Triggers and Treatments in Inflammatory Bowel Disease
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Overview Things to remember about the Triggers and Treatments in gut Inflammatory Bowel Disease Discuss the pathogenesis of 25 – 30 ft long 25 – 30 ft long Inflammatory Bowel Disease (IBD) 100 sq yds of surface area 100 sq yds of surface area Clarify our understanding of likely Gut lumen is not inside’ the body Gut lumen is not ‘inside’ the body triggers and mediators in IBD Dynamic physiologic organ Dynamic physiologic organ Review potential therapeutic options in Primary functions: Primary functions: Dan Lukaczer ND IBD Digestion & absorption of nutrients Institute for Functional Medicine August 22, 2007 August 22, 2007 Barrier to differentiate friend from foe Webinar Metabolism & detoxification GUT Function: Gut Activities A Simplified Approach Immune Function Immune Function Ingestion - Digestion - Absorption - Assimilation - GUT Defense “Defense & Repair” “Defense & Repair” Host -Bacteria Mutualism - The Host- The Mechanisms: Endocrine Function Endocrine Function Undiscovered Organ “Communication” “Communication” Barriers to Access, Immune Balance: Inflammation and Oral Tolerance Oral Tolerance & Enteric Nervous System (ENS) - Immune Activation Detoxification & the Second Brain Nutrition & Nutrition & Digestion Elimination Elimination Elimination Detoxification & Elimination “In” “In” “Out” “Out” Epithelial Cells Mucins Physical barrier Physical barrier trans- Selective trans-cellular absorption Semi-permeable secretion Semi- Tight junctions: desmosones Prevent adhesion of foreign (cell adhesion proteins) bind microbes adjacent cells together and Prevent absorption of prevent paracellular absorption. macromolecules Gap junctions: proteinaceous tubes that allow materials to pass between cells. Enzymes and other Digestive Secretions enzymes- Amylase, Salivary enzymes- Amylase, Lysozyme Lysozyme Gastric HCL, Pepsin Pancreatic enzymes Bile acids Intestinal brush border Enzymes Gastrointestinal Flora: The ‘Undiscovered Organ’ Vast and complex ecosystem Over 400 species identified: 30-40 species comprising up to 99% of the total population 10x the number of cells as human body 100x the genomic material Metabolic activity greater then the liver 2-3 pounds of microbiota Location of Microbes in the Types of Microbes In the GI Stimulates the intestinal immune GI Tract system Tract Metabolic Functions of Microbiota Metabolic Functions of Microbiota At birth - digestive tract of Mucus production Undigested dietary humans is sterile. Passive anti-microbial mechanisms: Short chain fatty fiber breakdown Colonized by microbes prevent adhesion of pathogenic bacteria within the first few days of by physically competing for binding sites acids metabolism Gas production life. (displacement) Primary bile acid Fermentation At first, predominantly deconjugation bifidobacteria (breast-fed alter local microenvironment through the Production of infants). production of organic acids to make it Vitamin absorption phenols more inhospitable for other microbes. With the introduction of Fats, TG, cholesterol Breakdown of starch other foods, a diverse regulation & oligosaccharides microbial population Active anti-microbial mechanisms: develops in the . . . & Detoxification gastrointestinal tract. Lactobacillus and Bifidobacteria species secrete anti-microbial substances active against a wide variety of microbes. Metabolic Functions of Microbiota Gut Associated Lymphoid Tissue (GALT) Immunological mechanisms Immunological defense Enhance serum and intestinal IgA Largest lymph organ in the body: 50-70% response of the immune system and Increase B cell frequency in peripheral immunoglobulin producing cells are blood located within the GI tract Increase phagocytosis of E coli (a Populated by T cells, B cells, plasma cells, general marker of increased immune activated TH cells and macrophages in response) loose clusters Secretory IgA (sIgA) Predominant immunoglobulin released onto the surface of the GI mucosa. Binds to and neutralizes microbes and other antigens before they can cross the mucosal barrier. Accumulations of lymphocytes or solitary lymph follicles found scattered beneath the epithelium in Peyer’s patches IgA Secretion Oral Tolerance & Immune Activation The first critical step is differentiation non-self. between self and non-self. Mucosal immune development requires environmental contact with commensal microflora and infections The Hygiene Hypothesis Evidence for the Hygiene Hypothesis • Increased allergy results from in decreased exposure to infections ‘ Hygiene Hypothesis’ Hypothesis’ has been tested in early life (small family size, clean infants with a family history of atopic environment) allergy who received a Lactobacillus • Some research suggest better living conditions in childhood associated with probiotic. increased risk of IBD later in life 50% drop in atopy at 2 and again at 5 • Suggestion is there is sub-optimal sub- stimulation of the sIgA-dependent sIgA- dependent year follow -up compared to controls. mucosal barrier function Conclusion: reduced microbial load in • Mechanisms include altering TH1/TH2 balance and induction of T regulator infancy has led to an increasing incidence of allergy. cells Brandtzaeg P. Ann NY Acad Sci. 2002;964:14- 45. Experimental inflammation occurs as a result of excessive effector T-cell function or Gut in Balance deficient regulatory T-cell function There is a constant state of balanced There is a constant state of balanced chronic inflammation present in the gastrointestinal tract. This physiologic inflammation is essential This for the maturing of the immune system and development of the normal morphology of the intestinal mucosa. Nature Reviews Immunology 2003;3:524 Genetic Propensity and Inflammation Gut on Fire Gut on Fire MAMPs and TLRs MAMPs and TLRs Microbe- Microbe- associated molecular patterns TLRs are expressed both in epithelial TLRs are expressed both in epithelial (MAMPs) are highly conserved cells and in phagocytic cells, thus cells and in phagocytic cells, thus structures of pathogenic and functioning as sensors of microbial functioning as sensors of microbial commensal bacteria and are recognized infection. They are critical to initiation infection. They are critical to initiation pattern- by pattern- recognition receptors, such of inflammatory and immune defense of inflammatory and immune defense Toll-like as Toll-like receptors (TLRs). responses. responses. TLRs act as gates [tolls] for controlling Crohn’s Crohn’s Disease more commonly has the immune system. the NOD2 portion of TLR altered, the NOD2 portion of TLR altered, leading to an increase in the NF- κ leading to an increase in the NF- B Sartor RB. ACG 2003. Baltimore, MD. induced inflammation. induced inflammation. Sartor RB. ACG 2003. Baltimore, MD. Inflammation or Inflammation or Balance Balance gene- Conclusions: Critical gene- Antecedents Genes Genes environment interactions (genetics, experiences, past illnesses, Cytokines Cytokines Gut flora plays a crucial role in maturation Gut flora plays a crucial role in maturation occupational exposure, nutrition, lifestyle) Immune Immune Response Response of the immune system. of the immune system. Environment Environment Bacterial species (commensal & Bacterial species (commensal & Triggers Feed-forward Infections or Infections or pathogenic) have different abilities to pathogenic) have different abilities to cycle Dysbiosis Dysbiosis cause inflammation. cause inflammation. (microbes, allergens, trauma, toxins, etc.) Normal Flora Normal Flora Food Antigens Food Antigens Genetic backgrounds… Genetic backgrounds… Probiotics Mediators Probiotics may have different dominant antigenic stimuli Prebiotics Prebiotics (food & flora) (psycho social stress, cytokines, may selectively respond to different antibiotic, prostanoids, nitric oxide, kinins, hormones, neurotransmitters, probiotic, and prebiotic therapies free radicals) What May Cause Dysregulation of What May Cause Dysregulation of Consequences of the GUT Environment? the GUT Environment? GUT Dysregulation (Triggers and Mediators) (Triggers and Mediators) Immunologically mediated localized inflammatory responses Nutrient insufficiencies Diminished HCL secretion Breach of mucosal integrity Medications (NSAIDs, cytotoxic Diminished enzyme secretion Portal circulation flooded with antigenic agents, antibiotics, antacids) Diminished bile secretion macromolecules resulting in detoxification Infectious agents: viruses, Food allergies pathway stress bacteria, protozoa, helminthes- Psycho/Emotional stress Increase in circulating immune complexes— Intestinal dysbiosis activation of the complement cascade and other Travel pathways. Ethanol Hypoxia, exposure to extreme Chronic (and local) inflammation may impact Localized free radical production altitude HPA axis Altered Mucosal Integrity Consequences of CROSS REACTIVITY MODEL GUT Dysregulation “Leaky Gut” and Autoimmunity Poor Dietary Choices Poor Dietary Choices Food Allergy Stress & Emotions Molecular mimicry – Antigens may possess similar Stress & Emotions Immune reaction occurs B cells form antibodies antigenic determinants as human tissue. by T & B lymphocytes Infection Infection Malnutrition B Cell Altered Translocation of microbial components may Altered Lectins Lectins Intestinal result in antibody production and cross reactivity. T Cell Elevated Total Permeability Toxic & Antigenic Toxic & Antigenic Antigen B Cell Burden Burden Example: Klebsiella and ankylosing spondylitis. Systemic Disease Systemic Disease Dysbiosis Many other intestinal microbes have been Transmigration of bacteria Antibodies confuse self Low Stomach Acid Low Stomach Acid or food antigen through (cartilage) with other (bacteria, implicated in systemic disease: Salmonella, leaky gut virus, microbe)) Toxic Exposure Toxic Exposure Toxic Overload Shigella, Campylobacter, Yersinia, Proteus . Immune reaction occurs, resulting in pain, swelling, tissue damage Knee Joint Systemic Disease Leaky gut Triggers: nutrient insufficiency, medication, Association between Systemic dysbiosis, parasite, food reaction, surgery, etc Localized Inflammatory Bowel Disease Symptoms and IBD Disturbance of irritation/ GI flora inflammation Evidence for a strong association Local reaction/localized symptoms Pathogenesis Pathogenesis between arthralgias and spondyloarthropathies and IBD has Physical disruption of Triggers and mediators Triggers and mediators mucosal barrier Potential therapeutic options been provided by several clinical and epidemiological studies. Increased mucosal permeability The role of bacterial flora and Food protein Bacterial/yeast/protozoa pathogenic microorganisms present in /toxin translocation translocation the intestinal lumen may induce these Portal and systemic overload joint diseases in patients with IBD. Immunologically mediated reactions (and perpetuation) Karimi O, Pena AS. Rev Esp Enferm Dig. 2005 Aug;97(8):570-4. Distant Signs and Symptoms:Systemic illness Genetics of IBD Ethnicity and IBD Autoimmunity and IBD (15- Familial occurrence (15 -20% patients have affected relative) Autoimmune reactions can occur when Genetic influence is lower in ulcerative there is a genetic susceptibility for the colitis than in Crohn’ s disease host immune system to recognize, and (potentially) misinterpret an environmental Human gene testing antigen presented to the body (e.g., within Nucleotide- binding oligomerization - the GI tract). domain For this to happen: Nod2 (CARD15) mutations on chromosome The host must be exposed to the antigen. 16 The antigen must be presented to the mucosal Nod1 (CARD4) immune system following its paracellular Basu, D; Am J Gastroenterology 100:2254 -2261, 2005 passage through a compromised intestinal Genetic influence manifested in ethnic permeability. prevalence Animal Models, Bacteria and the Lessons from Animal Models Pathogenesis of Chronic Immune Pathogenesis of Chronic Immune Role of Bacteria in IBD Mediated Intestinal Inflammation Mediated Intestinal Inflammation • Immune-manipulated mice do not Immune-manipulated mice do not develop colitis when germ- develop colitis when germ-free. • Certain animal strains induce colitis Certain animal strains induce colitis more than others. more than others. • No single strain will induce colitis No single strain will induce colitis consistently in all models. consistently in all models. • Host genetic background influences Host genetic background influences disease severity. disease severity. ETIOLOGIC HYPOTHESES The Hygiene Hypothesis Evidence for the Hygiene Hypothesis Etiologic Hypothesis • Increased allergy results from in decreased exposure to infections Hygiene Hypothesis’ has been tested in ‘Hygiene Hypothesis’ has been tested in early life (small family size, clean infants with a family history of atopic environment) allergy who received a Lactobacillus • Some research suggest better living conditions in childhood associated with probiotic. increased risk of IBD later in life in atopy at 2 and again at 5 50% drop in atopy at 2 and again at 5 • Suggestion is there is sub- optimal stimulation of the sIgA- dependent sIgA- sub- follow-up compared to controls. year follow-up compared to controls. Conclusion: reduced microbial load in mucosal barrier function • Mechanisms include altering TH1/TH2 balance and induction of T regulator infancy has led to an increasing incidence of allergy. cells Brandtzaeg P. Ann NY Acad Sci. 2002;964:14-45. Gene-Environment Interaction Gene- Conclusions on Etiology of IBD IBD probably represents an interaction between host genetic susceptibility, commensal flora, and a dysregulated host immune response. It is likely also a consequence of a defective mucosal barrier to luminal antigens. The flora and immune response are mediated by a variety of environmental factors. Altered Bacterial Milieu Intestinal Permeability Bacterial etiology has long been Considerable evidence supports postulated, however research has the presence of increased never confirmed a specific intestinal permeability (IP) in responsible agent. Crohn's disease. Triggers and Mediators in It is now thought that normal IP increases in patients with Inflammatory Bowel enteric flora, possibly triggered by Crohn's disease proportional to an initial change in the disease activity. Disease gastrointestinal milieu, (i.e., It is not entirely clear if IP is a dysbiosis, infection etc.) plays a trigger for dysfunction, a mediator, key role in the development of IBD. or a consequence of inflammation. Guarner F, et. al. Best Pract Res Clin Gastroenterol. 2003 Takeuchi K et. al. Novartis Found Symp. 2004;263:151 -8; discussion Oct;17(5):793-804. 159-63, 211-8 Healthy Gut Leaky Gut Leaky Gut - Pathophysiology Poor Dietary Choices Poor Dietary Choices Food Allergy Food Allergy Stress & Emotions Infection Malnutrition Malnutrition Healthy Villi/ Altered Good Damaged Lectins Intestinal Elevated Total Elevated Total Absorption Villi / Poor Permeability Permeability Toxic & Antigenic Absorption Systemic Disease Dysbiosis Dysbiosis Burden Low Stomach Acid Healthy Cell Healthy Cell Healthy Cell Junctions Damaged Cell Damaged Cell Toxic Exposure Junctions Junctions Toxic Overload Junctions Systemic Disease Microbes and Microbial Diet: Protein and Alcohol Protein and Sulfide Components Components Hydrogen sulfide is a luminally acting, Activate bacterially derived cell poison that has Consumption of meat, particularly red been implicated in ulcerative colitis. Intestinal immune and processed meat, protein and Sulfide generation in the colon is cells alcohol were associated with higher probably driven by dietary rate of relapse. sulfur- components such as sulfur-containing Secrete inflammatory products High sulphur or sulphate intakes were amino acids and inorganic sulfur (e.g., Cytokines also associated with relapse and may sulfite). Reactive oxygen species Reactive oxygen species offer an explanation for the observed Dietary protein from meat is an Eicosinoids Eicosinoids increased likelihood of relapse. important substrate for sulfide generation by bacteria in the human Develop large intestine. Jowett SL, et. al. Gut. 2004 Oct;53(10):1479-84. Magee EA, et al. Am J Clin Nutr. 2000 Dec;72(6):1488-94. Local mucosal damage Diet: Sugar and Fat Decreased Short Chain Fatty Acids Oxidative Stress A high sucrose consumption was A high sucrose consumption was SCFA, in particular butyrate, are a major Blood total antioxidant capacity is Blood total antioxidant capacity is associated with an increased risk for IBD associated with an increased risk for IBD source of energy for colonocytes. while fructose intake was negatively while fructose intake was negatively Additionally, they play a central role on significantly reduced in IBD significantly reduced in IBD associated with risk for IBD. Similar trends associated with risk for IBD. Similar trends the physiology and metabolism of the patients compared with controls, patients compared with controls, were noted in UC and CD. were noted in UC and CD. colon. irrespective of disease activity. irrespective of disease activity. A high fat intake was associated with an A high fat intake was associated with an Several studies have reported that IBD increased risk for UC; this was particularly increased risk for UC; this was particularly is associated with impairment in SCFA The decreased antioxidant The decreased antioxidant marked for animal fat. marked for animal fat. production. defenses may be a primary defenses may be a primary a higher consumption of sweets was a higher consumption of sweets was The effect of prebiotics on cell phenomenon severely phenomenon severely positively associated with UC risk, whereas positively associated with UC risk, whereas proliferation, differentiation, apoptosis, compromising the mucosa and compromising the mucosa and the consumption of sugars, sweeteners, the consumption of sugars, sweeteners, mucin production, immune function, therefore increase the therefore increase the sweets, fats and oils and fish and shellfish sweets, fats and oils and fish and shellfish and chemokine expression seem to be were positively associated with CD risk. were positively associated with CD risk. largely mediated by SCFA. susceptibility to oxidative tissue susceptibility to oxidative tissue SCFA concentrations in the intestinal damage. damage. Reif S et. al. Gut. 1997 Jun;40(6):754 -60. . 60. lumen vary markedly with diet. Feb;11(2):154- Wakai K et. al. Inflamm Bowel Dis. 2005 Feb;11(2):154-63. Sep;49(9):1433- Koutroubakis IE et. al. Dig Dis Sci. 2004 Sep;49(9):1433-7. Sanderson IR J Nutr. 2004 Sep;134(9):2450S-2454S Psychological Stress Antecedents (Predisposing factors) Genetic propensity (NOD/CARD15) Inadequate immunological stimulation Levels of depressive symptoms Western diet (fat, sugar, protein) are positively associated with future changes in Crohn ’s disease. Crohn’ s disease. Potential Therapeutic Triggers Psychological factors such as a (Activation) Feed-forward Options in Inflammatory depressive mood associated with cycle anxiety may exert a negative (Infection, Dysbiosis, other toxins?) Bowel Disease influence on the course of Crohn’ s and UC. Mediators (Perpetuation) Mittermaier C et. al. Psychosom Med. 2004 Jan-Feb;66(1):79-84. Dysbiosis, Depression/anxiety, Decreased SCFA, Mardini HE et. Al. Dig Dis Sci. 2004 Mar;49(3):492-7. Increased IP, low antioxidant reserves/increased free radicals, Inflammatory cytokines/prostanoids) Elemental and Exclusion Diets Elemental Diet Mechanisms Elemental Diets The mechanism by which elemental diets Total enteral nutrition (TEN) was Total enteral nutrition or purified liquid exert their positive effect is unclear. compared to partial enteral nutrition diets (elemental diets) with food exclusion can induce remission in Amino acids used as the sole nitrogen (PEN) in children with active Crohn's Crohn’ patients with active Crohn’ s disease source may be a major contributor. In animal disease for six weeks. The PEN group often comparable to steroids studies, the addition of dietary proteins was encouraged to eat an unrestricted result in intestinal damage. diet while those receiving TEN were However, food exclusion is difficult to In patients with Crohn's disease intestinal maintain long term with palatability, not allowed to eat. permeability (using measurement of solid- inability to stay on a solid-free diet for ingested non- metabolic monosacharide and non- Only TEN led to a reduction in weeks, and social inconvenience as disaccharides) is elevated before elemental diarrhea, an increase in hemoglobin major compliance issues diet therapy and drops following therapy, and albumin, and a fall in platelets and Unfortunately, exclusion diet studies suggesting elemental diets improve IP and ESR. have been sparse and inconclusive. may be related to symptomatic improvement Johnson T et al. Gut. 2006 Mar;55(3):356-61. Epub 2005 Sep 14 Iwata M et. al. Nippon Shokakibyo Gakkai Zasshi. 2001 Jun;98(6):636-43. Elemental Diets and Type of Fat Exclusion Diet Studies Exclusion Diet Studies Dietary fat has been suggested to determine the therapeutic effect of enteral diets in Only one trial with UC: 18 subjects Crohn’ Research in Crohn’s has been Crohn's disease. were randomized into active (diet Patients with active Crohn's disease were inconclusive. exclusion) or control groups and randomised to receive an enteral diet high Remission rates in CD patients on in oleate (79%) and low in linoleate (6.5%) followed for 6 weeks. (PEN1), high in linoleate (45%) and low in Diet group displayed significantly elimination diet do not appear to oleate (28%) (PEN2), or (c) oral prednisone be significantly better than those and a conventional ward diet. fewer symptoms than did the controls. Sigmoidoscopic findings improved in observed on unrestricted diets. Overall remission rates were 27%, 63% and 79%, respectively. 8 subjects in the diet group compared Pearson M et al. Gut. 1993 Jun;34(6):783-7. The type of dietary fat may be of importance with 2 of the controls. for the primary therapeutic effect of enteral No common foods provoked nutrition in active Crohn's disease. Gassull MA Gut. 2002 Aug;51(2):164 -8. symptoms in all patients. Candy S et. al. S Afr Med J. 1995 Nov;85(11):1176 -9. BACTERIA Probiotics and Prebiotics Prebiotics: Germinated Barley Foodstuff (GBF) Anti- Inflammatory inflammatory Probiotics: live microorganisms, Eighteen patients with mild to Eighteen patients with mild to moderately active UC were divided into moderately active UC were divided into which, when administered in two groups. two groups. adequate amounts, confer a health benefit on the host. GBF- treated group (n = 11) received 20 GBF-treated group (n = 11) received 20 to 30 grams of GBF daily together with to 30 grams of GBF daily together with Prebiotics: non digestible food the baseline treatment. the baseline treatment. ingredients that beneficially affect After 4 weeks, the GBF group showed a After 4 weeks, the GBF group showed a the host by selectively stimulating significant decrease in clinical activity significant decrease in clinical activity Certain bacteria may down regulate a the growth and/or activity of one or a index scores compared with controls. index scores compared with controls. limited number of bacteria in the GBF increased fecal concentrations of GBF increased fecal concentrations of chronic immune induced intestinal colon that can improve host health. Bifidobacterium Bifidobacterium and Eubacterium inflammatory process. limosum . limosum Kanauchi O, et. al. Gastroenterol 2002; 37 Suppl 14: 67-72 Prebiotics: Germinated Barley Prebiotics: Bifidogenic growth Prebiotics: Oat bran Foodstuff stimulator (BGS) BGS is a prebiotic preparation 22 patients with quiescent UC were 22 patients with quiescent UC were wenty- one patients with T wenty-one patients with produced by Propionibacterium instructed to add 60 grams of oat instructed to add 60 grams of oat treated moderately active UC treated with freudenreichii isolated from Swiss bran (corresponding to 20 g bran (corresponding to 20 g 20-30 grams daily of GBF for 24 20-30 grams daily of GBF for 24 cheese. dietary fiber) to the daily diet for 12 dietary fiber) to the daily diet for 12 weeks. Twelve patients with mildly to weeks. weeks. moderately active ulcerative colitis GBF significantly reduced clinical received orally 4.5 grams of BGS daily Fecal butyrate concentration Fecal butyrate concentration for 4 weeks. increased by 36% at 4 weeks. increased by 36% at 4 weeks. activity as compared to controls. Patients showed improvement in their clinical activity index scores and Patients reporting abdominal pain Patients reporting abdominal pain GBF prolonged remission and reflux complaints at entry endoscopic index score. and reflux complaints at entry compared to controls . Patients showed an increase in stool showed significant improvement at showed significant improvement at butyrate concentrations. 12 weeks that returned to baseline 12 weeks that returned to baseline Hanai H, et. al. Int J Mol Med 2004; 13: 643-647 Suzuki A, et. Al. Nutrition. 2006 Jan;22(1):76-81. 3 months later. 3 months later. Hallert C Bowel Dis. 2003 Mar;9(2):116 -21. Probiotics: E. coli Nissle1917 Probiotics: E. coli Nissle1917 Probiotics: Saccharomyces boulardii Non-pathogenic strain of Escherichia coli -pathogenic strain of Escherichia coli Double blind trial in patients with UC in Thirty- two patients with Crohn's disease Thirty-two patients with Crohn's disease 116 patients with UC were randomized to remission who received E. coli either in clinical remission were randomly in clinical remission were randomly receive either mesalazine or Nissle1917 mesalazine once daily (n = 162) or mesalazine 500 treated for six months with either treated for six months with either mg three times daily (n = 165). mesalamine 1 g three times a day or mesalamine 1 g three times a day or Initial responses to treatment were mesalamine 1 g two times a day plus mesalamine 1 g two times a day plus Relapses in 40/110 (36.4%) patients in the similar, with remission noted in 75% and Saccharomyces boulardii 1 g daily. Saccharomyces boulardii 1 g daily. E coli Nissle 1917 group and 38/112 68% of those receiving mesalaz ine and E (33.9%) in the mesalazine group. Relapses were observed in 37.5% of Relapses were observed in 37.5% of coli, respectively. respectively. patients receiving mesalamine alone vs. patients receiving mesalamine alone vs. E coli Nissle 1917 showed efficacy and 6.25% of patients (1/16) on mesalamine 6.25% of patients (1/16) on mesalamine 73% and 67% of patients remained in safety in maintaining remission plus Saccharomyces boulardii ( however plus Saccharomyces boulardii ( however remission for 12 months. equivalent to the gold standard this was not statistically significant). this was not statistically significant). mesalazine. Rembacken BJ, et. al. Lancet 1999; 354: 635-639 Guslandi M, et al. Dig Dis Sci. 2000 Jul;45(7):1462-4. Kruis W -23 Kruis W , et. al. Gut. 2004 Nov;53(11):1617-23 Probiotics: Lactobacillus GG Probiotics: Lactobacillus GG Probiotics: Saccharomyces boulardii double- placebo- 20 patients in a double-blind, placebo - 45 patients randomized in placebo 25 patients with a mild to moderate [(1- controlled trial of Lactobacillus GG [(1- clinical flare-up of ulcerative colitis controlled study to determine if 2)x 10(10) cfu vs. placebo for 3 months. Lactobacillus GG, taken for one received S. boulardii 250 mg three times a day for 4 weeks during ongoing No differences were observed between year, could reduce severity or maintenance treatment with mesalazine. the groups with regard to disease activity prevent Crohn's recurrent lesions index. after surgery 17/24 patients who completed the study attained clinical remission confirmed An observational trial showed Lacto GG decreased frequency of first episodes of No significant differences in the endoscopically. severity of the lesions between the pouchitis after 3 years. Kuisma J, et al. Aliment Pharmacol Ther. 2003 Feb 15;17(4):509-15. two groups Guslandi M, et. al. Eur J Gastroenterol Hepatol. 2003 Jun;15(6):697-8 Gosselink MP, et. al. Dis Colon Rectum. 2004 Jun;47(6):876 -84. Epub 2004 Prantera C, et al Gut. 2002 Sep;51(3):405-9. Apr 19. Probiotics: Lactobacillus GG Probiotics: Lactobacillus GG Probiotics: Lactobacillus johnsonii 187 ulcerative colitis patients with Seventy-five children with CD in remission Seventy-five children with CD in remission quiescent disease were randomized to were randomized to either LGG (n=39) or 98 patients who had undergone surgical receive Lactobacillus GG 18 x 10(9) (65 placebo (n=36) and followed for up to 2 Crohn’ s disease were randomized resection for Crohn’s disease were randomized patients), mesalazine 2400 mg/day (60 years. to receive Lactobacillus johnsonii (4 x 10(9) or patients) or Lactobacillus GG + The median time to relapse was 9.8 months placebo for six months. mesalazine (62 patients) for 12 months. in the LGG group and 11.0 months in the Endoscopic scores did not differ significantly placebo group. between groups. There were four clinical Overall analysis showed no difference in recurrences in the LA1 group and three in the LGG did not prolong time to relapse in relapse rate among the three treatment children with CD when given as an adjunct placebo group. groups. to standard therapy. L johnsonii did not have a sufficient effect in Zocco MA, Aliment Pharmacol Ther. 2006 Jun 1;23(11):1567-74. Bousvaros A, et al. Inflamm Bowel Dis. 2005 preventing endoscopic recurrence of Crohn's Sep;11(9):833-9. disease. Marteau P et. al. Gut. 2006 Jun;55(6):842-7 Probiotics: Lactobacillus Probiotics: VSL#3 Probiotics: VSL#3 johnsonii VSL#3: defined ratio of Bifidobacterium VSL#3: defined ratio of Bifidobacterium In double blind trials, VSL#3 prevented Seventy patients with CD were enrolled breve, Bifidobacterium longum, breve, Bifidobacterium longum, relapse of chronic pouchitis after prior to elective ileo-caecal resection and caecal resection and Bifidobacterium infantis, Lactobacillus Bifidobacterium infantis, Lactobacillus induction of remission by antibiotics. randomly assigned after surgery to daily acidophilus, Lactobacillus plantarum, acidophilus, Lactobacillus plantarum, Pilot studies have indicated that VSL#3 Lactobacillus casei, Lactobacillus Lactobacillus casei, Lactobacillus maintained remission of UC in 75% of treatment with either Lactobacillus bulgaricus and Streptococcus bulgaricus and Streptococcus patients over 12 months. johnsonii, 10 billion CFU, or placebo for salivarius subsp. thermophilus. salivarius subsp. thermophilus. Patients who developed pouchitis while 12 weeks. In vitro studies showed that epithelial In vitro studies showed that epithelial treated with placebo had low bacterial and Endoscopic score and clinical relapse barrier function and resistance to barrier function and resistance to high fungal diversity. Bacterial diversity was not significantly different between Salmonella invasion could be enhanced Salmonella invasion could be enhanced was increased and fungal diversity was by exposure to a proteinaceous soluble by exposure to a proteinaceous soluble reduced in patients in remission the two treatment groups at 3 months. factor secreted by the bacteria found in factor secreted by the bacteria found in maintained with VSL#3. the VSL#3 the VSL#3.. et. Al. Van Gossum A et. Al. Inflamm Bowel Dis. 2007 Feb;13(2):135- Mimura T, et. al. Gut 2004; 53: 108-114 75 42. Madsen K, et. al. Gastroenterology 2001; 121: 580 Madsen K, et. al. Gastroenterology 2001; 121: 580 -591 Kuhbacher T, et al. Gut. 2006 Jun;55(6):833-41. Epub 2006 Jan 9. Probiotics: VSL#3 Probiotics: VSL#3 Ulcerative Colitis and VSL#3 34 patients with active UC (non- 16 patients with quiescent IBD who responsive to conventional treatment), suffered from arthralgia were given were given 3.6 trillion cfu of VSL#3 VSL#3 for 2 weeks. daily for six weeks. 10 of the 16 patients had a Treatment resulted in a combined statistically significant improvement induction of remission/response rate as documented by the Ritchie of 77% -- with no adverse events. Articular Index. Bacterial species in VSL#3 were detected at the target site. Karimi O, et. al. Drugs Today (Barc). 2005 Jul;41(7):453-9. Bibiloni, R., et al. . Am J Gastroenterol. 2005;100:1539-1546. Ulcerative Colitis and VSL#3 Biochemical Individuality: Issues with Probiotics A Gut Check “The mammalian gut microbiota Optimal dose Optimal dose interact extensively with the host Duration of treatment Duration of treatment through metabolic exchange and co-metabolism of substrates. Selection of and differences Selection of and differences Appropriate consideration of between the several available between the several available individual human gut microbial probiotic strains probiotic strains activities will be a necessary part Specific mechanisms of action Specific mechanisms of action of future personalized health-care paradigms.” Nicholson JK, Holmes E, Wilson ID. Nature Reviews Microbiology. April 2005. Colonoscopy Images Poll Question Omega 3 Fatty Acids Omega 3 Fatty Acids How many of you have used the One-year, double-blind, placebo- One-year, double-blind, placebo- Pediatric patients with Crohn's Pediatric patients with Crohn's following probiotics in controlled study to investigate the disease in remission were disease in remission were Inflammatory Bowel Disease? effects of a fish-oil preparation fish-oil preparation randomized into two groups and randomized into two groups and (total of 2.7 g of n -3 fatty acids) in n- treated for 12 months with 5- ASA treated for 12 months with 5- (you can choose more then one the maintenance of Crohn's + omega- 3s (eicosapentanoic acid, + omega- answer) disease remission. EPA, 400 mg/g, docosahexaenoic EPA, 400 mg/g, docosahexaenoic After one year, 23 patients (59 acid, DHA, 200 mg/g) or 5 -ASA acid, DHA, 200 mg/g) or 5 fish-oil group percent) in the fish-oil group +placebo capsules. +placebo capsules. VSL#3 remained in remission, as The number of patients who The number of patients who Saccromyces Boulardi compared with 10 (26 percent) in relapsed at 1 year was significantly relapsed at 1 year was significantly Lacto GG the placebo group. lower in omega-3 group. lower in omega-3 group. Lactobacillus johnsonii Romano C, et. al. World J Gastroenterol. 2005 Dec 7;11(45):7118--21. 7;11(45):7118 21. Belluzzi A, et al. N Engl J Med. 1996 Jun 13;334(24):1557--60. 60. Other Antioxidants Omega 3 fatty acids and Omega 3 Fatty acids, Randomized controlled trial of stable Antioxidants Antioxidants and Prebiotics but oxidatively stressed CD subjects (n Patients with UC were randomized to = 57) supplemented with vitamins E Randomized placebo- controlled trial of - (800 IU) and C (1000 mg) or placebo for consume an oral supplement enriched 4 weeks. fish oil (2.7 g EPA and DHA/d; n = 31) with fish oil, fructooligosaccharides, gum and antioxidant preparation (vitamins arabic, vitamin E, vitamin C, and During supplementation, plasma A, C, and E and selenium) or placebo vitamin C and alpha-tocopherol alpha-tocopherol selenium, or a carbohydrate- based increased and all indices of oxidative (olive oil; n = 31) for 24 weeks in placebo formula each day for 6 months. stress decreased significantly. patients with CD. intent-to- treat and completed Both intent-to -treat and completed Conclusion: patients with inactive or Fish- Fish-oil/antioxidant arm was associated patients given supplement had a mildly active CD can be oxidatively with lower arachidonic acid, modified significantly greater rate of decrease in stressed and have increased peripheral blood mononuclear cell the dose of prednisone required to requirement in antioxidant vitamins. composition and lowered production of control clinical symptoms over 6 months PGE(2) and IFN- gamma by circulating as compared with the placebo group. Aghdassi E, et. al. Am J Gastroenterol. 2003 Feb;98(2):348-53. Feb;98(2):348- monocytes or macrophages. -69. Seidner DL et. al. Clin Gastroenterol Hepatol. 2005 Apr;3(4):358-69. Nov;80(5):1137-44. Trebble TM et. al. Am J Clin Nutr. 2004 Nov;80(5):1137-44. Dehydroepiandrosterone Helminths Worms? (DHEA) Induction of a Th2 immune response Induction of a Th2 immune response Dehydroepiandrosterone sulphate by intestinal helminths diminishes Th1 by intestinal helminths diminishes Th1 Th1 Th2 concentrations are decreased in patients with inflammatory bowel disease. responsiveness. responsiveness. Twenty patients with chronic active Certain helminths induce mucosal T Certain helminths induce mucosal T inflammatory bowel disease (seven Crohn's disease and 13 ulcerative colitis) cells to make Th2 and regulatory cells to make Th2 and regulatory took 200 mg DHEA per day orally for 8 cytokines. Helminth cytokines. Helminth -induced mucosal weeks. IL4, TGFbeta, and IL10 likely are part of IL4, TGFbeta, and IL10 likely are part of Six Crohn's disease patients and six ulcerative colitis patients went into the protective process. the protective process. remission. Helminths affect pathways of innate Helminths affect pathways of innate No patient withdrew from the study side-effects. because of side-effects. immunity like TLR4 expression and immunity like TLR4 expression and function. function. Feb;17(3):409- Andus T et al. Aliment Pharmacol Ther. 2003 Feb;17(3):409 -14. Weinstock JV Ann N Y Acad Sci. 2006 Aug;1072:356-64 . Aug;1072:356- Hygiene hypothesis Helminths: Trichuris suis Summary and Conclusions suis, the porcine whipworm, is genetically T suis, the porcine whipworm, is genetically The GI tract has developed elaborate related to T trichiura, the human whipworm. T suis is not a natural human parasite but it mechanisms to coexist with its has been shown experimentally to colonize commensal microflora, rapidly humans briefly without causing disease. respond to invading pathogens and Twenty nine patients with active Crohn's disease were enrolled in an open label antigens, and then returning to study. All patients ingested 2500 live T suis homeostasis. ova every three weeks for 24 weeks, and disease activity was monitored. If these tightly regulated homeostatic At week 24, 23 patients (79.3%) responded mechanisms are disturbed in a (decrease in CDAI >100 points or CDAI <150) susceptible individual, chronic and 21/29 (72.4%) remitted (CDAI <150). There were no adverse events. intestinal inflammation may be Elliott, D.E., Urban Jr., J.F., Argo, C.K., Weinstock, J.V. FASEB Journal 2000;14:1848-1855. induced. Summers RW, Gut. 2005 Jan;54(1):87 -90 . Summers RW, Gut. 2005 Jan;54(1):87 90 Summary and Conclusions Summary and Conclusions The induction of inflammation starts The induction of inflammation starts Once the mucosal epithelium is Once the mucosal epithelium is with a breakdown of the intestinal with a breakdown of the intestinal disrupted, luminal pathogens and disrupted, luminal pathogens and epithelial barrier. epithelial barrier. antigens are able to traverse the former antigens are able to traverse the former barrier, infiltrating the underlying barrier, infiltrating the underlying Triggers of this breakdown appear Triggers of this breakdown appear mucosal layers. mucosal layers. varied and may include: varied and may include: This enhances antigenic exposure to This enhances antigenic exposure to Infections: pathogenic bacteria, protozoa immune and non - immune cells located in immune and non or other microbes deeper mucosal compartments. deeper mucosal compartments. Changes in the normal gut mileau This process results in aggravation and This process results in aggravation and caused by medications, diet etc. chronification of mucosal inflammation, chronification of mucosal inflammation, This breakdown is considered central This breakdown is considered central which in turn further compromises the which in turn further compromises the and the initial step of mucosal and the initial step of mucosal barrier function of the intestinal barrier function of the intestinal epithelium. epithelium. inflammation. inflammation. To register for AFMCP and receive the additional 10% Summary and Conclusions discount for attending this webinar call us at 800.228.0622 or visit us online at www.functionalmedicine.org/ecommerce/registernow.asp Immunological tolerance to The Textbook of Functional Medicine Clinical Nutrition: A Functional Approach commensal bacteria is lost in This comprehensive guide to functional medicine comes at a This book will advance your understanding beyond the traditional patients with IBD. critical time for healthcare professionals. The Textbook of Functional Medicine provides a emphasis on isolated nutrient deficiencies and RDA guidelines by focusing on underlying metabolic patterns model of care that helps to improve and nutrient interactions. Combined with a functional medicine focus on the unique Repairing this intestinal barrier, the management of chronic disease and the health of an aging population in the 21st century. 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