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

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1 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 and investigator for Ironwood, Prometheus, Nestle and Perrigo; and a consultant for Astra- Zeneca, Froest, Sucampo, Takeda, furiex, SK, Ferring and Entera. SPEAKER William D. Chey, MD Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. New Insights into Functional Bowel Disorders Diagnostic and Non medical Treatment Challenges in IBS William D. Chey, MD Professor of Medicine New Insights into Functional Bowel Disorders Learning Objectives Differentiate the signs and symptoms of functional bowel disorders Understand the mechanisms by which food can impact GI function and sensation Describe dietary interventions that are directed at improving IBS symptoms Rome III criteria for Irritable Bowel Disorder (IBS) IBS Subtypes Based on Stool Consistency 1 Recurrent abdominal pain or discomfort at least 3 days / month in the last 3 months associated with 2 or more of the following: 75 Bristol Stool Form Scale 1 2 Bristol Stool Form Scale IBS-C IBS-M IBS M = IBS mixed IBS U = unclassified IBS Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form of stool 25 IBS-U IBS-D Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Percentage of loose or watery stools Longstreth et al. Gastroenterology. 26;13(5): Adapted from: Longstreth et al. Gastroenterology. 26;13(5):

Alarm Features Requiring Further Work up History Unintentional weight loss (>1% IBW) Onset in older patient (>5 y) Family history of GI malignancy or IBD/celiac disease Rectal/Gl bleeding Recurrent

FOBT, fecal occult blood test; Hb, hemoglobin; IBD, irritable bowel disease; IBW, ideal body weight; TSH, thyroid stimulating hormone; WBC, white blood cells IBS: Diagnostic Pearls Black TP et al.

2 Alarm Features Requiring Further Work up History Unintentional weight loss (>1% IBW) Onset in older patient (>5 y) Family history of GI malignancy or IBD/celiac disease Rectal/Gl bleeding Recurrent nausea and vomiting Physical Exam Rectal bleeding/obstruction Positive FOBT Flexible sigmoidoscopy or colonoscopy Laboratory Tests Hb WBC CRP Abnormal chemistry Abnormal TSH CRP, C reactive protein; FOBT, fecal occult blood test; Hb, hemoglobin; IBD, irritable bowel disease; IBW, ideal body weight; TSH, thyroid stimulating hormone; WBC, white blood cells IBS: Diagnostic Pearls Black TP et al. J Gastrointestin Liver Dis. 212;21(2): Lacy BS et al. Therap Adv Gastroenterol. 29;2: Drossman DA et al. Gastroenterology. 1997;113: Camillieri M et al. Aliment Pharmacol Ther. 1997;11:3 15. Paterson WG et al. Can Med Assoc J. 1999;161: IBS Masqueraders: What are the Biggest Concerns? Celiac Disease Colorectal Cancer Inflammatory Bowel Disease Microscopic Colitis Biopsy Proven Celiac Disease in IBS vs. Controls Results from a Meta analysis 7.29 (1.65, 66.52) 4.49 (.97, 17.3) (1.9, ) 1.52 (.22, 16.93).67 (., 26.11) 4.34 (1.78, 1.58) Ford et al. Archives Int Med 29:169:651 IBS and Celiac Disease: US Data Case-control study IBS patients (physician diagnosis) Positive for both ttga and EMA Celiac disease not biopsy-proven Prospective study Non-constipated IBS patients (Rome II) Biopsy-proven celiac disease IBS and Celiac Disease: US Data Case-control study IBS patients (physician diagnosis) Positive for both ttga and EMA Celiac disease not biopsy-proven Prospective study Non-constipated IBS patients (Rome II) Biopsy-proven celiac disease P = NS N=555 N=566 Controls IBS Patients P = NS N=458 N=492 Controls IBS Patients P = NS Non celiac gluten sensitivity is likely to be much more common N=555 than N=566celiac disease N=458 Controls IBS Patients Controls P = NS N=492 IBS Patients Celiac disease prevalence 1% among IBS patients in two US studies Screening is cost-effective if prevalence is greater than 1% Saito-Loftus Y, et al. Am J Gastroenterol. 28;13(suppl 1):S472. Abstract 128 Cash BD and Chey WD, Gastroenterol, 211;141:1187 Celiac disease prevalence 1% among IBS patients in 2 US studies Screening is cost-effective if prevalence is greater than 1% Saito-Loftus Y, et al. Am J Gastroenterol. 28;13(suppl 1):S472. Abstract 128 Cash BD and Chey WD, Gastroenterol, 211;141:1187

Control IBS IBS IBD.5 CRP (mg/dl) 4 IBD Calprotectin (ug/g) Microscopic colitis more common in female IBS-D patients aged 45 years IBD = inflammatory bowel disease Chey WD et al. Am J Gastroenterol.

3 Colonoscopy Findings in IBS Without Alarm Features? Prospective, multicenter US study in nonconstipated IBS pts and controls undergoing colon cancer screening Meta analysis of Serum & Fecal Biomarkers to rule out IBD in pts with IBS symptoms Control Control IBS IBS IBD.5 CRP (mg/dl) 4 IBD Calprotectin (ug/g) Microscopic colitis more common in female IBS-D patients aged 45 years IBD = inflammatory bowel disease Chey WD et al. Am J Gastroenterol. 21;15: ESR is of no value CRP of <.5 mg/dl confers a <1% risk of IBD Fecal calprotectin of <4 ug/g confers a <1% of IBD Menees et al DDW 214 IBS vs. Microscopic Colitis Majority of cases will be diagnosed with left colon biopsies alone Macaigne G, et al. Am J Gastroenterol 214 IBS: Diagnostic Pearls Non celiac gluten sensitivity (NCGS) is likely more common than celiac disease Test for celiac disease BEFORE trialing a GFD There is no increased risk of colon cancer or polyps in IBS pts vs. controls Age appropriate colon cancer screening recommended Consider screening for IBD with CRP and/or fecal calprotectin Clinical clues can help to identify IBS pts at increased risk for microscopic colitis MC can be diagnosed with left colon biopsies in most cases Work Up of Patients with Suspected IBS Typical IBS Symptoms IBS Subgroup No Alarm features Yes More detailed evaluation dictated by symptoms Lifestyle Options for IBS IBS D CBC CRP or fecal calprotectin Ttg (IgA and IgG) SeHCAT or C 4 if available Age appropriate colorectal cancer screening When colonoscopy or sigmoidoscopy performed, obtain random biopsies Chey et al. Publication pending IBS M Detailed history Stool diary CBC CRP or fecal calprotectin Ttg (IgA and IgG) Age appropriate colorectal cancer screening Consider AXR IBS C CBC Age appropriate colorectal cancer screening Severe or medically refractory, refer to GI specialist for physiologic testing

Hours 4 35 3 25 2 15 1 5 Colon Transit Time According to Physical Activity Level Mean Total Colon Transit Time in 49 Volunteers 9.2 P=.22 35.4 7.6 P=.26 3.5 5.2 P=.2 2.

4 Hours Colon Transit Time According to Physical Activity Level Mean Total Colon Transit Time in 49 Volunteers 9.2 P= P= P= Male (n = 24) Female (n = 25) P= Low Moderate High Total Physical Activity Level 25.8 Song BK, et al. J Neurogastroenterol Motil 212;18:64 Impact of Physical Activity on IBS IBS Severity Scoring System, IBS score N = 38 N = IBS pts by Rome II 12 wk intervention 2 6 moderate to vigorous activity 3 5 times/wk Johannesson E, et al. Am J Gastroenterol 21;16: Exercise for Depressive Symptoms Physical inactivity & comorbid depressive symptoms are common in patients with chronic diseases The effect of exercise on depressive symptoms in patients with chronic diseases were evaluated 9 articles including >1 patients Exercise reduced depressive symptoms Heterogeneity Mean effect size = Δ of.3 (95%CI.25.36) Larger effects seen with: Patients with mild to moderate depressive symptoms Patients met recommended physical activity levels Patients for whom function outcomes improved Herring et al. Arch Int Med 212;172:11 11 Does Food Cause IBS Symptoms? Percent Food and IBS Symptoms 7 Any Food Carbs Fatty Foods Histamine 197 IBS pts (Rome III) Symptom severity correlates with number of food sensitivities No impact of IBS subgroup Bohn et al. Am J Gastroenterol 213;18: Why Do We Care About Food in IBS Patients? Proportion of patients (n=247) reporting at least moderate effects on the three IBS QOL food related questions Nojkov B, et al. DDW 214: Sa199

Food and GI Symptoms Why Would Food Cause IBS Symptoms? Spencer M, et al. Cur Tx Opt GI. 214 Traditional Dietary Advice for IBS Dietary Interventions for IBS: What is the Evidence?

5 Food and GI Symptoms Why Would Food Cause IBS Symptoms? Spencer M, et al. Cur Tx Opt GI. 214 Traditional Dietary Advice for IBS Dietary Interventions for IBS: What is the Evidence? No standardized IBS diet! Avoid excess Caffeine, chocolate, alcohol Lactose & sorbitol Fatty or junk food Encourage Dietary fiber for hard stools Allow sufficient time and quiet for meals Gluten Free: More than a Fad? Euromonitor International forecasts: Sales have more than doubled since = $1.31 billion US, $2.67 billion worldwide 215 = $1.68 billion US, $3.38 billion worldwide Big Industry is buying in: General Mills: Chex cereal Betty Crocker: Cake & brownie mixes, Bisquick Anheuser Busch: Gluten free REDBRIDGE beer PF Changs & Subway 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 Reuters Online September 29, 211 Digestive Health SmartBrief October 5, 211 Eswaren S et al. GI Cl North Am 211;4:141 Sapone et al. BMC Medicine 211;9:23 Ludvigsson et al. Gut 212, online early

Symptoms Reported in Patients with Non Celiac Wheat Sensitivity Gluten Causes Symptoms in IBS Patients Without Celiac Disease Mean Change in Symptoms Over 6 Weeks 5 4 3 2 1 Overall Symptoms P=.

6 Symptoms Reported in Patients with Non Celiac Wheat Sensitivity Gluten Causes Symptoms in IBS Patients Without Celiac Disease Mean Change in Symptoms Over 6 Weeks Overall Symptoms P= Bloating P=.31 Gluten (n=19) Placebo (n=15) P=.2 Week Pain Week Tiredness P= Carroccio A, et al. Am J Gastroenterol. 5 Nov 213 [epub ahead of print] Week Week Reprint permission has been requested. Adapted from Biesiekierski JR, et al. Am J Gastroenterol. Jan 11, 211. [Epub ahead of print.] 2 P value for analyses at Week 1 and entire study period. Mean Bowel Movements per Day in Gluten Free and Gluten Containing Diets Single center, parallel group 4 week RCT in 45 gluten ingesting IBS D pts Gluten free diet Gluten containing diet N = 23 N = 22 All food provided by investigators: 2% protein, 3% fat, 5% CHO Vazquez Roque MI, et al. Gastroenterology 213;144:93. 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) P =.28 Pre Post Pre Post 2 hours 8 24 hours Effects pronounced in HLA DQ2/8 positive pts GCD associated with reduced ZO 1, occludin, claudin 1 mrna Vazquez Roque MI, et al. Gastroenterology 213;144:93. in colonic mucosa effect greater in HLA DQ 2/8 positives pg/ml Effects of Rice vs Gluten on In Vitro Cytokine Production by PBMCs Rice P <.1 IL1 Gluten Rice P <.5 Gluten GM CSF Rice P <.67 TNF α Gluten 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 Vazquez Roque MI, et al. Gastroenterology 213;144:93. Eswaran & Chey, GI Cl North Am 211;4:141Shepherd, et al, Clin Gastro Hepatol 28;6:765 Gibson & Shepherd. J Gastro Hepatol 21;25:252

Are Wheat Intolerance Symptoms from Gluten or FODMAPs?

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

Cur Tx Opt GI. 214 Outcomes of IBS Patients after 4 Weeks of an Open Elimination Diet N = 7 N = 61 N = 29 Open elimination diet: cow s milk, wheat, egg, tomato, and chocolate Carroccio A, et al.

7 Are Wheat Intolerance Symptoms from Gluten or FODMAPs? 37 pts with NCGS 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 Biesekierski JA et al Gastroenterol 213;online early 6/19/13 Proposed Mechanisms of Non celiac Wheat Sensitivity Spencer M, et al. Cur Tx Opt GI. 214 Outcomes of IBS Patients after 4 Weeks of an Open Elimination Diet N = 7 N = 61 N = 29 Open elimination diet: cow s milk, wheat, egg, tomato, and chocolate Carroccio A, et al. Clin Gastro Hepatol 211;9:965 Very Low CHO Diet for IBS D 15 females, mean age 46 yrs, BMI 32 Dietary interventions: 2 wks standard (55% CHO, 3% Fat, 15% Protein) 4 wks VLC (51% Fat, 45% Protein, 4% CHO) Responder: Adequate relief of GI symptoms for 2/4 weeks Responder rate = 13/13 (1%) 1/13 (77%) improved 4/4 weeks Improvements in stool frequency (p<.1), consistency (p<.1), pain (p<.1), QoL (p=.2) Mean weight loss of 3.1 kg Austin et al. Clin Gastro Hepatol 29;7:76 Osmotic Effects Spencer M, et al. Cur Tx Opt GI. 214 Cognitive and Emotional Factors Impact of FODMAP Diet on Breath Hydrogen Production and Symptoms Design Single blind crossover study in 15 healthy and 15 IBS patients 2 day consumption of high FODMAP diet (5 g/d) or low FODMAP diet (9 g/d) Results Higher levels of breath hydrogen produced with high FODMAP diet Gastrointestinal symptoms and lethargy induced by high FODMAP diet in IBS but not control patients Breath hydrogen production N= Hours HFD=high-FODMAP diet; LFD=low-FODMAP diet Health-HFD Healthy-LFD IBS-HFD IBS-LFD Ong DK et al. J Gastroenteorl Hepatol. 21;25:

Low FODMAP Diet: Effects on Gut Permeability, Microbiome & Sensation Wistar rats fed high or low FODMAP chow x 2 wks High FODMAP diet associated with: Immune activation by Increased ileal IL 6 & TNF

8 Low FODMAP Diet: Effects on Gut Permeability, Microbiome & Sensation Wistar rats fed high or low FODMAP chow x 2 wks High FODMAP diet associated with: Immune activation by Increased ileal IL 6 & TNF α (p<.5) Increased ileal permeability (p<.5) Alterations in the gut microbiota 454 pyrosequencing revealed decreased clostridiales (18% vs 7%), Peptostreptococaceal (<1% vs 12%) and Lactobacillaceae (<1% vs 12%) but increased Erysipelotrichaceae (69% vs 5%) and Lachnospiraceae (5% vs <1%; P<.5 for all comparison) Visceral Hypersensitivity to colorectal distention (p<.5) Take Home Point: FODMAP restriction leads to alternations in immune activation, permeability, microbiota, and visceral sensation Zhou SY et al. DDW 13, Abs 164 Proportion of patients (%) Daily Symptom Scores on low FODMAP vs. Control Diet Symptoms Control Intervention P <.5 Staudacher HM, et al. J Nutr 212;142:151. Fecal Bifidobacteria Concentration in IBS Patients after a low FODMAP diet A Low FODMAP Diet Reduces Symptoms in IBS Change in [Bifidobacteria] log1/g r =.54 (P = 1..33) Baseline [Bifidobacteria] log1/g Staudacher HM, et al. J Nutr 212;142:151. P<.1 3 IBS patients & 8 controls: 1 week baseline followed by 21 days of low fodmap diet or typical Australaian diet before crossing over to other diet Significant benefits for overall IBS symptoms, bloating, pain, & wind (p<.1) Benefits for King s Stool Chart only for IBS D (p<.4) Halmos, et al. Gastroenterology 214;146:67 Mechanisms of GI Symptoms After Intake of FODMAPs Absorption: Lactase Transit time Dose Mucosal disease Food Composition Stress Anxiety and depression Expectation Attention/ distraction Conditioning Gut microbiota composition Dose/type of FODMAPs Visceral hypersensitivity Gut inflammation/ immune activity Barrier defects? Other factors 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 Low carbohydrate Gluten free Empiric elimination diets Low FODMAP Simrén M. Gastroenterology 214;146:1

9 Where Do We Go from Here? Rigorous, adequately powered validation data from other parts of the world Long term efficacy and safety data Better understanding of the pathophysiology of the clinical benefits Predictors of response to specific diets Clinical parameters Biomarkers Practical ways by which to operationalize dietary interventions

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

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