Irritable Bowel Syndrome

1. Irritable Bowel Syndrome Leonard Weinstock, MD President, Specialists in Gastroenterology Associate Professor of Clinical Medicine Washington University School of Medicine

2. Disclosures • Speakers bureau: Salix, Allergan Syndromes don’t get no respect

3. IBS-D and IBS-C • Definition • Impact and perspective • Pathophysiology – role of SIBO • FDA-approved treatment • Role for naltrexone

4. B.S. 55 y.o. disabled ICU Nurse • Acute persistent diarrhea (1 mo) • IBS-A – 22 yrs • FMS - 21 yrs • RLS - 13 yrs • IC - 10 yrs Case from 2005 • Testing and treatment • Breath test abnormal • RLS, IBS, FM 90% better • after SIBO Rx

5. Rome IV Criteria for IBS Pain >6 mo duration with avg ≥1 d/wk in last 3 mo, assoc w ≥ 2: 1. Related to defecation 2. Assoc w change in BM frequency 3. Assoc w change in BM form 60% D .

6. IBS Sx: gas/bloating are frequent Most Frequently Reported Sx N = 242 females Percent (%) of Days Cain KC, et al. Am J Gastroenterol. 2006;101:124-132.

7. Prevalence of IBS in USA • Peak ages for current IBS sx were 25-54 yrs old • 1/3 of pts had IBS for >10 yrs Hungin. Aliment Pharmacol Ther. 2005:21;1365.

8. Annual Economic Impact of IBS • Direct Medical Costs: $1.7 billion • Drugs: $80 million • Indirect Medical Costs: $20 billion • 39% missed workdays • Employees cost employers 1.5x more • Sandler et al. Gastroenterology. 2002.

9. Theories in IBS-D in 40’s-90’s CORE PROBLEMS - Visceral Hypersensitivity - Altered Gut Motility and Secretion - Bloating d/t relaxed abdominal wall Stress/depression Brain-Gut Food Intolerance Serotonin

10. Theories in IBS-D Now Immune and inflammatory changes Stress/depression • CORE PROBLEMS • - Visceral Hypersensitivity • - Altered Gut • Motility and Secretion • - Gas • Maldigestion • Bloating Brain-Gut Specific gases Genetics Serotonin Bile salt & dysbiosis Food Intolerance Pi-IBS • Enzyme deficiencies • Lactase • Sucrase-Isomaltase • Pancreatic enzymes Small Intestinal Bacterial Overgrowth or Dysbiosis

11. IBS-C Pathophysiology Brain-Gut Visceral Hypersensitivity Decreased Secretion Abnormal uroguanylin or opioid (?) Slow Motility High methane in some

12. Inflammation in IBS

13. circular & longitudinal Muscles and vessels spinal, vagal, & pelvic nerves to CNS;

14. TNF IL-6 Dendritic cells circular & longitudinal Muscles and vessels Cytokines/Histamine spinal, vagal, & pelvic nerves to CNS;

15. Mast Cells in IBS Normal IBS Abdominal pain and severity correlated with the number of mast cells <5µm Proximity to nerves. Tryptase (3x) and histamine (2x) Barbara. Gastroenterology. 2004;126:3.

16. Lymphocyte Infiltrates by Nerves Myenteric neuron (thick arrow); lymphocytes (thin arrow) Tornblom. Gastroenterology2002;123:1972-9

17. Toll-like Receptors in IBS • TLR 2 and 4 up-regulated in IBS Belmonte. Plos One. 2012

18. Increased Permeability in IBS

19. IP Studies in IBS: 2000-2012 • Increased IP in 10/12 studies of IBS • Examples: 36%, 39%, and 42% were abnormal • 4 looked just at the colon • Think how many IBS pts have SIBO • Mixed IP results in IBS-c Camillieri. Am J Physiol Gastrointest Liver Physiol 2012:G775.

20. Dysbiosis in IBS

21. Balance (metabolism) vs. Dysbiosis (disease) Gut bacteria vs. Human cells 10:1 H2 H2 H2 H2 H2 H2 Other gases CH4 H2S

22. SIBO vs. Dysbiosis Your own folks move to a new location Bad guys take over the country

23. Colonic Dysbiosis in IBS • 113 IBS-D and IBS-M vs. 66 healthy controls, rRA • IBS pts • Significantly lower diversity • Lower butyrate-producing bacteria (P=0.002) • Lower Methanobacteria (P=0.005) • Correlations w certain bacteria and sensation of flatulence and abdominal pain (P < 0.05) 1. Possible role in visceral hypersensitivity 2. Butyrate producing bacteria help barrier function Pozuelo. Scientific Reports. 2015.

24. Dysbiosis in IBS – 3 other studies • Bifidobacteria lower in IBS-D vs. IBS-C or controls • Differences found in several bacterial genera: Coprococcus, Collinsella, and Coprobacillus • More Enterobacteriaceae, less Fecalibacterium Parkes. Neurogastroenterol Motil. 2012. Kassinen. Gastroenterology. 2007. Carroll. Neurogastroenterol Motil. 2012. Geography dependent

25. Healthy Functions Prevent SIBO Stomach 0 - 1000 oral bacteria (streptococcus, lactobacillus) Mucosal Absorption Pancreas Acid Distal ileum 100,000,000 - 1,000,000,000 coliforms Duodenum & Jejunum 1,000 oral bacteria Motility Immunity Colon 1,000,000,000,000 coliforms (bacteroides, firmicutes, bifidobacter, clostridium) ICV Proximal ileum 10,000 oral bacteria

26. Effects of bacterial fermentation • Hydrogen and methane excess in SB • Bloating (IBS) • Methane excess in colon and/or SB • Altered motility (IBS-c, CC) • Hydrogen sulfide production • Increased nociception (IBS, IC) • Other gases • Bad odor (breath, flatus, urine) Lin. JAMA 2004. Pimentel. Dig Dis Sci. 2003. Pimentel. Am J Gastroenterol. 2005.

27. Additional P-physiology • Intraluminal bacteria • Bile salt deconjugation • Fat malabsorption • steatorrhea • Secretory effects • diarrhea

28. SIBO in IBS

29. Evidence for the Bacterial Theory Enteric infections Diseases: Pi-IBS, SIBO, …

30. Post Infectious-IBS (Pi-IBS): incidence 75 million cases of infectious diarrhea per year in USA

31. Phase III of Interdigestive Motility MMC

32. Phase III Frequency in IBS with SIBO 68% less frequent Pimentel. Dig Dis Sci 2002;47:2639-43.

33. Camphylobacter effect in Rats • 60 rats – ½ got C. jejuni, ½ got sham • 3 mo later: • 57% infected rats had diarrhea vs. 7% sham • Segmental resection/cultures: 27% of the infected rats had SIBO (Neuropathy by EM) Pimentel. Am J Gastroenterol 2006;A1216.

34. Consequences of Abnormal Phase III • Poor clearance and overgrowth of innate SB bacteria • Adherence and translocation of bacteria • Increased intestinal permeability • Inflammatory mediators • Inflammatory cells Pimentel. Dig Dis Sci 2002;47:2639-43 Lin. JAMA 2004;292:852-8

35. IBS Pathophysiologic Sequence ? Bacterial Toxin Gut Nerve Damage Bacterial Overgrowth Autoimmunity Food Poisoning IBS Cytolethal Distending Toxin (CDT B) - Less ICC - Less MMC - Breath testing - Culture - qPCR - Deep sequencing E. Coli C. jejuni Shigella Salmonella C. difficile Abx & MMC Rx Anti-vinculin

36. Recent SIBO pathophysiology Autoimmune Pathway Bacterial infections leads to: Cytotoxic antibody then anti-vinculin Ab Myenteric plexus damage and loss of MMC Adherent bacteria Translocation is allowed by increased intestinal permeability due to TNF-a • Cytokines • Lymphocytes • Mast cells Pimentel. Plos1. 2015 Riordin. Scand J Gastroenterol 1996;31:977-84. Ye. Am J Phys GI Liv Phys 2006. Riordin. Scand J Gastroenterol 1996;31:977-84.

37. Systemic effects of increased intestinal permeability • Introduction of bacterial, viral and food antigens • Triggers inflammatory cells leading to visceral hypersensitivity • LPS alters Hypothalamic Pituitary Adrenal axis Hadid. Neuroimmunomodulation 1999;6:336-43. Grinevich. J Neuroendocrinol. 2001;13:711-23.

38. How many IBS pts have SIBO? Culture of proximal SB 43% 24% Subjects (%) 12% 4% p<0.05 p<0.001 Posserud. . DDW 2006. Abstract W1832.

39. How many IBS pts have SIBO? Breath Testing

40. SIBO Diagnosis: breath testing • Indirect test • Measures fermentation • Transit: too fast gives false positive • Substrate: • Glucose spec>sens • Lactulose sens>spec

41. SIBO Diagnosis: culture/aspiration • Culture via aspiration during small bowel endoscopy • Culture by catheter insertion • Oral contamination • Cannot sample mid- jejunum and ileum • Culture technology is limited

42. Symptomatic vs. Specific Rx • FDA hurdles: • Safety • Primary outcome • Statistical diff from placebo • Take a Bentyl and Metamucil and call me in 3 months

43. IBS Rx • Other • Diarrhea • Diets • EnteraGam (SBI) • Anti-depressants • Probiotics • Narcotics • Bile binder • Digestive enzymes • Low dose naltrexone • Peppermint • L-menthol (IBgard) • Hypnotherapy • Anti-cholinergic • Constipation • Probiotics • FDA-approved • IBS-D • Alosetron • Rifaximin • Eluxadoline • IBS-C • Lubiprostone • Linaclotide

44. AntispasmodicsSummary of RTCs Duration (wks) Global Symptom No. Pts 48 30* 29 178 P NS P<0.001 NS NS 12 2 2 12 Drug 30% 94% 38% 52% Placebo 24% 54% 25% 44% Study Ritchie 1979 Page 1981 Group 1976 Nigam 1984 Medication Hyoscyamine (1 tb tid) Dicyclomine (40 mg qid) Dicyclomine (20 mg qid) Hyoscyamine (1 tb tid) *Constipation and pain predominant Lesbros-Pankoflickova. APT 2004;20:1253..

45. Alosetron for IBS-D • FDA approved for women

46. Eluxadoline for IBS-D • Mixed, non-absorbed mu & gamma opioid agonist and delta antagonist • FDA approved for men and women 30 20 16 N=2400 3 months 6 months

47. Rifaximin in IBS-D • Target 1 & 2 data • RTC: N=1,258 • 1200 mg/d/2wks, 10 wks observation • 1o endpoint: dual response in pain & BM at 1 month Pimentel. N Engl J Med. 2011.

48. Rifaximin in IBS-D: Results 30% less pain and no diarrhea • 47% vs. 39% • p=0.008 Global adequate relief – daily • 41% vs. 31% • p=0.00001 Pimentel M. N Engl J Med. 2011.

49. Rifaximin Retreatment in IBS-D • 1st Rx – open label – 36% no relapse >18 wks • Others Re-Rx w 1650 mg/d/2-wks vs. Placebo • At time of relapse – 30% less severe Sx than at baseline in N=636 • Follow up for 4 wks • Dual response in 38% vs. 31% (p<0.05) (worst case data: missed entries and drop outs)

50. IBS-d SIBO Retreatments Weinstock. Dig Dis Sci. 2011.