Transcript The Gut-Immune Interface
The Gut-Immune Interface
David Rakel, MD Director, UW Integrative Medicine Asst. Professor, Dept of Family Medicine UW School of Medicine and Public Health
Surface Area Exposed to the External Environment
Surface Area (Sq M) 200 180 160 140 120 100 80 60 40 20 0 Skin Lungs GI
The Enterocyte: Regenerate every 3-5 days!
3 Main Modes of Defense
Mucous Barrier (Prostaglandins, IgA) NSAIDS, Chemotherapy, Lack of fiber, Infection, Stress Microflora (Probiotics, Prebiotics) Antibiotics, Poor nutrition, Infection, Stress Local Immune system (GALT) Food allergy, intolerance (IgG), Infection, Stress
Positive Balance Peace: Balance of sympathetic & Para-sympathetic tone Proper Acidity (pH 1-3) Healthy Mucous Layer Low bacterial growth Intact gut-immune barrier bacterial growth & balanced flora Regular evacuation Negative Balance Stress: Sympathetic tone or Acidity Poor Mucous Layer High bacterial growth Intestinal Permeability Imbalanced bacterial growth (dysbiosis) Irregular evacuation
Method of Birth…..
Vagina
Inoculates GI tract with healthy flora Less Atopy (asthma, eczema)
Abdomen
Not exposed to vaginal flora More atopy (asthma, eczema)
Method of feeding… Breast Bottle
Prebiotics (FOS) = Bifidobacteria & Lactobacillli = IgA (Mucosal defense) Balance of Th1=Th2 Enterococci, Enterobacteria & Clostridia = Imbalance of humoral response Th2 = Atopy
Am J Clin Nutr2003;78:675 –83.7
Hygiene Hypothesis
Bifidobacteria, Lactobacilli = IgA in Mucous = (Th1=Th2) Intestinal Permeability = Th2 imbalance (Allergic..Atopy) or a Th1 imbalance (Autoimmune.. Crohns)
Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial
Lancet, 2001. Vol.
357
(
9262
) Probiotics given prenataly and postnataly for a total of 6 months.
Lactobicillus GG reduced eczema by 50% NNT = 4.5
Follow-up study showed that effect persisted to 5 yrs of age.
An evolving GI environment..
Eat on the run New proteins (Wheat, Dairy, pasteurization) Sugar, dense foods Nutrient Different bacteria Less fiber More Rx (PPI, steroids, Abx) Cordain L.
Origens & Evolution of the Western Diet: Health Implications for the 21st Century. Am J of Clinic Nutr. 2005
Healthy Gut
Healthy Villi/Good Absorption Healthy Cell Junctions
Intestinal Permeability & Malabsorption
Damaged Villi/ Poor Absorption Damaged Cell junctions
Intestine Healthy Intestine Blood Intestine Increased Permeability Ab Ab Systemic Inflammatory response Blood
Brain-Gut Stress (Mast Cells) Antigen Exposure Inflammatory Cell Recruitment Histamine Seratonin Intestinal Permeability Calprotectin ROS Release Epithelial Damage H+ Glutathione in Liver Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: An interface between health and disease. J Gastroenterol Hepatol. 2003; 18(5):479-497.
Phase 2 Detoxification
Conjugation Phase II System Glutathione Amino Acid Methylation Sulfation Acetylation Glucoronidation Neutralized Toxin Fat Soluble Required Nutrients Glutathione, B 6 Glycine SAMe Cysteine, methionine, molybdenum Acetyl-CoA Glucuronic Acid Toxin Prepared for Excretion Bile/Intestines Water Soluble Urine/Kidneys
Increasing Glutathione
Safe with long-term use; Vitamin C 500 mg/d Vitamin E 800 IU/d (Mixed Tocopherols) B-Complex Vit.
(Thiamine & B6)
Milk Thistle Needs Further Study; NAC
(N-Acetylcysteine aka; Mucomyst)
Glutathione
(Good in food: fruits, vegetables & fish. Or a Mediterranean type diet)
Intestinal Permeability - Pathophysiology
Poor Dietary Choices Stress & Emotions Infection Chronic Abx/Steroids Food Intolerance Malnutrition Altered Intestinal Permeability Dysbiosis Systemic Disease Low Stomach Acid Toxic Exposure Toxic Overload Elevated Total Toxic & Antigenic Burden Systemic Disease
Key Questions to Ask….
Was there a disruption to the normal GI environment?
Infection Trauma Antibiotics/Chemo Chronic Stress Surgery
Treatment
“4 R” Approach Remove (Foods, Pathogens, Rx) Replace (Acid, Enzymes) Re-Inoculate (flora) Repair (Gut Mucosa)
Remove…..
Stress (Change interpretation) High risk foods Gluten (wheat), dairy What food do you crave the most?
Chronic acid suppression (PPI, H2 blocker) if able.
If able: Antibiotics, steroids
Mind Body
Neuropeptides from the gut influence our emotions.
Metaphor “Gut Instinct” “Something's eating me up inside” “Listen to your gut”
Soderholm JD. Stress and gastrointestinal tract. II. Stress and intestinal barrier. Am J Physiol Gastrointest Liver Physiol, 280(1), G7-G13. 2001
Mind-Body Influences (Stress)
Monkeys: Separation of infant and mother = fecal flora (Lactobacilli) Rats: Chronic stress = Permeability Cortisol results in; Permeability Mucin production IgA secretion
Stress induced changes reversed with nutrition
Rat pups separated from mothers = Permeability Reversed with: Omega-3 fatty acids (DHA) Arachadonic Acid Prebiotics (FOS) Probiotics (Lactobacillus) Garcia-Rodenas CL, et al. Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J Pediatr Gastroenterol Nutr. 2006; 43(1):16-24.
Elimination Diets
Elimination Diets
Ogle KA, Bullock JD. Children with allergic rhinitis and or bronchial asthma treated with elimination diet: A five-year follow-up. Annals of Allergy. 44(5)273. 1980, May.
Asthma 1980 study of 322 <1 year olds w/ negative skin tests Ate only Meat Base Formula, beef, carrots, broccoli, apricots 91% with improvement of respiratory symptom scores 51% reproduced symptoms with food challenges Milk, eggs, chocolate, soy, legumes (peanuts), cereals, in that order
Food Intolerance: The Usual Suspects (IgG)
Dairy Wheat Corn (including corn syrup) Eggs Citrus Soy Beef Refined sugar Food additives Tartrazine (Yellow dye #5) Aspartame
Figure 2 Mean change in symptom severity scores at 12 weeks according to degree of adherence. Difference between the groups with high adherence: 101 (95% confidence interval 54, 147); ***p<0.001.
Atkinson, W et al. Gut 2004;53:1459-1464
Copyright ©2004 BMJ Publishing Group Ltd.
Replace…
Acid (Betaine HCL) Elderly Significant indigestion Digestive Enzymes Short term use only To help with malabsorption if present Consider Lactulose/Mannitol permeability test
Lactulose (Big Sugar) Mannitol (Small Sugar) Results: Mannitol Lactulose = Normal Lactulose and Mannitol = Malabsorption Mannitol Lactulose = Permeability
Re inoculate…
Probiotics Prebiotics Consider Comprehensive Diagnostic Stool Analysis
Stool Transplant!?
Human Probiotic Infusion(HPI) Aas J, Gessert CE, Bakken JS. Recurrent clostridium difficile colitis: Case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003; 36(5):580 585.
HPI via retention enema for UC
Before After Borody TJ,et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003; 37(1):42-47.
Repair…
Exercise Nutrition Supplements
Exercise: Don’t Overdo it!
Intense running = Intestinal Permeability Combining NSAIDS with Marathon running = Permeability Lambert GP, et al. Gastrointestinal permeability during exercise: Effects of aspirin and energy-containing beverages. J Appl Physiol. 2001; 90(6):2075-2080.
Change in American Diet
Rich in refined sugars and vegetable oils = 36.2% of total energy in the American Diet.
These foods are essentially void of nutrients (empty foods..just energy)
Sugar + Yeast =
Fiber!
Viscous fiber absorbs water, slows glucose absorption (lowers glycemic Index), cholesterol absorption.
Is needed for healthy mucous layer Increases thermogenesis during digestion.
Prolongs digestion = satiety Reduces insulin secretion by glycemic index.
Sources of Viscous Fiber
Consider 1/2-1 tsp TID qAC with 8 oz of Water Guar Gum
(Benefiber)
Psyllium
(Metamucil)
Ground Flax seed Konjac Asian tubor: 5 times more potent that psyllium, guar gum & oat fiber in cholesterol.
Caution: these agents expand like sponges and if taken with little water can cause obstruction, particularly Konjac.
Zinc
HCL Acid depends on Zinc for its secretion Needed for IgA and immune function Beneficial for shortening infectious diarrhea and pneumonia in kids.
Inhibits copper absorption
Percentage of all Individuals >2 yo
NOT
meeting 100% US Recommended Dietary Allowances 1.
2.
3.
4.
5.
6.
7.
8.
Zinc Calcium Magnesium Vitamin A Vitamin B6 Iron Vitamin C Folate 9.
Thiamine 10.
Riboflavin 65.1% 73.3% 61.6% 56.2% 53.6% 39.1% 37.5% 33.2% 30.2% 30.0% Cordain L.
Origens & Evolution of the Western Diet: Health Implications for the 21st Century. Am J of Clinic Nutr. 2005
Zinc and Endothelial Repair
10 Patients given Indomethacin to cause permeability Randomized Cross-over trial Zinc 37.5 mg resulted in 75% in gastric and small bowel injury & 50% less villous shortening.
Indomethacin = 3-4x in those tx with Zinc permeability vs none Mahmood A,
Zinc carnosine, a health food supplement that stabilizes small
bowel integrity and stimulates gut repair processes. Gut. 2006
L-Glutamine
Non-essential Amino Acid Used as energy source for rapidly growing cells Good evidence to support use for the very sick (intensive care, chemo & Rx therapy) 5-10 gms BID (Powder)
Glutamine MOA
Reduces Inflammation by reducing gut associated cytokine release Wischmeyer PE. Can glutamine turn off the motor that drives systemic inflammation? Crit Care Med. 2005; 33(5):1175-1178.
Reduces risk of gut derived septicemia in critically ill Antioxidant, Increases Glutathione (GSH) Enhances Heat Shock Protein (HSP) that protects enterocytes from injury.
Does not reduce permeability in those without inflammation who are nutritionally deprived Hulsewe KW, et al. Clin Nutr. 2004; 23(5):1217-1225.
Glutamine’s Benefit in the ICU De-Souza DA, Crit Care Med. 2005; 33(5):1125-1135.
Omega 3
Doc, those antibiotics you gave me made my IBS go away!
Small Bowel Bacterial Overgrowth (SBBO) Coliform and anaerobic bacteria normally found in the colon, grow in the small intestine.
? Chronic acid suppression Consider in those with severe IBS
Hydrogen Breath Test
Oral administration of lactulose or glucose.
Elevated levels of bacteria ferment the sugar hydrogen and methane gas that can be detected in exhaled gas.
If elevated, also check H. Pylori Ab
IBS & SBBO
202 w/ Rome Criteria for IBS 78% had SBBO on Hydrogen Breath Test Those with SBBO that were eradicated with Abx had significant improvement in Sxs 48% had resolution of Rome criteria for IBS post treatment Pimentel M. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel. Am J. Gastroenterol. 95(12), 3503-3506, 2000.
Treatment of SBBO
Low carbohydrate diet Abx: TMP/Sulfa & Metronidazole (low dose for 2-4 weeks) Probiotics post antibiotics, or alone if Abx not used (Lactobacillus GG,
Culturelle
) Avoid acid suppressing agents
What Worked?
Food elimination?
Supplements?
Having a plan?
Increased sense of control?
Relationship?
All or One?
The Origins of S _ _ _ (Kaka)
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