L eaky G ut S yndrome

1. Leaky GutSyndrome 최 준 영

2. The Intestinal Barrier

3. Regulation of Intestinal Permeability • Open & Close Factor of Tight Junction • Dietary factors • Humoral or neuronal signals • Stress • Microbial or viral pathogens • Inflammatory mediators • Mast cell products

4. Dietary Factors • Dietary factor modulate transcellular absorptive processes • Dietary factor activate Sodium dependent glucose transproter1 (SGLT1) • SGLT1 allow physiological opening of tight junction of small molecule:2000 MW

5. Biochem Cell Biol. 2006 Dec;84(6):870-80.

6. Tight junction regulation Am J Physiol Gastrointest Liver Physiol. 2000 Nov;279(5):G851-7

7. Causes of increased IPPhysiology of Intestinal Permeability

8. Cause of Increased Intestinal Permeability

9. Intestinal Mucosal PermeabilityCritical Care Medicine Vol 27(8) 1999 • Splanchnic hypoperfusion → Gut mucosal ischemia • Increased intestinal permeability • Translocation of bacteria • Endotoxin, other mediators into circulation • Activation of proinflammatory cascade • Local and systemic tissue injury • Multiple Organ Dysfunction Syndrome (MODS)

10. Increased permeability in the absence of mucosal hypoxia ; Acidosis In acidosis → conversion NO to toxic products(by + superoxide); peroxynitrite, peroxynitrous acid → extensive nitrosylation of protein(ex, tyrosine, actin) → impairment of modulatory function of the actin-based cyto-skeletal ring (controlled by Ca++, c-AMP) → impairment of tight junctions and epithelial paracellular permeability • Small Intestine Bacterial Overgrowth

11. SmallIntestine BacterialOvergrowth

12. Etiologic Factors Associated with SIBO • Anatomic Disorders - Diverticula - Intestinal resection with dilation - Sugical loops - Loss of ileocecal valve - Bowel obstruction - Intervocalic fistula • Motor disorders -Chronic intestinal pseudo-obstruction - Autonomic neuropathy(diabetic) • Decreased Motility in small bowel - Scleroderma, - SLE intestinal adhesions - Radiation damage - High refined sugar in meal • Lowered Digestive Enzyme - Hypochlorhydria, achlorhydria, - Acid-lowering drugs, - Low bile juice - Pancreatic insufficiency • Immunologic mechanisms - Immune deficiencies(innate or induced) - Malnutrition - Reduction of GALT after resection - Decreased secretory IgA

13. Pathophysiology of SIBO ….. Histologic change; subtotal atropy and mucosal inflammation • Facultative anaerobes; • injure the intestinal surface by direct adherence & production of enterotoxins Aerobes; • produce enzymes and metabolic products capable of causing epithelial cell injury • Deconjugation of bile salt by bac. • Bile salt injury to the mucosal surface • Mal absorption of fat • Degradation of intestinal brush-border & pancreatic enzymes by bac. Proteases • Malabsorption of protein • CHO malabsorption related to decreased brush-border hydrolase activities • AA to Vasoactive amine by bac. Decarboxylase → Dilation & contraction of bowel vessel

14. 소화 및 배설과정

22. The Intestinal Barrier

23. Pathophysiology of LGS • 1. Endotoxemia • 2. Ag-Ab immune complex • 3. Etc

24. Endotoxin

25. Endotoxemia

26. Immune Complex ResorceJ Gastroenterol & Hepatol 2003;18:479~497

29. Disease & Leaky Gut

30. Inflammatory bowel disease Crohn’s disease Inflammatory joint disease Food allergy Rheumatoid arthritis Celiac disease Ankylosing spondylitis Chronic dermatological condition Allergic disorders Diseases associated with abnormal intestinal permeability

31. Inflammatory bowel disease …Sixfold increase in permeability in people with Crohn’s disease • Inflammatory joint disease • Pathology in the gut as underlying etiology by many researchers • Ab generated against gut Ag, cross-react with joint tissue – essentially autoimmune disease • Ankylosing spondylitis, RA, vasculatis – increased intestinal permeability • Reiter’s syndrome or reactive arthritis caused by Shigella, Salmonella, Yersinia, Campylobacter -- d/t tissue deposition of circulating immune complexes arising from increased permeability of source Ag

32. Food allergy • ↑ permeability leads to sensitization of the immune system, type I, III, IV • Na cromoglycate; .. stabilize mast cell & IgE-producing plasma cells → reduce the local inflammation • Atopic dermatitis & urticaria; .. ↑ intestinal permeability .. ↑ permeability by oral challenge of food provoked Sx • NSAID • Disruption of intestinal barrier function → ↑ intestinal permeability

33. NSAID & Intestinal Permeability • 60-70% of chronic NSAID using for more than 6 months • Unknown mechanism; • Inhibit oxidative phosphorylation in mitochondria → ↓ATP → loss of mucosal cell tight junction • Injury of paracellular tight junction, not change of transcellular permeability • Metronidazole; ↓ bacterial overgrowth, no ↑ permeability • Lactobacillus GG; improve gastric permeability, intestinal permeability

34. Pancreatic insufficiency • The degree of ↑ permeability correlated with the level of duodenal trypsin & with the degree of undigested fat in the stool. • Alcoholism • Gut-derivated endotoxins; may play a role in the initiation and aggravation of alcohol-induced liver disease • Aging • Aging in animal study diminishing capacity to prevent larger size molecules from penetrating the intestinal mucosa

35. Journal Review of SIBO & Related Diseases

36. Cirrhosis & SIBO • SIBO in cirrhosis – ↑significantly than controls • Associated with severity of cirrhosis(Child B,C > A) More impaired hepatic function than cirrhosis without SIBO • Associated with systemic endotoxemia in cirrhosis • ↑ Plasma endotoxin → ↑ IL-2,6, TNF-alpha → may deteriorate cirrhosis, Cx • No difference among various causes of cirrhosis • Prokinetic, Antibiotics; ↓SIBO in cirrhosis(2RCT)

37. Arthritis & SIBO • Chlamydia trachomatis, yersinia, and salmonella the causative pathogen in about 50% of patients with probable or possible reactive arthritis(ReA) • A bacteria-specific lymphocyte proliferation (LP) is often found in synovial fluid (SF) of ReA(27%) at first week of arthritis • Increased immune response to Klebsiella in patients with AS, UC, CD and to Proteus in patients with RA

38. Symptoms of SIBO • Abdominal distention, diarrhea, cramping, weight loss ..Result mainly from nutrient mal-absorption • Anemia; from mal-absorption, aggravated by occult blood loss, Vit. B12 deficiency • Ataxia and delirium; result of assimilation of neurotoxic fermentation products such as D-lactate • Rashes, Arthritis,Nephritis; result of systemic distribution of bacterial Ag-Ab complexes • Abnormal motility; result or/and cause of SIBO

39. Diagnosis Intestinal Permeability SIB0

40. IntestinalPermeability Assessment • Physiologic permeability • Trans-cellular absorption(relatively huge area) • Simple sugars, glycerol, AA, many vitamin, minerals, many nutrients • Para(inter)cellular junction; tight Junction • Very small molecules; some dipeptides, tripeptides

41. Intestinal Permeability Assessment • Paradoxical Leakiness • Villous atrophy decreased trans-cellular permeability • Mal-absorption of small molecule(nutrients, vitamin etc) → Mal-nutritions • Damage of tight junction • Increased uptake of food Ag, bac. toxins, bac, protein → Food allergy, autoimmune diseases, etc

42. Measure of Intestinal Permeability • Markers for Trans-cellular Permeability • Mannitol, Polyethylene glycol 400, Rhamnose, Glucose • Markers for Para-Cellular Permeability • Lactulose, Polyethylene glycol 1000~3000, 51Cr-EDTA(chromium-ethylene diamine tetraacetic acid) • Ratio of low molecule and high molecule • Exquisite marker of subtle changes in intestinal permeability

44. Measure of Intestinal Permeability • Mannitol • Monomeric sugar, readily absorbed • Marker of transcellular uptake • Lactulose • Dimeric sugar, only slightly absorbed • A marker for paracellular permeability • Ratio of mannitol and lactulose • Exquisite marker of subtle changes in intestinal permeability

45. Diagnosis of SIBO • Culture of upper small bowel fluid by aspiration; the most direct and accurate means of confirmation (≧105 colony forming units of non-pharyngeal bacteria) • Identification of unconjugated bile acids and short-chain fatty acids in duodenal fluid • Noninvasive screening studies; • Comprehensive Diagnostic Stool Analysis • Glucose breath hydrogen test; .. lactulose is less effective than glucose(confirmed) • Urinary indicans • UGI with Small bowel Series; .. partial bowel obstruction, bowel dilatation

46. Glucose Challenge Test • Normally absorbed before in reaches the large intestine • Metabolize by bac. in small bowel before absorption of glucose • Fasting breath sampling • Ingestion of 75g glucose solution • Collect breath samples every 15mins for 2 hrs

47. Glucose Challenge Test • Typical normal fasting breath sample • < 10 ppm of breath hydrogen or methane • Positive indication of bac. overgrowth • Rise of 12 ppm in breath hydrogen within 1 hr • high fasting breath hydrogen or methane level > 20 ppm

48. Comprehensive Digestive Stool Analysis Diagnostic tools for analysis of • Digestion • Absorption • Intestinal function • Colonic environment

49. Digestion Triglycerides Chymotrypsin Meat fibers Vegetable fibers Valerate, iso-butyrate Absorption Long-chain fatty acids Cholesterol Total short-chain fatty acid Total fecal fat Colonic Environment Beneficial bacteria Additional bacteria Mycology Metabolic markers Immunology Dysbiosis index Macroscopic Analysis Components of CDSA

50. Urine Indican Test(Obermeyer Test)