William D. Chey, MD, FACG. Page 1 of ACG Midwest Regional Postgraduate Course Copyright 2016 American College of Gastroenterology

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1 Dietary and Other Non-pharmacological Management of IBS William D. Chey, MD, FACG Nostrant Professor of Medicine Director GI Nutrition Program University of Michigan Peter Loftus, May 2, 2016 Page 1 of 14

2 IBS: Rome IV Criteria* Recurrent abdominal pain or discomfort at least 3 days/month 1 day per week associated with two or more of the following: Improvement with Related to defecation Onset associated with a change in the frequency of stool Onset associated with a change in the form of stool *Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Fermín Mearin et al. Gastroenterology. May 2016 IBS Subtypes Based on Stool Consistency * Bristol Stool Form Scale 1-2 Bristol Stool Form Scale IBS-C* IBS-M IBS-M = IBS-mixed IBS-U = unclassified IBS 25 IBS-U IBS-D Percentage of loose or watery stools Adapted from: Longstreth et al. Gastroenterology. 2006;130(5): Page 2 of 14

3 Does Food Cause IBS Symptoms? Why Do We Care About Food in IBS Patients? Proportion of UMHS patients (n=247) reporting at least moderate effects on the three IBS-QOL food related questions Nojkov B, et al DDW 2014 Page 3 of 14

4 Dietary restrictions are associated with reduced Quality of Life in IBS Patients Those with vs. those without diet restriction Multivariate linear regression model adjusting for age, gender, marital status, alcohol/tobacco use & education level Nojkov et al DDW 14 Dietary Interventions for IBS: What is the Evidence? Gluten-free Low-FODMAP Page 4 of 14

5 Non-Celiac Gluten Sensitivity or Wheat Sensitivity? Encompasses a collection of medical conditions in which gluten leads to an adverse effect True population prevalence is unknown Can be clinically indistinguishable from celiac disease but testing is negative or inconclusive Not associated with increased intestinal permeability Innate immunity markers TLR2 & FOXP3 altered in GS but not Celiac disease Improves with a gluten free diet Eswaren S et al. GI Cl North Am 2011;40:141 Sapone et al. BMC Medicine 2011;9:23 Ludvigsson et al. Gut 2012, online early Gluten Causes Symptoms in IBS Patients Without Celiac Disease Mean Change in Symptoms Over 6 Weeks P=0.047 Overall symptoms P=0.031 Bloating Gluten (n=19) Placebo (n=15) Week Pain Week Tiredness 40 P=0.02* 40 P=0.001* Week *P-value for analyses at Week 1 and entire study period. Reprint permission has been requested. Biesiekierski JR, et al. Am J Gastroenterol. 2011;106: Week Page 5 of 14

Effect of a GFD on Small Intestinal & Colonic Permeability by Mannitol Excretion in IBS-D Single center, parallel group 4 week RCT in 45 gluten ingesting IBS-D pts Cumulative urine mannitol, mg 180

6 Effect of a GFD on Small Intestinal & Colonic Permeability by Mannitol Excretion in IBS-D Single center, parallel group 4 week RCT in 45 gluten ingesting IBS-D pts Cumulative urine mannitol, mg GFD (n = 23) GCD (n = 22) 0 Pre Post Pre Post 0-2 hours 8-24 hours Effects pronounced in HLA DQ2/8 positive pts GCD associated with reduced ZO-1, occludin, claudin-1 mrna in colonic mucosa effect greater in HLA DQ 2/8 positives * * P =.028 Vazquez-Roque MI, et al. Gastroenterology 2013;144:903. Structure of a Wheat Kernel Gibson P, et al. Gastro 2015;148:1158 Page 6 of 14

7 Are Wheat Intolerance symptoms from Gluten or FODMAPs? 37 pts with NCWS and IBS Interventions: All pts received a low FODMAP diet for 2 weeks Then assigned to high gluten (16 g/d), low gluten (2 g/d), or control (16 g whey/d) x 1 week Serum and fecal biomarkers for intestinal inflammation/injury and immune activation No significant changes in biomarkers with diets FODMAP restriction led to symptom improvement No specific or dose dependent effects of gluten in patients on a low FODMAP diet were observed Biesiekierski JA et al Gastroenterol 2013;145:320 Proposed mechanisms of Non-celiac Wheat Sensitivity What s the big deal with Gluten TED Ed Spencer M, et al. Cur Tx Opt GI Page 7 of 14

8 What are FODMAPs? Fermentable oligo-, di-, monosaccharides and polyols Fruits with fructose exceeding glucose Apples, pears, watermelon Fructan-containing vegetables Onions, leeks, asparagus, artichokes Wheat-based products Bread, pasta, cereal, cake, biscuits Sorbitol and lactose-containing foods Raffinose-containing foods Legumes, lentils, cabbage, Brussels sprouts Eswaran & Chey, GI Cl North Am 2011;40:141 Shepherd, et al, Clin Gastro Hepatol 2008;6:765 Gibson & Shepherd. J Gastro Hepatol 2010;25:252 Osmotic Effects Spencer M, et al. Cur Tx Opt GI. 2014;12:424 Cognitive and Emotional Factors Page 8 of 14

9 Low FODMAP vs. mnice Diets for IBS-D: Adequate Relief 60% 50% 40% 41% p= % 30% 20% 10% 0% m-nice N=38 Low FODMAP N=45 In the last week, have you had adequate relief of your GI symptoms? Proportion of patients that answered Yes for 50% of weeks 3 and 4 Eswaran, Chey et al. AJG 2016, in press Weekly Abdominal Pain & Bloating Scores Average Daily Abdominal Pain Scores (0-10) Baseline Week 1 Week 2 Week 3 Week 4 m-nice Low FODMAP Average Daily Abdominal Bloating Score (0-10) # Baseline Week 1 Week 2 Week 3 Week 4 m-nice Low FODMAP * = p.05 = p.01 # = p.001 = p.0001 P values refer to the change WITHIN group comparing to baseline score Eswaran, Chey et al. AJG 2016, in press Page 9 of 14

10 LFD vs. mnice Diet: IBS-QOL Scores p< Mean Score p= p< Baseline Week 4 Baseline Week 4 m-nice Low FODMAP Eswaran, Chey et al. DDW 2016 LFD vs. mnice Diet: IBS-QOL Scores Proportion with Improvement from Baseline 10 Proportion with Improvement from Baseline 14 70% p = % 60% p = % 60% 50% 50% 40% 40% % 30% 27% % 30% 21% 20% 20% 10% 10% 0% m-nice Low FODMAP 0% m-nice Low FODMAP Minimal Important Response Meaningful Clinical Response Eswaran, Chey et al. DDW 2016 Page 10 of 14

11 Hypnotherapy vs. Low FODMAP Diet for IBS: Factorial RCT N=25 N=24 N=25 N=25 N=24 N=25 All IBS subgroups Primary outcome: Overall IBS symptoms (>20 mm improvement in VAS) Significant improvements compared to baseline but not between groups Improvements in trait anxiety and trait depression with hypnotherapy (STPI) Peters S, et al. Aliment Pharmacol Ther 2016; 44: 447 FODMAP Effects on the Microbiome Low FODMAP diet led to higher fecal ph (7.37 vs. 7.16; P=0.001). LFD and Australian diets led to similar SCFA levels LFD associated with increased microbial diversity and reduced total bacterial abundance (9.63 [ ] vs [ ] log 10 copies/g; P<0.001). The functional significance and health implications of such changes might lead to caution about reducing FODMAP intake in the longer term, Halmost et al. Gut 2015;64: Page 11 of 14

FODMAP Microbiome Biomarkers and Response to the Low-FODMAP Diet 33 children with IBS completed the study Less abdominal pain occurred during the low FODMAP diet vs.

eater saccharolytic metabolic capacity e.g.

12 FODMAP Microbiome Biomarkers and Response to the Low-FODMAP Diet 33 children with IBS completed the study Less abdominal pain occurred during the low FODMAP diet vs. typical US childhood diet Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii Responders also enriched at baseline for 3 Kyoto Encyclopedia of Genes and Genomes orthologues two relate to carbohydrate metabolism Chumpitazi et al. Aliment Pharmacol Ther 2015; 42: Low FODMAP vs. High FODMAP diet: Effects on the Metabolome Principal component analysis of urine metabolome on day 0 & day 21 p=0.77, R 2 =0.13, Q 2 =-0.62 p=0.0001, R 2 =0.63, Q 2 =0.33 Urine Histamine Levels P<0.05 McIntosh et al. Gut 2016, online early Page 12 of 14

& mobile apps can help patients to implement the Low FODMAP diet in a

A one page handout is NOT sufficient to implement the diet.

Bloating and abdominal pain are the most likely symptoms to respond.

The full Low FODMAP diet is NOT intended to last a lifetime.

13 Key Points about the Low FODMAP Diet Teaching is ideally provided with the assistance of a trained dietician. In the absence of a dietician, appropriately vetted books, web-based resources & mobile apps can help patients to implement the Low FODMAP diet in a medically responsible manner. A one page handout is NOT sufficient to implement the diet. A 2-4 week trial is usually sufficient to gauge clinical response. Bloating and abdominal pain are the most likely symptoms to respond. Diarrhea is more likely to improve than constipation. The full Low FODMAP diet is NOT intended to last a lifetime. Responders should be instructed to implement a stepwise reintroduction of foods containing individual FODMAPs to identify triggers and allow diversification of their diet. The Low FODMAP diet is NOT intended for persons who do not experience gastrointestinal symptoms Chey. Am J Gastroenterol 2016 Page 13 of 14

Summary Food can affect GI function and sensation resulting in GI

diarrhea Emerging evidence supports a primary role of diet in the

diet changes GFD and LFD are evidence based diet therapies

patients with GI disorders Center for GI Nutrition & Behavioral

14 Summary Food can affect GI function and sensation resulting in GI symptoms such as abdominal pain, cramping, bloating, urgency and diarrhea Emerging evidence supports a primary role of diet in the treatment of patients with IBS More than half of will improve with diet changes GFD and LFD are evidence based diet therapies Registered dieticians should play a prominent role in the care of patients with GI disorders Center for GI Nutrition & Behavioral Wellness Functional Bowel Disorders Clinic Page 14 of 14

New Insights into Functional Bowel Disorders. Diagnostic and Non medical Treatment Challenges in IBS

Presenter Disclosure Information 1:45 2:45pm New Insights into Functional Bowel Disorders The following relationships exist related to this presentation: William Chey, MD, AGAF, FACG, FACP, is a consultant