GI Gut

1. GI = Gut/Immune:Going to the Source for IBS & Beyond Patrick Hanaway, MD Chief Medical Officer 

2. Be open minded, but not so open minded that your brains fall out. Groucho Marx

3. What is Irritable Bowel Syndrome? IBS - Rome II Criteria 12 or more weeks of continuous or recurrent abdominal pain or discomfort Plus at least two of the following: Relieved by defecation and/or Associated with change in frequency of stool and/or Associated with a change in form (appearance) of stool

4. IBS Epidemiology Epidemiology Summary The key epidemiological features of IBS are summarized. The disorder is common, affecting up to 15% of the population. It is more frequently seen in women than men (in Western countries), and the prevalence may decline with advancing age. Sociocultural factors influence who goes to the physician, and in clinical practice, IBS accounts for a large proportion of both primary and specialty practice. Finally, IBS is associated with a considerable health and economic burden. Drossman DA, Camilleri M, Whitehead WE. American Gastroenterological Association technical review on irritable bowel syndrome. Gastroenterology 1997; 112:2137Epidemiology Summary

5. Self-selection into Clinical Practice Self-selection into Clinical Practice Among those with IBS, the majority (about 75%) will not see a physician, either because they have only mild symptoms, or they possess certain psychosocial features (e.g., effective coping style, good social support, cultural or economic influences) that lead them to not seek health care. - Of those with IBS who see physicians, most (about 20% with IBS) are in the primary care sector with mild symptoms that are relatively easy to manage. A smaller proportion (about 4%) are seen in specialty practices, and only about 1% end up in medical centers for evaluation and treatment. It is this small group of patients seen in specialty/referral practices that are referred psychiatrists and even surgeons for further evaluation.Drossman DA, Thompson WG. The irritable bowel syndrome: Review and a graduated, multicomponent treatment approach. Ann Intern Med. 1992; 116:1009-16. Self-selection into Clinical Practice

6. The other 75%?

7. Quality of Life (SF-36) of IBS and Other Medical Disorders Health related quality of life (HRQOL) is compared between IBS, Type II Diabetes, clinical depression and a national norm by using the SF-36, a generic quality of life measure. A lower score indicates poorer quality of life. It is noted that patients with IBS have similar impairment in HRQOL as patients with clinical depression with regard to physical and social functioning, general health and vitality, but have less impairment in their emotional state. Specifically, patients with IBS have poor HRQOL, similar to depression, although they do not perceive themselves to be sad or emotionally distressed. Patients with either IBS or depression have poorer HRQOL than those with diabetes (for many subscales) or those in the national norm. Wells NEJ, Hahn BA, Whorwell PJ. Clinical economics review: Irritable bowel syndrome. Aliment Pharmacol Ther 1997; 11:1019-1030.Quality of Life (SF-36) of IBS and Other Medical Disorders Health related quality of life (HRQOL) is compared between IBS, Type II Diabetes, clinical depression and a national norm by using the SF-36, a generic quality of life measure. A lower score indicates poorer quality of life. It is noted that patients with IBS have similar impairment in HRQOL as patients with clinical depression with regard to physical and social functioning, general health and vitality, but have less impairment in their emotional state. Specifically, patients with IBS have poor HRQOL, similar to depression, although they do not perceive themselves to be sad or emotionally distressed. Patients with either IBS or depression have poorer HRQOL than those with diabetes (for many subscales) or those in the national norm. Wells NEJ, Hahn BA, Whorwell PJ. Clinical economics review: Irritable bowel syndrome. Aliment Pharmacol Ther 1997; 11:1019-1030.

8. Slide 129 Prognosis: Change in Diagnosis and Retention of Symptoms IBS is a chronic disorder that may wax and wane for many years if not for a lifetime. Several studies have shown that the symptoms are usually retained (averaging 88% of the time) when patient cohorts are followed up years later (right pie chart). Importantly, there are also several studies that support the notion that a positive diagnosis as determined by the use of symptom-based criteria and exclusion of red flags is not associated with a change in diagnoses. The summarized data shows that no other diagnosis is made 98% of the time when patients are followed for several years. Also, most of the other diagnoses that are subsequently found (e.g., hypothyroidism, peptic ulcer) may be considered to be concurrent diagnoses. Thompson WG, and Heaton KW. Irritable Bowel Syndrome, 1999, Health Press, OxfordSlide 129 Prognosis: Change in Diagnosis and Retention of Symptoms IBS is a chronic disorder that may wax and wane for many years if not for a lifetime. Several studies have shown that the symptoms are usually retained (averaging 88% of the time) when patient cohorts are followed up years later (right pie chart). Importantly, there are also several studies that support the notion that a positive diagnosis as determined by the use of symptom-based criteria and exclusion of red flags is not associated with a change in diagnoses. The summarized data shows that no other diagnosis is made 98% of the time when patients are followed for several years. Also, most of the other diagnoses that are subsequently found (e.g., hypothyroidism, peptic ulcer) may be considered to be concurrent diagnoses. Thompson WG, and Heaton KW. Irritable Bowel Syndrome, 1999, Health Press, Oxford

9. Differential Diagnosis Differential Diagnosis There are 6 major categories to consider in the differential diagnosis of chronic or recurrent abdominal discomfort and bowel dysfunction: 1) Malabsorptive conditions including post-gastrectomy, intestinal diseases (e.g., sprue) or pancreatic insufficiency can cause cramps and diarrhea; 2) Dietary factors including lactose (in lactose intolerant patients), caffeine, alcohol, fat containing or gas producing (e.g., cruciferous vegetables) foods, may exacerbate or, if taken in excess, explain the symptoms; 3) Infection may be due to bacterial etiologies (e.g., Campylobactor jejuni, salmonella species) if recent in onset, but more typically may be due to a common parasite like Giardia lamblia; 4) Inflammatory bowel disease, typically Crohn�s disease more than ulcerative colitis can mimic IBS, and less common microscopic colitides (e.g., collagenous colitis or mast-cell disease) when being considered, can be diagnosed by colonic biopsy; 5) Psychologic disorders, particularly panic disorder, depression and somatization are associated with increased symptom reporting; and 6) miscellaneous conditions including endometriosis, endocrine tumors (e.g., carcinoid, Zollinger-Ellison syndrome, VIPoma) and HIV disease and associated infections should be considered, but are relatively uncommon.Drossman DA, Camilleri M, Whitehead WE, American Gastroenterological Association technical review on irritable bowel syndrome. Gastroenterology 1997; 112:2137 Drossman DA, Irritable bowel syndrome. The Gastroenterologist. 1994; 2:315-26. Differential Diagnosis

10. Alarm Symptoms Anemia Fever Heme-positive stools New or recent onset if > 50 years old Nocturnal symptoms Recent antibiotic use Weight loss Palpable abdominal or rectal mass Persistent diarrhea or severe constipation

11. Initial Investigations CBC ESR/CRP Low albumin Ferritin SMA-6 Liver Function Tests Calcium B12/folate Thyroid panel Occult Blood Testing

13. Integrative Medicine Clinical Approach Science-based approach to healthcare: Emphasis on Wellness and Wholeness Restores balance Focus on individual�s unique biochemistry Employs individually tailored treatments

14. Evaluating Gut Function Digestion - Interaction Absorption - Assimilation Excretion � Elimination NeuroEndocrine Regulation Immune System Modulation

15. At birth - digestive tract of humans is sterile. Colonized by microbes within the first few days of life At first, predominantly bifidobacteria (breast fed infants). With the introduction of other foods, a diverse microbial population develops in the gastrointestinal tract. By now, of all the cells in a human body, the overwhelming majority are non-human.

16. Colonization begins with birth and breast-feeding and continuing through life, leading to: 100 trillion bacteria 70% of human immune system localized in digestive tract accounts for half of the volume of contents in the colon

17. GUT INFLAMMATION! There is a constant state of balanced chronic inflammation present in the gastrointestinal tract. This physiologic inflammation is essential for the maturing of the immune system and development of the normal morphology of the intestinal mucosa.

18. Metabolic Functions of Bacteria Mucous production Short Chain Fatty Acids Metabolism Primary Bile Acid Deconjugation Vitamin absorption Fats, TG, Cholesterol regulation Undigested dietary fiber breakdown Gas production Fermentation Production of Phenols Breakdown of starch & oligo-saccharides

21. Important immune system effects of intestinal flora: activation of mucosal-associated lymphoid tissue (MALT) immunologic sampling via M cells dendritic cells and antigen-presenting cells (APCs) initiate immune response balancing TH1/ TH2 cytokine profiles Important immune system effects include: activation of mucosal-associated lymphoid tissue (MALT) balancing TH1/ TH2 cytokine profiles immunologic sampling via M cells dendritic cells and antigen-presenting cells (APCs) initiate immune responseImportant immune system effects include: activation of mucosal-associated lymphoid tissue (MALT) balancing TH1/ TH2 cytokine profiles immunologic sampling via M cells dendritic cells and antigen-presenting cells (APCs) initiate immune response

22. Important immune system effects of intestinal flora: activation of mucosal-associated lymphoid tissue (MALT) immunologic sampling via M cells dendritic cells and antigen-presenting cells (APCs) initiate immune response balancing TH1/ TH2 cytokine profiles Important immune system effects include: activation of mucosal-associated lymphoid tissue (MALT) balancing TH1/ TH2 cytokine profiles immunologic sampling via M cells dendritic cells and antigen-presenting cells (APCs) initiate immune responseImportant immune system effects include: activation of mucosal-associated lymphoid tissue (MALT) balancing TH1/ TH2 cytokine profiles immunologic sampling via M cells dendritic cells and antigen-presenting cells (APCs) initiate immune response

25. Hygiene Hypothesis Altered microbial education: Improved sanitation Increased refrigeration Increased sterile food consumption Decreased fermented food consumption Decreased infection Increased antibiotics Vaccination Delayed exposure to childhood infections

26. Let them eat . . . dirt? Children who are �too clean� are more likely to develop asthma & atopy Mycobacteria in dirt stimulate cell-mediated (TH-1) immunity whereas vaccinations stimulate humoral immunity (TH-2) A modern, sanitized, vaccinated child is likely to over-develop TH-2 immunity and under-develop TH-1 immunity, rendering him or her susceptible to asthma & atopy

27. Post-Natal Development of Mucosal Immunity Antigen Exposure and Nutrition � sub-optimal stimulation of the sIgA-dependent mucosal barrier function ? increased frequency of: allergies, asthma, inflammatory mucosal disorders INCREASED RISK OF SYSTEMIC INFLAMMATION Infants with a family history of atopic allergy who received a Lactobacillus probiotic had a 50% ? in atopy @ 2yo. Brandtzaeg P. Current Understanding of Gastrointestinal Immunoregulation and Its Relation to Food Allergy. Ann NY Acad Sci. 2002;964:14-45. Post-Natal Development of Mucosal Immunity Antigen Exposure and Nutrition � sub-optimal stimulation of the sIgA-dependent mucosal barrier function may lead to the increased frequency of certain diseases, such as allergies, asthma, and other inflammatory mucosal disorders (e.g. Crohn�s Disease). This �Hygiene Hypothesis� has been tested, for example: infants with a family history of atopic allergy had a 100% higher prevalence @ 2yo than infants who received a Lactobacillus probiotic. We see that the reduced microbial load in infancy has led to an increasing incidence of allergy. Brandtzaeg P. Current Understanding of Gastrointestinal Immunoregulation and Its Relation to Food Allergy. Ann NY Acad Sci. 2002;964:14-45. Post-Natal Development of Mucosal Immunity Antigen Exposure and Nutrition � sub-optimal stimulation of the sIgA-dependent mucosal barrier function may lead to the increased frequency of certain diseases, such as allergies, asthma, and other inflammatory mucosal disorders (e.g. Crohn�s Disease). This �Hygiene Hypothesis� has been tested, for example: infants with a family history of atopic allergy had a 100% higher prevalence @ 2yo than infants who received a Lactobacillus probiotic. We see that the reduced microbial load in infancy has led to an increasing incidence of allergy.

28. Post-Natal Development of Mucosal Immunity Mucosal Homeostasis vs. Allergy Intestinal TH1 cell activity is minimal: due to decreased microbial stimulation requires the presence of commensal bacteria to drive TH1 dominance. Breast milk contains immunoregulatory factors that stimulate lactic-acid producing bacteria. This also promotes a TH1 cytokine balance and oral tolerance. Brandtzaeg P. Current Understanding of Gastrointestinal Immunoregulation and Its Relation to Food Allergy. Ann NY Acad Sci. 2002;964:14-45. Post-Natal Development of Mucosal Immunity Antigen Exposure and Nutrition � sub-optimal stimulation of the sIgA-dependent mucosal barrier function may lead to the increased frequency of certain diseases, such as allergies, asthma, and other inflammatory mucosal disorders (e.g. Crohn�s Disease). This �Hygiene Hypothesis� has been tested, for example: infants with a family history of atopic allergy had a 100% higher prevalence @ 2yo than infants who received a Lactobacillus probiotic. We see that the reduced microbial load in infancy has led to an increasing incidence of allergy. Brandtzaeg P. Current Understanding of Gastrointestinal Immunoregulation and Its Relation to Food Allergy. Ann NY Acad Sci. 2002;964:14-45. Post-Natal Development of Mucosal Immunity Antigen Exposure and Nutrition � sub-optimal stimulation of the sIgA-dependent mucosal barrier function may lead to the increased frequency of certain diseases, such as allergies, asthma, and other inflammatory mucosal disorders (e.g. Crohn�s Disease). This �Hygiene Hypothesis� has been tested, for example: infants with a family history of atopic allergy had a 100% higher prevalence @ 2yo than infants who received a Lactobacillus probiotic. We see that the reduced microbial load in infancy has led to an increasing incidence of allergy.

30. GUT in BALANCE! There is a constant state of balanced chronic inflammation present in the gastrointestinal tract. This physiologic inflammation is essential for the maturing of the immune system and development of the normal morphology of the intestinal mucosa.

31. Host-Microbe CrossTalk There is a delicate BALANCE: Innocuous Food Antigens VS. Normal Flora VS. Invasive Pathogens

32. 1st Line of Recognition aka �Oral Tolerance� The first critical step is differentiation between self and non-self. Increases O3 & decreased O6, in utero, leads to stimulation and development of oral tolerance!

33. 1st Line of Recognition aka �Oral Tolerance� The first critical step is differentiation between self and non-self. Mucosal immune development requires environmental contact with commensal microflora and infections i.e. Immuno-Exercise = FITNESS!

34. FITNESS?

35. Host-Microbe CrossTalk There is a delicate BALANCE: Innocuous Food Antigens VS. Normal Flora VS. Invasive Pathogens

37. Probiotics ? Anti-Inflammatory Recent evidence demonstrates the anti-inflammatory and anti-allergic effects of probiotics on healthy infant gut. One mechanism of action includes reversal of increased intestinal permeability (aka �Leaky Gut�)

39. GUT INFLAMMATION! There is a constant state of balanced chronic inflammation present in the gastrointestinal tract. This physiologic inflammation is essential for the maturing of the immune system and development of the normal morphology of the intestinal mucosa.

40. Neutrophils are mobilized and activated in the gut in response to: Cell or tissue damage Increased permeability of the mucosa Infectious processes Reliable marker for the presence of infectious, inflammatory or malignant disease

41. Here we see fecal calprotectin levels on the left and three groups of patients along the bottom. You can see that sensitivity and specificity are very high for this test when differentiating between CD and IBS. Note, however, that nearly 20% of the IBS subjects had increased inflammation. Although a minority, some IBS patients do have inflammation present. Adapted from Tibble J, et al. A simple method for assessing intestinal inflammation in Crohn�s disease. Gut 2000;47:506-513. Here we see fecal calprotectin levels on the left and three groups of patients along the bottom. You can see that sensitivity and specificity are very high for this test when differentiating between CD and IBS. Note, however, that nearly 20% of the IBS subjects had increased inflammation. Although a minority, some IBS patients do have inflammation present. Adapted from Tibble J, et al. A simple method for assessing intestinal inflammation in Crohn�s disease. Gut 2000;47:506-513.

42. Dysbiosis: A state of imbalanced microbial ecology that contributes to disease The overgrowth of micro-organisms of low intrinsic virulence induces disease by altering the nutritional status and/or the immune response of the host elimination capacity

45. Host-Flora Interactions Look at the massive amount of influence the intestinal flora has on our metabolism! 10x the number of cells 100x the genomic material Metabolic activity > liver 3# of body mass THE HIDDEN ORGAN!!!

46. Flora Balance Dysbiosis Broad-spectrum antibiotics Chronic maldigestion (including PPIs) Chronic constipation Stress suppresses Lactobacillus, Bifidobacteria, and sIgA Catecholamines stimulate growth of gram-negative organisms 45-50% of total body production of NE occurs in mesenteric organs Anger or fear increases Bacteroides fragilis Stress: Study on 20 infant rhesus macaques separated from their mothers: Over the wk of separation, there was a significant decrease in Lacto concentration that followed a brief increse in Lacto shedding on the 1st day post-separation. An inverse correlation also found between fecal concentrations of Shigella and Campylobacter and shed Lacto. (PMID #10461128) Stress also leads to reduced production of mucin and a decreased presence of acidic mucopolysaccharides on the mucosal surface. Both of these factors normally inhibit pathogens from colonizing. (PMID #3657919) Study of Soviet cosmonauts returning from space: Decrease in bifido and Lacto. (PMID #3657919) In vitro study of effects of catecholamines on growth of bugs: The addition of NE, epi, dopamine, and dopa to E coli cultures led to increased growth compared to non-catecholamine-supplemented cultures. The largest increase in growth observed with NE, including E coli, Yersinia enterocolitica, and Pseudomonas aeruginosa (PMID #1731173) Stress ? increased catecholamines ? increased growth (esp by NE) of pathogens in the intestine. (PMID #2663100) 45-50% of total body production of NE occurs in the mesenteric organs (PMID 7733289). Lots of catecholamines wind up in the gut lumen from �spillover� (concentration gradient within the mesenteric organs). Same spillover effect occurs with serotonin (PMID 8371072) 20-30% rise in proportion of Bacteroides fragilis subsp. thetaiotamicron in feces of individuals experiencing anger or fear. Effect may be mediated by epinephrine, which stimulates both intestinal motility and bile flow (Jones GP� book). Bile enhances growth of this organism (PMID #98032).Stress: Study on 20 infant rhesus macaques separated from their mothers: Over the wk of separation, there was a significant decrease in Lacto concentration that followed a brief increse in Lacto shedding on the 1st day post-separation. An inverse correlation also found between fecal concentrations of Shigella and Campylobacter and shed Lacto. (PMID #10461128) Stress also leads to reduced production of mucin and a decreased presence of acidic mucopolysaccharides on the mucosal surface. Both of these factors normally inhibit pathogens from colonizing. (PMID #3657919) Study of Soviet cosmonauts returning from space: Decrease in bifido and Lacto. (PMID #3657919) In vitro study of effects of catecholamines on growth of bugs: The addition of NE, epi, dopamine, and dopa to E coli cultures led to increased growth compared to non-catecholamine-supplemented cultures. The largest increase in growth observed with NE, including E coli, Yersinia enterocolitica, and Pseudomonas aeruginosa (PMID #1731173) Stress ? increased catecholamines ? increased growth (esp by NE) of pathogens in the intestine. (PMID #2663100) 45-50% of total body production of NE occurs in the mesenteric organs (PMID 7733289). Lots of catecholamines wind up in the gut lumen from �spillover� (concentration gradient within the mesenteric organs). Same spillover effect occurs with serotonin (PMID 8371072) 20-30% rise in proportion of Bacteroides fragilis subsp. thetaiotamicron in feces of individuals experiencing anger or fear. Effect may be mediated by epinephrine, which stimulates both intestinal motility and bile flow (Jones GP� book). Bile enhances growth of this organism (PMID #98032).

47. Common Symptoms of Parasites Diarrhea or constipation Abdominal pain Belching, flatulence, distention Anorexia, nausea, chills, fever, headache, rash, pruritis Blood or mucous in stools Intractable fatigue And don�t forget white, foot-long worms coming out of the nose, mouth, and anus, as one of the more subtle signs. http://www.dpd.cdc.gov/dpdx/HTML/Para_Health.htm � everything you ever wanted to know about parasitesAnd don�t forget white, foot-long worms coming out of the nose, mouth, and anus, as one of the more subtle signs. http://www.dpd.cdc.gov/dpdx/HTML/Para_Health.htm � everything you ever wanted to know about parasites

48. Common Parasites A recent study revealed 23.5 % of clinical samples tested positive for at least one parasite (3,223/ 13,857) Blastocystis hominis (12.5%) Dientamoeba fragilis (3.8%) Entamoeba spp. (3.4%) Endolimax nana (2.2%) Giardia lamblia (0.7%)

49. Pharmaceutical Treatmentfor Parasites Medical Letter� lists pharmaceutical protocols (Flagyl & other �-azoles�) Metronidazole (Flagyl) Tinidazole (Tindamax) Nitazoxanide (Alinia) Iodoquinol (Yodoxin) Paromomycin (Humatin)

50. Natural Treatment for Parasites Herbal Therapies: Juglans nigra (black walnut hulls) Artemesia absinthium/annua (wormwood) Quassia amara (bitterwood) Allium sativum (garlic) Hydrastis canadensis (goldenseal) Oil of Oregano Olive Leaf Extract

51. Evaluating Gut Function Digestion - Interaction Absorption - Assimilation Excretion � Elimination NeuroEndocrine Regulation Immune System Modulation

52.

53. Hypochlorhydria - Causes Aging 50% of people over 60 80% of people over 80 Fasting Viral or bacterial infection (fever) Any debilitated chronic condition (~600-800 Cal/day to concentrate enough H+ ions) H2 blockers, PPIs and antacid abuse Davies D and James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Brit J Med 1930;1:1-14. Rafsky HA and Weingarten M. A study of the gastric secretory response in the aged. Gastroent 1946;348-52.Davies D and James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Brit J Med 1930;1:1-14. Rafsky HA and Weingarten M. A study of the gastric secretory response in the aged. Gastroent 1946;348-52.

54. Hypochlorhydria � Consequences Small Intestinal Bacterial Overgrowth (SSx: carbohydrate intolerance + immediate bloating) Dysbiosis Chronic Candida Infections Mineral Deficiencies (Ca, Mg, Zn, Fe, Cr, Mo, Mn, Cu) B12 deficiency

55. Pancreatic Insufficiency Common dysfunction of GI system Pancreatic enzymes commonly prescribed empirically A number of conditions are associated with pancreatic insufficiency without overt symptoms of maldigestion Pancreatic Elastase provides the most accurate non-invasive measure of the exocrine pancreas

56. Pancreatic Insufficiency Common symptoms Post-prandial bloating, pain, or nausea Loose or watery stools Undigested food in stool Hypochlorhydria Food intolerances Gastroesophageal reflux symptoms Loose or watery stools - particularly foul-smelling � the kind that drives people from the house! Floaters Vs. sinkersLoose or watery stools - particularly foul-smelling � the kind that drives people from the house! Floaters Vs. sinkers

57. Evaluating Gut Function Digestion - Interaction Absorption - Assimilation Excretion � Elimination

58. Absorption Intestinal mucosa�s paradoxical role Absorbing nutrients Excluding toxins and larger molecules Any breach of the mucosa can lead to Malabsorption Increased exposure to toxins & antigens

59. Malabsorption - Causes Maldigestion Hypochlorhydria Bacterial overgrowth of the small intestine Deficient bile production Chronic inflammation of the small intestine Food sensitivities Gluten enteropathy Inflammatory bowel conditions Irritable bowel/Colonic HyperActivity

60. MalAbsorption - Assessment Endoscopy and histological assessment Pancreatic imaging Non-invasive tests for small bowel enteropathy Fecal Fats Testing for Celiac Disease Intestinal Permeability testing

61. Healthy Gut

62. Leaky Gut & Malabsorption

63. Increased Intestinal Permeability CAUSES: IBD (Crohn�s disease) NSAID therapy Small bowel overgrowth Celiac sprue Protozoal infections Food allergy Chronic alcoholism Diarrhea Strenuous exercise Increasing age Nutritional depletion

64. Altered Intestinal Permeability

65. Food Allergy & IBS IgG Food Allergy testing with ELISA performed on 150 patients. TRUE Elimination diet given to 75 patients SHAM Elimination diet given to 75 patients 26% decline in IBS symptoms and improved QOL, which reversed when �allergens� added back

66. Food Allergy Studies show that desmosomal rupture can be provoked by histamine �Evaluation of intestinal permeability in this way provides an objective means of diagnosing food allergy and assessing the effectiveness of anti-allergic agents such as sodium cromoglycate�

67. Food allergies/sensitivities ELISA Testing IgE and IgG Most food intolerances/sensitivities are IgG related Symptoms appear up to 24-72 hrs after ingestion of offending food

68. IgE vs IgG IgE immediate sensitivity fixed to mast cells serum Ab levels stay fairly constant but low reintroduction of foods very difficult IgG delayed sensitivity stimulate phagocytosis serum Ab levels vary with Ag exposure reintroduction possible after 3-6 mo. avoidance

69. Intestinal Permeability � Treatment Options Endogenous Protection: sIgA (blocks potentially antigenic proteins) Mucin Exogenous Protection: L-Glutamine (supports enterocytes and microvilli) N-acetylglucosamine (mucous enhancement) Quercetin (anti-inflammatory) Probiotics (normalize gut flora and increase sIgA)

70. L-Glutamine Supplemental L-Glutamine Preferred fuel for enterocytes of small intestine increases intestinal villous height stimulates gut mucosal cellular proliferation maintains mucosal integrity prevents intestinal hyperpermeability and bacterial translocation

71. Celiac Disease Gluten intolerance is an IgG and IgA auto-immune phenomenon Prevalence Previous US Studies - 1 in 6,000 Studies conducted in Europe � 1 in 105-300 In some studies of patients with IBS the rate is up to 5% Average 11 years = Time to Diagnosis! Until recently, celiac disease was considered to be relatively uncommon. Previous U.S. figures suggested that it affected one in 6,000 persons.6 However, population studies published in the past four years suggest a much higher prevalence, particularly in persons of European ancestry.7 Studies conducted in Europe estimate the seroprevalence of celiac disease to be one case per 130 to 300 persons.8-10 In a recent U.S. study,11 investigators tested sera from 2,000 healthy Red Cross blood donors and found eight samples that were positive for antibodies associated with gluten-sensitive enteropathy (seven samples from white persons, one sample from a black person). The seroprevalence rate in this study (one case per 250 persons tested) is consistent with the rates in European studies. The case-control study was done at a university hospital in which 300 consecutive new irritable bowel syndrome patients who met the Rome II criteria for their diagnosis were compared against 300 healthy age and sex-matched controls. Both groups were investigated for celiac disease by analysis of their serum IgA antigliadin, IgG antigliadin, and endomysial antibodies (EMA). Patients and controls with positive antibody results were offered duodenal biopsy to confirm the possibility of celiac disease. An amazing 66 patients with irritable bowel syndrome tested positive for the antibodies, and 14 of them or 4.6% had active celiac disease as compared with 2 or 0.66% of the non-IBS matched controls. In other words there is a sevenfold increase over the normal population in the number of people with IBS who have celiac disease. All of the patients with celiac disease in the IBS group were therefore misdiagnosed. Lancet Nov 2001 Volume 358, Number 9292 1504-08 03 March edition of American Journal of Gastroenterology indicate that around 4% of those who suffer from migraine headaches may have celiac disease, and in such cases a gluten-free diet can reduce or eliminate migraine symptoms. Am J Gastroenterol. 2003;98:625-629 Ingested protein does not normally provoke an immune response. This phenomenon is termed "oral tolerance." Patients who exhibit true allergy to an ingested protein (e.g., milk or soy protein) have a typical IgE-mediated response consisting of urticaria, angioedema, and bronchoreactivity. The autoimmunity in gluten-sensitive enteropathy involves plasma cells that produce IgA and IgG; there is little or no IgE involvement. Current theory suggests that ingested alpha-gliadin (a component of the gluten protein) and related peptides bind with tissue transglutaminase (a ubiquitous intracellular enzyme) in enterocytes. The alpha-gliadin is rich in glutamine; transglutaminase deamidates glutamine residues, forming glutamic acid. Deamidation enhances the immunogenicity of alpha-gliadin by creating epitopes that are recognized as foreign by host cell�mediated immunity.2 Plasma cells produce IgA and IgG that are directed against a variety of antigens, including transglutaminase, endomysium, gliadin, and reticulin. Locally elaborated lymphokines attract inflammatory cells.3 This intense local inflammatory reaction produces the villous flattening characteristic of gluten-sensitive enteropathy. Malabsorption of micronutrients (e.g., vitamins and minerals) and macronutrients (e.g., protein, carbohydrate, fat) follows. Small-bowel involvement is most prominent proximally and may be "patchy," especially in patients with "silent" celiac disease (i.e., minimal or no symptoms) and those with dermatitis herpetiformis. Approximately 95 percent of patients with celiac disease exhibit specific Human Leukocyte Antigen (HLA) class II alleles DQA1*0501 and DQB1*0201.4 Patients with type 1 diabetes, autoimmune thyroid disease,5 Sj�gren's syndrome, primary biliary cirrhosis, Addison's disease, systemic lupus erythematosus, selective IgA deficiency, and alopecia areata may also exhibit similar genotypes and are at risk for gluten-sensitive enteropathy (Table 1). Because many persons have these genotypes and only a few develop gluten-sensitive enteropathy, investigators have hypothesized that other genes or cofactors may be involved.1 Until recently, celiac disease was considered to be relatively uncommon. Previous U.S. figures suggested that it affected one in 6,000 persons.6 However, population studies published in the past four years suggest a much higher prevalence, particularly in persons of European ancestry.7 Studies conducted in Europe estimate the seroprevalence of celiac disease to be one case per 130 to 300 persons.8-10 In a recent U.S. study,11 investigators tested sera from 2,000 healthy Red Cross blood donors and found eight samples that were positive for antibodies associated with gluten-sensitive enteropathy (seven samples from white persons, one sample from a black person). The seroprevalence rate in this study (one case per 250 persons tested) is consistent with the rates in European studies. The case-control study was done at a university hospital in which 300 consecutive new irritable bowel syndrome patients who met the Rome II criteria for their diagnosis were compared against 300 healthy age and sex-matched controls. Both groups were investigated for celiac disease by analysis of their serum IgA antigliadin, IgG antigliadin, and endomysial antibodies (EMA). Patients and controls with positive antibody results were offered duodenal biopsy to confirm the possibility of celiac disease. An amazing 66 patients with irritable bowel syndrome tested positive for the antibodies, and 14 of them or 4.6% had active celiac disease as compared with 2 or 0.66% of the non-IBS matched controls. In other words there is a sevenfold increase over the normal population in the number of people with IBS who have celiac disease. All of the patients with celiac disease in the IBS group were therefore misdiagnosed. Lancet Nov 2001 Volume 358, Number 9292 1504-08 03 March edition of American Journal of Gastroenterology indicate that around 4% of those who suffer from migraine headaches may have celiac disease, and in such cases a gluten-free diet can reduce or eliminate migraine symptoms. Am J Gastroenterol. 2003;98:625-629 Ingested protein does not normally provoke an immune response. This phenomenon is termed "oral tolerance." Patients who exhibit true allergy to an ingested protein (e.g., milk or soy protein) have a typical IgE-mediated response consisting of urticaria, angioedema, and bronchoreactivity. The autoimmunity in gluten-sensitive enteropathy involves plasma cells that produce IgA and IgG; there is little or no IgE involvement. Current theory suggests that ingested alpha-gliadin (a component of the gluten protein) and related peptides bind with tissue transglutaminase (a ubiquitous intracellular enzyme) in enterocytes. The alpha-gliadin is rich in glutamine; transglutaminase deamidates glutamine residues, forming glutamic acid. Deamidation enhances the immunogenicity of alpha-gliadin by creating epitopes that are recognized as foreign by host cell�mediated immunity.2 Plasma cells produce IgA and IgG that are directed against a variety of antigens, including transglutaminase, endomysium, gliadin, and reticulin. Locally elaborated lymphokines attract inflammatory cells.3 This intense local inflammatory reaction produces the villous flattening characteristic of gluten-sensitive enteropathy. Malabsorption of micronutrients (e.g., vitamins and minerals) and macronutrients (e.g., protein, carbohydrate, fat) follows. Small-bowel involvement is most prominent proximally and may be "patchy," especially in patients with "silent" celiac disease (i.e., minimal or no symptoms) and those with dermatitis herpetiformis. Approximately 95 percent of patients with celiac disease exhibit specific Human Leukocyte Antigen (HLA) class II alleles DQA1*0501 and DQB1*0201.4 Patients with type 1 diabetes, autoimmune thyroid disease,5 Sj�gren's syndrome, primary biliary cirrhosis, Addison's disease, systemic lupus erythematosus, selective IgA deficiency, and alopecia areata may also exhibit similar genotypes and are at risk for gluten-sensitive enteropathy (Table 1). Because many persons have these genotypes and only a few develop gluten-sensitive enteropathy, investigators have hypothesized that other genes or cofactors may be involved.1

72. Serologic Tests for Celiac Disease When the diagnosis of gluten-sensitive enteropathy is suspected, serologic tests can identify many affected patients.19 (Figure 5). IgA antiendomysial antibody has been shown to be 85 to 100 percent sensitive and 96 to 100 percent specific for celiac disease. IgA antiendomysial antibody is measured using direct immunofluorescence of monkey esophagus or umbilical cord tissue processed with suspect serum The presence of IgA antiendomysial and antitransglutaminase antibodies correlates with intestinal damage. Tests for these antibodies are highly sensitive in patients with total and subtotal villous atrophy. IgA antiendomysial antibody testing has been reported to be 100 percent sensitive in patients with total villous atrophy. The combination of IgA antiendomysial antibody and IgG and IgA antigliadin antibodies detects 76 percent of patients with mucosal damage. It is important to note that 2 to 3 percent of patients with gluten-sensitive enteropathy also have selective IgA deficiency. Because these patients may not produce the diagnostic IgA antibodies, a positive IgG antigliadin antibody test may be the only serologic evidence of the disease. If clinical suspicion is high, quantitative IgA measurements should be obtained in these patients.26 Endoscopy and biopsy should be strongly considered in patients with selective IgA deficiency. Declining autoantibody titers correlate with resolution of the gastrointestinal lesion and may be used to document clinical improvement. In equivocal cases or when a patient has been on a gluten-free diet, a gluten challenge test may be used to provoke the gastrointestinal lesion and serologic response When the diagnosis of gluten-sensitive enteropathy is suspected, serologic tests can identify many affected patients.19 (Figure 5). IgA antiendomysial antibody has been shown to be 85 to 100 percent sensitive and 96 to 100 percent specific for celiac disease. IgA antiendomysial antibody is measured using direct immunofluorescence of monkey esophagus or umbilical cord tissue processed with suspect serum The presence of IgA antiendomysial and antitransglutaminase antibodies correlates with intestinal damage. Tests for these antibodies are highly sensitive in patients with total and subtotal villous atrophy. IgA antiendomysial antibody testing has been reported to be 100 percent sensitive in patients with total villous atrophy. The combination of IgA antiendomysial antibody and IgG and IgA antigliadin antibodies detects 76 percent of patients with mucosal damage. It is important to note that 2 to 3 percent of patients with gluten-sensitive enteropathy also have selective IgA deficiency. Because these patients may not produce the diagnostic IgA antibodies, a positive IgG antigliadin antibody test may be the only serologic evidence of the disease. If clinical suspicion is high, quantitative IgA measurements should be obtained in these patients.26 Endoscopy and biopsy should be strongly considered in patients with selective IgA deficiency. Declining autoantibody titers correlate with resolution of the gastrointestinal lesion and may be used to document clinical improvement. In equivocal cases or when a patient has been on a gluten-free diet, a gluten challenge test may be used to provoke the gastrointestinal lesion and serologic response

73. Genetic Tests for Celiac Disease Genetic pre-disposition Always present in Celiac Disease: HLA-DQ2 HLA-DQ8 Negative Predictive Value > 99% Positive Predictive Value is only 1-3%! (i.e. a positive test tells you nothing) When the diagnosis of gluten-sensitive enteropathy is suspected, serologic tests can identify many affected patients.19 (Figure 5). IgA antiendomysial antibody has been shown to be 85 to 100 percent sensitive and 96 to 100 percent specific for celiac disease. IgA antiendomysial antibody is measured using direct immunofluorescence of monkey esophagus or umbilical cord tissue processed with suspect serum The presence of IgA antiendomysial and antitransglutaminase antibodies correlates with intestinal damage. Tests for these antibodies are highly sensitive in patients with total and subtotal villous atrophy. IgA antiendomysial antibody testing has been reported to be 100 percent sensitive in patients with total villous atrophy. The combination of IgA antiendomysial antibody and IgG and IgA antigliadin antibodies detects 76 percent of patients with mucosal damage. It is important to note that 2 to 3 percent of patients with gluten-sensitive enteropathy also have selective IgA deficiency. Because these patients may not produce the diagnostic IgA antibodies, a positive IgG antigliadin antibody test may be the only serologic evidence of the disease. If clinical suspicion is high, quantitative IgA measurements should be obtained in these patients.26 Endoscopy and biopsy should be strongly considered in patients with selective IgA deficiency. Declining autoantibody titers correlate with resolution of the gastrointestinal lesion and may be used to document clinical improvement. In equivocal cases or when a patient has been on a gluten-free diet, a gluten challenge test may be used to provoke the gastrointestinal lesion and serologic response When the diagnosis of gluten-sensitive enteropathy is suspected, serologic tests can identify many affected patients.19 (Figure 5). IgA antiendomysial antibody has been shown to be 85 to 100 percent sensitive and 96 to 100 percent specific for celiac disease. IgA antiendomysial antibody is measured using direct immunofluorescence of monkey esophagus or umbilical cord tissue processed with suspect serum The presence of IgA antiendomysial and antitransglutaminase antibodies correlates with intestinal damage. Tests for these antibodies are highly sensitive in patients with total and subtotal villous atrophy. IgA antiendomysial antibody testing has been reported to be 100 percent sensitive in patients with total villous atrophy. The combination of IgA antiendomysial antibody and IgG and IgA antigliadin antibodies detects 76 percent of patients with mucosal damage. It is important to note that 2 to 3 percent of patients with gluten-sensitive enteropathy also have selective IgA deficiency. Because these patients may not produce the diagnostic IgA antibodies, a positive IgG antigliadin antibody test may be the only serologic evidence of the disease. If clinical suspicion is high, quantitative IgA measurements should be obtained in these patients.26 Endoscopy and biopsy should be strongly considered in patients with selective IgA deficiency. Declining autoantibody titers correlate with resolution of the gastrointestinal lesion and may be used to document clinical improvement. In equivocal cases or when a patient has been on a gluten-free diet, a gluten challenge test may be used to provoke the gastrointestinal lesion and serologic response

74. Diagnosis of Celiac Disease IgG and IgA antigliadin antibodies are also useful in diagnosing celiac disease. The antibody directed against endomysium has recently been identified as identical to the antibody directed against (tissue) transglutaminase. An enzyme-linked immunosorbent assay has been developed to measure IgA antitransglutaminase; this test will generally replace the more tedious direct fluorescent antibody test for IgA antiendomysial antibody.20-22 In diagnosing celiac disease, antitransglutaminase antibody is considered to be approximately as sensitive and specific as antiendomysial antibody IgG and IgA antigliadin antibodies are also useful in diagnosing celiac disease. The antibody directed against endomysium has recently been identified as identical to the antibody directed against (tissue) transglutaminase. An enzyme-linked immunosorbent assay has been developed to measure IgA antitransglutaminase; this test will generally replace the more tedious direct fluorescent antibody test for IgA antiendomysial antibody.20-22 In diagnosing celiac disease, antitransglutaminase antibody is considered to be approximately as sensitive and specific as antiendomysial antibody

75. Other Indicators of Malabsorption Investigations of change in bowel habits due to specific conditions: Small Bowel Bacterial Overgrowth (SBBO) [aka Bacterial Overgrowth of Small Intestine] Bile salt malabsorption Lactose malabsorption

76. Gut Flora in SBBO Composition varies: Coliforms and strict anaerobes Concentrations always higher than normal Bottom line� Bacteria that are normal in the colon may produce deleterious effects within the delicate environment of the small intestine� Bottom line:� Many of the same microorganisms that are normal and even beneficial in the colon may lead to deleterious effects within the delicate environment of the SI.Bottom line:� Many of the same microorganisms that are normal and even beneficial in the colon may lead to deleterious effects within the delicate environment of the SI.

77. Clinical Consequences of Bacterial Overgrowth Gas & bloating, abdominal discomfort Bacterial fermentation of intraluminal sugars Classic SBBO presentation: Megaloblastic anemia (B12 deficiency) Weight loss and diarrhea secondary to fat malabsorption The classic BOSI syndrome is characterized by� Gas & bloating result from bacterial fermentation of intraluminal sugars and associated production of gases. The classic BOSI syndrome is characterized by� Gas & bloating result from bacterial fermentation of intraluminal sugars and associated production of gases.

78. Small Bowel Bacterial Overgrowth SIBO is an abnormal colonization wtihin the SI by bacteria normally found in the colon. SIBO is a frequently overlooked contributing factor in several common disorders� (IBS study (>200 IBS pts): Pimentel M, Chow EJ, Lin HC: Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 95:3503-3506, 2000) Fibromyalgia & CFS: (Pimentel M, Chow EJ, Hallegua D, et al: Small intestinal bacterial overgrowth: A possible association with fibromyalgia. J Musculoskelet Pain 9:107-113, 2001_ (Aaron LA, Burke MM, Buchwald D: Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 160:221-227, 200) SIBO is an abnormal colonization wtihin the SI by bacteria normally found in the colon. SIBO is a frequently overlooked contributing factor in several common disorders� (IBS study (>200 IBS pts): Pimentel M, Chow EJ, Lin HC: Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 95:3503-3506, 2000) Fibromyalgia & CFS: (Pimentel M, Chow EJ, Hallegua D, et al: Small intestinal bacterial overgrowth: A possible association with fibromyalgia. J Musculoskelet Pain 9:107-113, 2001_ (Aaron LA, Burke MM, Buchwald D: Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 160:221-227, 200)

79. Treatment for SBBO Flora in SBBO is typically comprised of both coliforms and strict anaerobes Non-absorbed antibiotics may minimize side effects: Rifaximin 7 day course of Rifaximin (400 mg TID) normalized breath H2 in 70% of pts; TCN normalized breath H2 in 27% of pts. Probiotics to minimize side effects Most pts with clinically significant SBBO host a flora largely consisting of anerobes; however, some SBBO pts harbor a predominance of gram-negative aerobes, e.g., E coli, Klebsiella, or Pseudomonas ? need agent that targets both aerobes and anaerobes. For most pts, a single course (7-10 days) is adequate. (TCN dose = 250 mg QID) In others, cyclic therapy (e.g. 1 week out of q. 4) or continuous (e.g. 1-2 mos) may be needed. (Keep in mind that prolonged AB therapy increases the risk of C diff infection and bacterial resistance). Up to 60% of SBBO pts are already resistant to TCN. Augmentin = Amoxicillin with clavulanic acidMost pts with clinically significant SBBO host a flora largely consisting of anerobes; however, some SBBO pts harbor a predominance of gram-negative aerobes, e.g., E coli, Klebsiella, or Pseudomonas ? need agent that targets both aerobes and anaerobes. For most pts, a single course (7-10 days) is adequate. (TCN dose = 250 mg QID) In others, cyclic therapy (e.g. 1 week out of q. 4) or continuous (e.g. 1-2 mos) may be needed. (Keep in mind that prolonged AB therapy increases the risk of C diff infection and bacterial resistance). Up to 60% of SBBO pts are already resistant to TCN. Augmentin = Amoxicillin with clavulanic acid

80. Treatment for SBBO (cont) Probiotics to minimize side effects Natural approach: Broad-spectrum botanicals Enteric-coated peppermint oil to reduce symptoms? Lactobacillus acidophilus and L. casei Address underlying causes! Stasis, slow transit time, low stomach acid (betaine HCl, stop PPIs), maldigestion, lactose intolerance Temporarily restrict CHOs, especially disaccharides such as lactose Peppermint oil (dose of 0.2 ml TID) dramatically reduced GI sxs in a patient with SBO (case study), although F/U breath testing indicated some persistent SBBO. Might add an agent like berberine. (Logan AC, Beaulne TM: The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Altern Med Rev 7:410-417, 2002) Probiotics: Small, double-blind study: Significant decrease in H2 concentration was noted as early as 1 wk into tx. (Gaon D, Garmendia C, Murrielo NO, et al: Effect of Lactobacillus strains (L. casei and L. Acidophillus Strains cerela) on bacterial overgrowth-related chronic diarrhea. Medicina (B Aires) 62:159-63, 2002) Short-term (5 wks) omeprazole tx ? SBBO that was assoc�d with increased deconjugation of bile acids and fat malabsorption, thought to be induced by a shift to neutral pH in the gastric juice. (Shindo K, Machida M, Fukumura M, et al: Omeprazole induces altered bile acid metabolism. Gut 42:266-271, 1998)Peppermint oil (dose of 0.2 ml TID) dramatically reduced GI sxs in a patient with SBO (case study), although F/U breath testing indicated some persistent SBBO. Might add an agent like berberine. (Logan AC, Beaulne TM: The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Altern Med Rev 7:410-417, 2002) Probiotics: Small, double-blind study: Significant decrease in H2 concentration was noted as early as 1 wk into tx. (Gaon D, Garmendia C, Murrielo NO, et al: Effect of Lactobacillus strains (L. casei and L. Acidophillus Strains cerela) on bacterial overgrowth-related chronic diarrhea. Medicina (B Aires) 62:159-63, 2002) Short-term (5 wks) omeprazole tx ? SBBO that was assoc�d with increased deconjugation of bile acids and fat malabsorption, thought to be induced by a shift to neutral pH in the gastric juice. (Shindo K, Machida M, Fukumura M, et al: Omeprazole induces altered bile acid metabolism. Gut 42:266-271, 1998)

81. Evaluating Gut Function Digestion - Interaction Absorption - Assimilation Excretion � Elimination NeuroEndocrine Regulation Immune System Modulation

83. Integrative Therapies for IBS Treat Underlying CAUSE! Infection Inflammation Immune Dysfunction Dysbiosis MalDigestion Malabsorption Food Intolerance/ Allergies

84. Integrative Therapies Infection & Inflammation Prebiotics Probiotics Antibiotics Antimicrobial Herbs Fish Oils & EPO/GLA COX-2 inhibitors (?)

85. Integrative Therapies Digestion/ Absorption Digestive Enzymes Betaine HCL Nutritional SupplementsEnteric-coated Peppermint (& Caraway) Oil Metabolism Medical Foods Dietary Fiber (e.g. psyllium) Diet Improvement � Eat your vegetables!

86. Integrative Therapies Mind-Body Therapies Biofeedback Stress Reduction Hypnosis Acupuncture

87. The 4-R Program Remove Replace Repopulate Repair 56. Bland J, Costarella, L, Levin B, et al. Clinical Nutrition: A Functional Approach. Gig Harbor, WA; The Institute for Functional Medicine; 1999.56. Bland J, Costarella, L, Levin B, et al. Clinical Nutrition: A Functional Approach. Gig Harbor, WA; The Institute for Functional Medicine; 1999.

88. The 4-R Program Remove pathogenic organisms allergic foods Removing the source of the imbalance is the critical first step, but the functional medicine approach does not stop here�

89. The 4-R Program Replace hydrochloric acid digestive enzymes herbal support lipotropic factors

90. The 4-R Program Repopulate Lactobacilli Bifidobacteria Saccharomyces if using antibiotics

91. The 4-R Program Repair SI: glutamine, gamma oryzanol, duodenum glandular, N-acetyl glucosamine LI: fiber, butyrate Boswellia, geranium, licorice, quercetin, hydrastis, cheledonium, artemisia, aloe okra, cabbage , rice protein ,GLA, EPA fasting

92. The 5th R Rebalance modify attitude, diet and lifestyle of the patient to promote a healthier way of living

94. GI = Gut/Immune:Going to the Source for IBS & Beyond Patrick Hanaway, MD Chief Medical Officer