1. Collins.Exp Biol 2007 MODELLING GI DISEASES MODELLING GI DISEASES Translating Symptoms into Mechanisms Stephen Collins McMaster University Hamilton, Ontario, Canada

2. Collins.Exp Biol 2007 GI DISEASE PROCESSES Acid-peptic disease (post-H.pylori era) Gastric acid secretion Mucosal barrier Inflammatory Bowel Disease (Crohns, Colitis) Immune dysfunction Barrier dysfunction GI InfectionsHost defense Ischemic InjuryMucosal blood flow Functional GI Disorders (e.g. IBS) Altered gut physiology

3. Collins.Exp Biol 2007 FUNCTIONAL GI DISORDERS Chronic abdominal symptom complexes for which there is no discernible underlying structural abnormality. By far the most common category of GI disease They are disorders of function – and reflect altered physiology The symptoms are non specific and mimic those of organic diseases such as peptic ulcers or inflammatory bowel disease

4. Collins.Exp Biol 2007 THE CHALLENGE OF FUNCTIONAL GI DISORDERS These disorders are poorly conceptualized There are no diagnostic or other biomarkers Few, if any, drugs are highly efficacious Socio-economic burden is high (absenteeism, diagnostic tests, treatments) Traditionally, they are diagnosed by excluding “organic GI disease”

5. Collins.Exp Biol 2007 THE DIAGNOSIS OF FUNCTIONAL GI DISORDERS “ If I can’t see it, it ain’t there. It’s all in your head.” WHAT HAPPENED TO COGNITIVE GASTROENTEROLOGY? Diagram from National Cancer Institute showing GI tract and colonoscopy procedure Diagram available at http://www.cancer.gov/Te mplates/db_alpha.aspx?C drID=45648 http://www.cancer.gov/Te mplates/db_alpha.aspx?C drID=45648

6. Collins.Exp Biol 2007 SYMPTOMS ARE IMPORTANT THEY MAY TELL YOU ABOUT UNDERLYING MECHANISMS (not the cause of disease) THIS WILL INFLUENCE TREATMENT & DIRECT RESEARCH ENQUIRY

7. Collins.Exp Biol 2007 The Conceptualization of Functional GI Disorders 1Top Down Model Bottom up Model 2 1.Top Down Model: A “psychosomatic disorder” Stress & Major affective disorders. GI tract: Innocent bystander 2.Bottom up Model: A peripheral trigger such as infection or inflammation Behavioral issues still relevant ARE THEY MUTUALLY EXCLUSIVE CONCEPTS ?

8. Collins.Exp Biol 2007 CONSTRUCTING A MODEL OF FUNCTIONAL GI DISORDERS End point: Altered gut physiology in the absence of overt tissue damage. The stimulus used to induce gut dysfunction must be relevant to the pathogenesis of these conditions The resulting dysfunction should be chronic rather than acute.

9. Collins.Exp Biol 2007 Common Symptoms of Functional GI Disorders Abdominal pain or discomfort Indigestion Early post prandial fullness Bloating Excessive Gas Diarrhea Constipation Behavioral symptoms

10. Collins.Exp Biol 2007 Translating Symptoms in Mechanisms Qualitative Aspects of Abdominal Pain: 1.Cramping and related to bowel movements or eating Abnormal motility: smooth muscle, enteric nerves or ICCs 2. Non cramping persistent pain Visceral hyperalgesia or allodynia: sensory nerves or specific chemical sensitivity (e.g. acid)

11. Collins.Exp Biol 2007 MECHANISMS OF ABDOMINAL PAIN Abnormal sensory perception i.e. Central Processing Altered spinal modulation Sensitization of visceral afferent fibres Spasm of GI smooth muscle

12. Collins.Exp Biol 2007 CONSTIPATION Multiple definitions Artificial clinical classifications (Rome criteria versions I-III) Underlying physiology of defecation is usually forgotten by clinicians Mechanistic classification is helpful (if you plan to actually listen to the patient!)

13. Collins.Exp Biol 2007 NORMAL COLONIC FUNCTION 3.5 litres of fluid per day arrive at cecum 200-300ml of solid stool/day >90% EFFICIENCY FOR REABSORBTION OF WATER OVER ~1m

14. Collins.Exp Biol 2007 ROLE OF COLONIC MOTILITY 3.5 litres of fluid per day arrive at cecum 200-300ml of solid stool/day 1. Segmenting non peristaltic contractions to slow fecal stream H20H20 2. Occasional peristaltic activity to push solid stool forward 3. Rare mass movement (sustained peristaltic wave) to push formed stool to rectum

15. Collins.Exp Biol 2007 ANO-RECTAL PHYSIOLOGY 1. STOOL DISTENDS THE RECTUM 2. REFLEX RELAXATION OF INTERNAL ANAL SPHINCTER 3. STOOL ENTERS THE ANAL CANAL 4. AWARENESS “DO SOMETHING!” 5. YOUR CALL ! Contract the sphincter & postpone Relax the sphincter & take the consequences S2 S3 S4

16. Collins.Exp Biol 2007 TRANSLATING SYMPTOMS INTO MECHANISMS POOR INTAKE OF WATER, FIBRE & CHO SLOW COLONIC TRANSIT and/or OUTLET DYSFUNCTION Pelvic Floor Anal Sphincter ALTERED SENSATION & ACCOMODATION “Doctor, I can go for weeks without a bowel movement, I never get the urge…I get progressively more distended.. I always feel I should go; I never feel emptied I go several times a day, I strain for hours…

17. Collins.Exp Biol 2007 MECHANISTIC APPROACH TO MECHANISTIC APPROACH TO CONSTIPATION POOR INTAKE OF WATER, FIBRE & CHO Reduced bulk & altered fermentation SLOW COLONIC TRANSIT Slow Transit Constipation OUTLET DYSFUNCTION Pelvic Floor Anal Sphincter Pelvic Floor Dyssynergia Anismus ALTERED SENSATION & ACCOMODATION Normal Transit Constipation

18. Collins.Exp Biol 2007 RELEVANT PATHOPHYSIOLOGY Abnormal colonic motility Diminished or altered rectal sensory function Abnormal co-ordination between pelvic floor, recto-sigmoid and anal sphincter muscles

19. Collins.Exp Biol 2007 BLOATING & FULLNESS Early Post Prandial Fullness Abnormal gastric physiology: antral dysmotility, impaired accommodation Abdominal Bloating Increase gas production? Reduced accommodation of gas? Increased perception of distension ? Abnormal fermentation by commensal bacteria Abnormal compliance of gut wall or allodynia Abnormal motility Bacterial load Altered motility

20. Collins.Exp Biol 2007 GUT FLORA The average human body, consisting of about 10 13 cells The gut contains > 10 14 microorganisms. Bacteria make up most of the flora in the colon and 60% of fecal mass. Gut microbiota reflects > 500 different bacterial species. Fungi are also part of the gut eco-system The majority of bacteria are strict anaerobes and cannot be cultured. Identification is based on DNA analysis.

21. Collins.Exp Biol 2007 THE DIVERSITY OF HUMAN GUT MICROBIAL FLORA Eckburg P et al Science 2005 Diversity between individual subjects Diversity between individual subjects Diversity between fecal and mucosal-associated samples Diversity between fecal and mucosal-associated samples Patchy distribution of bacteria but not uniform gradient along the length of the colon Patchy distribution of bacteria but not uniform gradient along the length of the colon 395 bacterial phylotypes identified; 244 (64%) were novel and 80% have not been cultured 395 bacterial phylotypes identified; 244 (64%) were novel and 80% have not been cultured

22. Collins.Exp Biol 2007 THE ROLE OF GUT FLORA Provide nutrition to the host, influence caloric consumption and regulate fat handling Regulate epithelial function Instruct innate immunity, imprint adaptive immunity and maintain “physiological inflammation” Influence intestinal angiogenesis Metabolize drugs and pre-carcinogens Maintain normal gut physiology

23. Collins.Exp Biol 2007 Antibiotic treatment (10 days) increased CRD responses Figure from Verdú EF, et al. Gastroenterology 127 (3): 826-837, 2004 Available at http://www.gastrojournal.org (under subscription access)http://www.gastrojournal.org Figure of 3 graphs showing AUC vs. colonic distension for placebo, antibiotic therapy, and ATB+L.paracasei and 1 graph of MPO on Day 1 vs. Day 10 for those 3 treatments

24. Collins.Exp Biol 2007 DIARRHEA Usually associated with eating; better on fasting (gastro-colic reflex?) Typically low-volume diarrhea (not dominant secretory) Stool consistency is variable (not dominant secretory) No weight loss (no clinical malabsorption or maldigestion) Mechanisms - Motility (rapid transit) - Secretory (minor) - Rectal sensory dysfunction (pseudo-diarrhea) - Normal pancreatic and absorptive function

25. Collins.Exp Biol 2007 EPITHELIUM IN FUNCTIONAL GI DISORDERS Some evidence that CHO absorption may be abnormal in some patients with diarrhea Bile acid reabsorption is abnormal in some patients with diarrhea Permeability of small intestine to lactulose- mannitol is abnormal in some patients with IBS (post-infective IBS)

26. Collins.Exp Biol 2007 INSIGHTS IN THE PATHOGENESIS OF FUNCTIONAL GI DISORDERS POST-INFECTIVE IBS

27. Collins.Exp Biol 2007 INFLAMMATION & INFECTION IN IBS Low grade inflammation is evident in a subset of IBS patients The analogy is made with asthma: i.e. low grade inflammation causes tissue dysfunction without significant structural damage. There is an established relationship between acute bacterial gastroenteritis and the development of IBS. Infection is a trigger for IBS

28. Collins.Exp Biol 2007 65 HOSPITALIZATIONS (27 HUS) 6 FATALITIES MAY 2000 Walkerton, Ontario CONTAMINATION OF TOWNS WATER SUPPLY BY OVERFLOW FROM FARMS

29. Collins.Exp Biol 2007 Walkerton: May 2000 Walkerton: May 2000 1346 reported cases* of acute Gastroenteritis 799 were residents of Walkerton 1304 had “primary” exposure (to municipal water) E.Coli and C.jejuni were main pathogens A substantial number of patients remain symptomatic almost 7 years later BGOS Health Unit Investigative Report

30. Collins.Exp Biol 2007 ALTERED GI PHYSIOLOGY IN PI-IBS Rapid gut transit (Gwee et al. Gut 1999;44:400-406) Bile acid malabsorbtion (Niaz et al. J R Coll Physicians Lond. 1997 Jan-Feb;31(1):53-6) Reduced rectal compliance (Bergin et al. Eur J Gastroenterol Hepatol 1993 5: 617-620) Visceral hypersensitivity (Bergin et al. Eur J Gastroenterol Hepatol 1993 5: 617-620) Increased numbers of entero-endocrine cells (Spiller Gut 2000;47:804-811)

31. Collins.Exp Biol 2007 INCREASED INTESTINAL PERMEABILITY IN PI-IBS Figure from R C Spiller et al., Gut 2000;47:804-811 Under access control at http://gut.bmj.com/cgi/content/abstract/47/6/804 http://gut.bmj.com/cgi/content/abstract/47/6/804 Also see J. Marshall et al., Aliment Pharmacol Ther. 2004 Dec;20(11-12):1317-22 Under access control at http://www.blackwell-synergy.com/toc/apt/20/11-12 http://www.blackwell-synergy.com/toc/apt/20/11-12 Figure showing Lactulose/Mannitol Ratio in control and PI-IBS treatment at 12 weeks

32. Collins.Exp Biol 2007 INFLAMMATORY CHANGES IN PI-IBS Increased cellularity of lamina propria but normal mucosal architecture. Increased numbers of IELs and CD3 cells Increased IL1  mRNA expression Increased numbers of mast cell-nerve clusters (Gwee et al 1999 & 2003; Spiller et al 2000; Barbara et al 2004; Wang et al 2004)

33. Collins.Exp Biol 2007 CONCEPTUAL MODEL OF GUT DYSFUNCTION IN PI-IBS Bacterial & Other Antigens LYMPHOCYTIC & MAST CELL ACTIVATION IMMUNE ACTIVATION ALTERED SENSORY-MOTOR FUNCTION INCREASED PERMEABILITY

34. Collins.Exp Biol 2007 IMPLICATIONS FOR TEACHING Clinically relevant changes occur in the following GI systems: Motility apparatus Sensory circuits Epithelial biology There a clinically relevant interfaces of these systems with: The Central Nervous System The mucosal immune system Pathogenic and commensal bacteria