
  • Lars Agreus
  • Bodil Ohlsson
  • Magnus Simren
  • Anna Nixon Andreasson
  • Peter T Schmidt
  • Aldona Dlugosz
  • Paula J Carlson
  • Jonas Halfvarson
  • Greger Lindberg
  • Mauro D'Amato
  • Maria E Guicciardi
  • Suwebatu T Odunsi-Shiyanbade

Detail Information

Publications24

  1. pmc Genetics of human gastrointestinal sensation
    M Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research C E N T E R, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 25:458-66. 2013
    ..The objective was to review the genetics of human visceral pain with particular emphasis on pain associated with irritable bowel syndrome...
  2. pmc A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function
    Maria I Vazquez-Roque
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, USA
    Gastroenterology 144:903-911.e3. 2013
    ..Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD)...
  3. pmc Functions and imaging of mast cell and neural axis of the gut
    Michael Schemann
    Human Biology, Technische Universitat Munchen, Freising, Germany
    Gastroenterology 144:698-704.e4. 2013
    ..Studies of motility and functional gastrointestinal disorders would be feasible without the need for full-thickness biopsy...
  4. pmc Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea
    Maria I Vazquez-Roque
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Charlton 8 110, 200 First St SW, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 303:G1262-9. 2012
    ....
  5. pmc Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea
    Banny S Wong
    Clinical Enteric Neuroscience Translational and Epidemiological Research C E N T E R, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Clin Gastroenterol Hepatol 10:1009-15.e3. 2012
    ..We investigated features of BA synthesis and excretion and genetic features of patients with different types of IBS...
  6. pmc Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation
    Sara Nullens
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Gut 61:1132-9. 2012
    ..To differentiate dys-synergic defaecation (DD) from normal function and slow transit constipation (STC)...
  7. pmc Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls
    Archana S Rao
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Am J Physiol Gastrointest Liver Physiol 301:G919-28. 2011
    ..Urine sugars at 0-2 h and 8-24 h reflect SB and colonic permeability, respectively. IBS-D is associated with increased SB and colonic mucosal permeability...
  8. pmc Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders
    M Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Neurogastroenterol Motil 23:995-9, e458. 2011
    ..Our aim was to assess the association of genetic variation in TGR5 and small bowel transit (SBT) and colonic transit...
  9. pmc Brain-gut axis: from basic understanding to treatment of IBS and related disorders
    Michael Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    J Pediatr Gastroenterol Nutr 54:446-53. 2012
    ..The criteria are similar in children and adults. The focus of the present review is the bowel dysfunction associated with IBS...
  10. pmc Methods for the assessment of small-bowel and colonic transit
    Lawrence A Szarka
    Clinical Enteric Neuroscience Translational and Epidemiological Research CENTER, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Semin Nucl Med 42:113-23. 2012
    ..New approaches include experimental stable isotope measurement of orocecal transit and the recently approved method using a wireless motility capsule that is validated as an accurate measurement of small-bowel and colonic transit...
  11. pmc Sensations of gas and pain and their relationship with compliance during distension in human colon
    J Iturrino
    Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 24:646-51, e275. 2012
    ..Our aim was to analyze the relationships of gas and pain sensations during graded distensions, and the association of sensations with colonic compliance in conscious humans...
  12. pmc Genetic susceptibility to inflammation and colonic transit in lower functional gastrointestinal disorders: preliminary analysis
    M Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research CENTER, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:935-e398. 2011
    ..Our aim was to preliminarily assess association between 30 susceptibility loci for CD, three genes associated with PI-IBS, and PARM1, with colonic transit in lower functional gastrointestinal disorders (FGID)...
  13. pmc Association of TNFSF15 polymorphism with irritable bowel syndrome
    Marco Zucchelli
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
    Gut 60:1671-7. 2011
    ..This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS...
  14. pmc Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis
    Archana S Rao
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Gastroenterology 139:1549-58, 1558.e1. 2010
    ..Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C)...
  15. pmc Behavioural and new pharmacological treatments for constipation: getting the balance right
    Michael Camilleri
    Mayo Clinic, Charlton 8 110, 200 First St S W, Rochester, MN 55905, USA
    Gut 59:1288-96. 2010
    ....
  16. pmc LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin
    M Camilleri
    Clinical Enteric Neuroscience Translational and Epidemiological Research CENTER, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:193-200. 2011
    ....
  17. pmc Performance characteristics of the measurement of gastric volume using single photon emission computed tomography
    M Breen
    Clinical Enteric Neuroscience Translational and Epidemiological Research CENTER, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:308-15. 2011
    ..The natural variation in gastric volume responses and performance characteristics of SPECT imaging are unclear...
  18. pmc A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea
    Banny S Wong
    Division of Gastroenterology and Hepatology, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
    Gastroenterology 140:1934-42. 2011
    ..We hypothesized that variants of genes regulating hepatic BA synthesis play a role in IBS-D...
  19. pmc HLA-DQ genotype is associated with accelerated small bowel transit in patients with diarrhea-predominant irritable bowel syndrome
    Maria I Vazquez-Roque
    Clinical Enteric Neuroscience Translational and Epidemiological Research C E N T E R, Mayo Clinic, Rochester, Minnesota 55905, USA
    Eur J Gastroenterol Hepatol 23:481-7. 2011
    ..Improvement in IBS-D with gluten withdrawal is associated with human leukocyte antigen (HLA)-DQ2 positivity; the mechanism of improvement is unclear...
  20. pmc Effect of the α2δ ligand, pregabalin, on colonic sensory and motor functions in healthy adults
    Johanna Iturrino
    Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
    Am J Physiol Gastrointest Liver Physiol 301:G377-84. 2011
    ..Pregabalin did not significantly affect colonic compliance, sensation thresholds, colonic fasting tone, and MI. Thus 200 mg of pregabalin reduces gas and pain sensation and should be tested in patients with colonic pain...