Disorders in which symptoms cannot be explained by the presence of structural or tissue abnormalities Irritable bowel syndrome Functional heartburn Functional dyspepsia Functional constipation Functional diarrhea The Rome Foundation is an independent notfor profit organization that provides support and educational information to assist in the diagnosis and treatment of functional gastrointestinal disorders http://www.romecriteria.org/criteria/ Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool Symptom onset at least 6 months prior to diagnosis Prevalence: 3% to 2% in the United States Sex: female > male Race: white > non white Risk factors: Bacterial gastroenteritis Affluent childhood environment Estrogen use Recent antibiotic use Food intolerance Extraintestinal somatic symptoms U.S. prevalence rates for other common diseases: Diabetes 3% Asthma 4% Heart disease 8% Hypertension 11% Irritable bowel syndrome 2% results in an estimated $2 billion annually in the U.S. in total direct and indirect expenditures Patients with consume >5% more healthcare resources than matched controls without Days per year 14 12 1 8 6 4 2 Absenteeism from work or school during the last 12 months P=.1 Non Talley et al. Gastroenterology. December 1995;19:1736 1741 Drossman et al. Dig Dis Sci. September 1993;38:1569 158. Everhart JE et al. Gastroenterology 29;136(3): 741 754. Inadomi JM et al. Aliment Pharmacol Thera 23;18:671 82. Drossman et al. Dig Dis Sci. September 1993;38:1569 158.

Food Enhanced Perceptions Genetics Abnormal Motility Visceral Hypersensitivity Brain Gut Interaction Serotonin Modulation Psychosocial Factors Infection Inflammation 195 Present Altered Motility Altered Sensation Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3 14. 2. 6 Pain produced by rectosigmoid balloon distension Normal % Reporting Pain 4 2 Normal Colonic Distension Ice Water Immersion 2 6 1 14 18 Rectosigmoid balloon volume (ml) Whitehead et al. Gastroenterology. May 199;98:1187 1192. Whitehead et al. Dig Dis Sci. June 198;25:44 413. Enteric system has multiple hormones and signal molecules Serotonin (5 HT) Acetylcholine ATP Motilin Nitric Oxide Peptide YY Vasoactive Intestinal Peptide CNS 5% Mediate reflexes controlling gastrointestinal motility and secretion Mediate perception of visceral pain GI tract 95% enterochromaffin cells neuronal Gershon. Aliment Pharmacol Ther. 1999;13(suppl 2):15 3.

Incidence of after acute bacterial gastroenteritis ranges from 7% to 32% 6% remain symptomatic over 6 years of follow up Usually diarrhea predominant Psychological distress and severity/duration are predictive Campylobacter/Shigella > Salmonella Results from immune system activation Altered gut transit Increased rectal sensitivity Increased intestinal permeability Increased 5 HT containing enterochromaffin cells in the colon Neal KR, et al. BMJ. 1997;314:779 782 Gwee KA, et al. Lancet. 1996;347:15 153 McKendrick MW, et al. J Infect. 1994;29:1 3. Spiller RC, et al. Gut. 2;47:84 811. History & physical Identify abdominal pain as a dominant symptom with altered bowel function Look for red flags Diagnostics (lab/procedures) to rule out organic disease Make the diagnosis Initiate treatment Red Flags Nocturnal symptoms of pain and/or abnormal bowel function Fever Rectal bleeding Weight loss Persistent diarrhea: dehydration, electrolyte issues Anemia Family history of GI malignancy, inflammatory bowel disease, or celiac disease New onset of symptoms in patients over age 5 Malabsorption Celiac Post Surgical Pancreas Psychological Anxiety Depression Somatization Infection Bacterial Overgrowth Giardia Differential Diagnosis Inflammation Crohn s Ulcerative Colitis Microscopic Colitis Miscellaneous Endocrine Tumors Diet Lactose Caffeine Gas Producing Foods Age < 5 CBC CMP Thyroid Celiac Age > 5 CBC CMP Thyroid Celiac Colonoscopy: for colon cancer screening purposes GI Disease Patients (Pre Test Probability %) General Population (Prevalence %) Inflammatory Bowel.51 to.98.3 to 1.2 Disease Colorectal Cancer to.51 4 to 6 GI Infection to 1.7 N/A Thyroid Dysfunction 6 5 to 9 Lactose Malabsorption 22 to 26 25 Celiac Disease 4.67.5 to 1

Loperamide Rifaximin Alosetron Eluxidoline Diarrhea Bloating Constipation Pain Fiber (psyllium) Docusate, PEG Linaclotide Lubiprostone Patient education Physician patient interaction Medical therapies Diet Physical exercise Stress management Manage psychological/psychiatric comorbidities Probiotics Low FODMAP diet Rifaximin Anticholinergics Tricyclics SSRI/SNRI Psychotherapy Patient driven interview with focus on predominant symptom Review medications for possible exacerbating side effect (e.g. NSAIDs, iron, antibiotics, CCBs, opioids, metformin, antidepressants) Realistic goals of therapy Close follow up with frequent visits Encourage patient to provide feedback about treatment effect Loperamide Rifaximin* 55 mg PO TID x 14 days, repeat x 2 Alosetron 1 mg PO BID Selective 5 HT3 antagonist FDA withdrawal 11/21, reinstated 6/22 under restricted prescribing program Eluxidoline* 1 mg PO BIDCC Locally active, mixed μ and κ opioid receptor agonist and δ opioid receptor antagonist Low oral bioavailability Ford AC et al. Am J Gastroenterol. 29 Jul;14(7):1831 43. Dove LS et al. Gastroenterology 213;145:329 338. Fiber (psyllium) Laxatives (e.g. docusate, polyethylene glycol) Linaclotide 29 mcg PO QAM (3 min AC)* binds/activates guanylate cyclase C receptor on lumen of intestinal epithelium CFTR activation secretion of HCO3 and Cl into lumen Lubiprostone 8 mcg PO BIDCC* Derivative of prostaglandin E1 activates ClC 2 on apical surface of intestinal epithelium Cl and H2 flux into lumen Moayyedi P et al. Am J Gastroenterol. 214 Sep;19(9):1367 74. Li et al. Mayo Clin Proc. April 216;91(4):456 468. Probiotics No major differences between Lactobacillus, Bifidobacterium, nor Streptococcus VSL#3 (combination Bifidobacterium, Lactobacillus, and Streptococcus) Rifaximin* TARGET 1, TARGET 2, and TARGET 3 55 mg PO TID for 1 14 days May repeat treatment with 2 additional courses separated by at least 1 weeks Kim HJ et al. Aliment Pharmacol Ther. 23;17:895 94. Menees SB et al. Am J Gastroenterol 212;17:28 35. Moayyedi P et al. Gut 21; 59:325 332. Rivkin A and Rybalov S. Pharmacotherapy 216 Mar; 36(3):3 16.

Anticholinergic agents Dicyclomine Hyoscyamine Clinidium +/ chlordiazepoxide Antidepressants Tricyclic antidepressants SSRIs SNRIs Peppermint oil Low FODMAP Diet Fermentable, Oligosaccharides, Disaccharides, Monosaccharides, And Polyols Acronym for variable chain carbohydrates that are poorly digested by the human small intestine reach colon fermented by microbiome Produce short chain fatty acids and a number of gases including hydrogen and methane Symptoms may include gas, bloating, and pain Ruepert L et al. Cochrane Database Syst Rev. 211 Aug 1;(8):CD346. Ford AC et al. Am J Gastroenterol. 214 Sep;19(9):135 65. Khanna R et al. J Clin Gastroenterol. 214 Jul;48(6):55 12. Chey WD. Am J Gastroenterol. 216 Mar;111(3):366 71. Staudacher HM et al. J Nutr 212;142:151 8. Cognitive behavioral therapy Hypnotherapy Psychotherapy Relaxation therapy % Responders 1 8 6 4 P<.1 NNT=3 7 37 P<.1 NNT=3 73 41 CBT Education 12 wks 2 ITT n=21 PP n=168 Ford AC et al. Am J Gastroenterol. 214 Sep;19(9):135 65. Drossman, Gastro 23;125:19. General well-being (VAS) 5 4 3 2 1 4.1 *p=.5 4.1 3.6 Visit 1 Visit 2 No change in pain or stool characteristics *p=.15 3.7 Acupuncture Placebo 11 wk crossover trial n = 25 (PP analysis) Acupuncture at LI-4 Fireman, Digestion 21;64:1. Rome III diagnostic criteria (Rome IV due May 216) High economic burden of disease There is evidence basis for medical therapies for, but... Therapeutic gains of 8% to 2% over placebo Half or less of patients improve Physician patient relationship Alternative and complementary therapies for Chey WD et al. JAMA 215;313:949 58.