Nutrition and the Gastrointestinal Ecosystem

1. Nutrition and the Gastrointestinal Ecosystem Leo Galland M.D. Foundation for Integrated Medicine www.mdheal.org

2. BEYOND DIGESTION • The gut is a sensory organ. Protozoa know their environments by ingestion. • The gut is a neuroendocrine organ. Every CNS neurotransmitter is present and active here. • The gut has a brain of its own, an intact and independent nervous system. • The gut is the largest organ of immune function in the body; 70% of our lymphocytes live here.

3. BEYOND DIGESTION • The gut contents are an inner world that is “outside” the cellular body. Its surface is a frontier of 100 square meters and a thickness of one cell • Gut flora are an organ that contains as many microbial cells as the cellular body has mammalian cells (100 trillion) -Over 500 species -Over 90% are anaerobic

4. BEYOND DIGESTION • The normal intestinal microflora constitute a huge chemical factory that alters our food and our GI secretions • The normal intestinal microflora present our immune systems with a mass of antigens that are partially absorbed

5. Three Components of the GI Ecosystem • Diet • Microbial flora • Mucosa • Epithelium • Mucus layer • Immune cells • Blood vessels • Nerve endings

6. Gastric Ecosystem • Low fasting pH • Reduces bacterial population • Denatures protein, initiates protein digestion • Enhances solubility of Ca, Mg, Fe, Zn… • Thick coat of protective mucus • Intermittent exposure to food and oral or exogenous microbes • Rapid emptying (60 minutes)

7. Gastric Acid Production • Two liters of gastric juice per day • Fasting HCl secretion is 10% of maximum, yielding pH 1.0-2.0 and bacteriostatic barrier • Food buffers gastric acid despite post-prandial HCl secretion. pH of the fed stomach is typically 3.5 – 4.5 • Ageing slows gastric reacidification but has little effect on fasting or fed pH

8. Gastric Ecosystem Disruptors • H. pylori infection • Acid-lowering drugs • NSAIDs • Malnutrition (B12) • Delayed emptying (gastroparesis) • Drugs (clonidine) • Disease (diabetes)

9. Helicobacter pylori • Most common chronic bacterial pathogen of humans • Prevalence in adults is approximately 1%/year of life • Infection can be life-long • Lives under the mucous layer, protected from HCl • Pathogenicity is associated with provocation of TH1 cells and gastric mucosal IL-8 secretion and bacterial synthesis of CagA, a disruptor of mammalian cell signaling mechanisms • Raises gastric pH by producing ammonia and by damaging gastric epithelial cells • May cause hyperacidity by destroying somatostatin-producing antral mucosal cells

10. H. Pylori Effects: GI • Atrophic and autoimmune gastritis • Erosive gastritis and NSAID gastropathy • Hypertrophic gastritis • Duodenal ulcer disease • Gastric carcinoma • Gastric lymphoma • Functional dyspepsia/gastroparesis

11. H. Pylori Associations: Systemic • Coronary heart disease • Stroke • Rosacea • Raynaud’s syndrome • Sjogren’s syndrome • Open angle glaucoma(Kountouras et al. Arch Int Med 2002; 162: 1237-1244.) • Food allergies • Vitamin B12 deficiency

12. Atrophic Gastritis • Atrophic gastritis is non-erosive inflammation associated with loss of secretory function • Usually asymptomatic but may produce • Dyspepsia • Abdominal pain • Bloating • Nausea/vomiting • May co-exist with erosive peptic disease • Allows gastric bacterial overgrowth • Increases susceptibility to pathogens in food

13. Achlorhydria and Atrophic Gastritis • Achlorhydria affects 15% of people > 25, 30% of people > 65 • Achlorhydria is a symptom of atrophic gastritis, not a normal effect of aging Hurwitz et al, JAMA 1997;278: 659-62. • Achlorhydria is usually caused by H. pylori or by the use of acid-lowering drugs

14. H. Pylori: After Effects • Residual gastritis and achlorhydria can take 2 years or more to resolve. • HCl supplementation: 2 grams of Betaine HCl is needed to take 400ml of gastric juice from neutral to pH 2.0 • B12 repletion improves gastroparesisGumurdulu et al J Clin Gastroenterol 2003; 37:230-3.

15. Food Effects on H. Pylori • Mastic gum (P lentiscus), used in rice pudding and for treatment of dyspepsia, kills H. pylori • Raw garlic and aqueous garlic extract inhibit growth (thiosulfinate, MIC of 40 mcg/ml) • Garlic and onion consumption inversely associated with gastric cancer • Sulforaphane (cabbage and broccoli) has MIC of <4 mcg/ml • Cabbage juice and broccoli sprouts have been used to treat PUD

16. Acid Lowering Drugs • May increase development of atrophic gastritis in H. pylori-infected individuals • Allow gastric bacterial/yeast overgrowth and post-prandial intra-gastric production of ethanol and nitrosamines • May impair absorption of vitamin B12, folic acid, carotene, minerals and medication

17. Esophageal Reflux • Results from reflex relaxation of the LES in response to gastric vagal mechanoreceptors (programmed in brainstem, unrelated to swallowing or gastric pH). Post-prandial gastric distension is a key trigger. • PPI’s and H-2 blockers convert acid reflux into non-acid reflux. Pepsin and bile present in gastric juice may still act as esophageal irritants. • Intra-gastric calcium increases LES tone, independent of antacid effects, and may be a more physiologic treatment, along with consumption of small meals eaten slowly in a relaxed fashion to decrease gastric distention. • Red-pepper powder 800 mg t.i.d. relieves symptoms Bortolotti et al, NEJM 2002; 346: 947-8.

18. Colonic Ecosystem • Relatively slow motility (about 48 hours) • Immense bacterial count (100 trillion organisms, weight of about 3 lbs) • pH of 6-8, determined by SCFAs vs NH4 • Water gradient caused by re-absorption of fluid • Ileo-cecal backflow may damage the terminal ileum

19. Colonic Ecosystem Disruptors • Antibiotics • Infection • Unabsorbed bile acids • Bacterial putrefaction • Altered motility • Disease • Drugs, supplements • Stress, lifestyle

20. GI MICROFLORA AND COLON CANCER • Large bowel cancer is associated with high fat, high protein, low fiber diets • This effect is in part mediated by bacterial enzymes induced by the nature of the diet, the substrates supplied for these enzymes and the carcinogenic products of enzyme activation

21. BILIARY STEROID METABOLISM BY GI MICROFLORA • chenodeoxycholate lithocholate • cholic acid deoxycholic(DCA) -DCA in feces correlates with colon cancer incidence -DCA may 20-CH3-cholanthrene • Deconjugation of bile salts

22. GI MICROFLORA AND COLON CANCER • Incidence proportional to DCA excretion • inversely proportional to Lactobacillus concentration • Vegetarians have less cancer and lower bacterial enzymes in stool: Beta-glucuronidase, nitro-reductase, 7-alpha-dehydroxylase; • Lactobacilli lower these when fed to omnivores and prevent colon cancer in rats given dimethylhydrazine

23. GI MICROFLORA AND COLON CANCER(continued) • High meat diets increase indole and skatole in stool: inducing bacterial tryptophanase • Human fecal mutagen (FCM), a vinyl ether of propanediol, is associated with a Western diet. Requires bile and low oxygen. Produced by 5 Bacteroides spp • High protein diets high GI ammonia and high fecal pH. This increases fecal LCFA and bile acid solubility

24. GI MICROFLORA AND COLON CANCER(continued) • High CHO/fiber diets high SCFA and low fecal pH. This decreases fecal LCFA and bile acid solubility Dietary Ca also renders LCFA insoluble

25. DIETARY PREVENTION OF COLONIC DYSBIOSIS • Plant-based, high fiber diet • Fermented foods, Lactobacilli • Crucifers, flavonoid-rich vegetables & fruits • Vegetable cellulose, an insoluble fiber • Colostrum, a source of lactoferrins -Lactoferrins bind iron, inhibiting the growth of all bacterial species except lactic acid producers

26. Probiotics • Lactic acid producers: Lactobacilli (acidophilus, plantarum, casei, salivarius, sporogenes), Bifidobacteria, Streptococci • Non-pathogenic E. coli • Soil-derived organisms: Bacilli (laterosporus, subtilis) • Saccharomyces boulardii (yeast against yeast)

27. Prebiotics • Foods that support the growth of probiotics: bran, psyllium, resistant starch (high amylose), oligofructose (FOS), inulin, germinated barley foodstuff (GBF) • FOS is found in onions, garlic, rye, blueberries, bananas, chicory. Dietary intake averages 2-8 gm/day. • Inulins are derived from chicory and artichoke

28. GBF and Ulcerative Colitis • GBF 20-30 gm/day helps to induce and maintain remission in patients with ulcerative colitis. • Mechanism: Increased colonic butyrate production decreases NFkB activation. Hanai et al. Int J Mol Med. 2004 May;13(5):643-7. Kanauchi et al. J Gastroenterol. 2003;38:134-41. Kanauchi et al, Int J Mol Med. 2003;12:701-4 Kanauchi et al. J Gastroenterol. 2002; 37 Suppl 14:67-72. .

29. E.COLIAND ULCERATIVE COLITIS • E. coli in colonic crypts of UC patients shows abnormal adherence Burke, Axon J Clin Path 40: 782-786 (1987) • After inducing remission with gentamycin and prednisone, Nissle 917 strain E. coli were as effective as mesalamine in maintaining remission at 12 months Rembacken et al, Lancet 354: 635-640 (1999)

30. BENEFITS OF BACILLUS LATEROSPORUS • Laterosporamine: antibiotic • Suppress auto-antibody formation • Suppress murine lupus nephritis • Spergualin: anti-tumor, antibiotic

31. BENEFITS OF SACCHAROMYCES BOULARDII • Stimulates production of sIgA • Protects against antibiotic and traveler’s diarrhea • Helps reverse C difficile colitis • Improves acute diarrheal disease in children

32. LACTOBACILLI: BENEFICIAL EFFECTS • Produce organic acids: lower bowel pH • Produce H202 • Antagonize enteropathogenic E. Coli, Salmonella, Staphylococci, Candida albicans, and Clostridia spp • Degrade N-nitrosamines • Anti-tumor glycopeptides (L. bulgaricus) • Stimulate balanced immune responses • Decrease rate of post-op infection (L plantarum)

33. Lactobacilli for Prevention of Food Allergy in Infants • DBPCT: Lactobaciilus GG given to high risk mothers during last 2 weeks of pregnancy and for 6 months after birth to their offspring • Atopic eczema at 2 years • Controls: 31/68 (46%) • Lactobacillus 15/64 (23%), RR=0,51 Kalliomaki et al, Lancet 357: 1076-79 (2001)

34. Lactobacilli for Managing Food Allergy • Infants with atopic eczema and cow’s milk allergy fed hydrolyzed whey formula with or without Lactobacillus GG -Clinical improvement associated with 95% decline in fecal TNF-alpha in the Lactobacillus group, signifying reduced GI inflammation Majamaa, Isolauri, J All Clin Immunol 1997

35. Small Intestinal Ecosystem • Great length (25 ft) and immense surface area (= a doubles tennis court) • Enzyme/bile acid gradient • Bacterial gradient • Intense immune activity • Intraepithelial lymphocytes (CD8) • Peyer’s patch lymphocytes (CD4)

36. Enteric Ecosystem Disruptors • Loss of beneficial flora (Lactobacilli) • Bacterial overgrowth/fermentation • Exuberant immune responses • Mucosal hyperpermeability • Altered motility • Malnutrition (systemic and local: parenteral feeding, low fiber diets) • Infection

37. Achlorhydria/hypo-chlorhydria Surgical resection/blind loops Stasis from abnormal motility Strictures Fistulas Diverticulosis Immune deficiency Intestinal giardiasis Tropical sprue Malnutrition CAUSES OF UPPER GI BACTERIAL OVERGROWTH

38. EFFECTS OF UPPER GI BACTERIAL OVERGROWTH • Carbohydrate/fiber intolerance, bloating, altered bowel habit, fatigue • Vitamin B12 deficiency • Bile salt dehydroxylation • Impairs formation of micelles • Bile salt deconjugation • Increases colonic water secretion • Inhibit monosacchardide transport

39. EFFECTS OF UPPER GI BACTERIAL OVERGROWTH(continued) • Inhibition of folate conjugases • Increased fecal nitrogen, hypoalbumenia • Bacterial degradation of CHO • Villi: blunted and broadened • Lamina propria: increased mononunuclear cells

40. EFFECTS OF UPPER GI BACTERIAL OVERGROWTH(continued) • Mucosal damage by bacterial enzymes • Loss of brush border • Endotoxemia/antigenemia • Liver damage • Joint disease

41. BREATH TESTING FOR BACTERIAL OVERGROWTH • FALSE POSITIVES • Smoking, sleeping, eating • Soluble fiber/FOS • Rapid intestinal transit • FALSE NEGATIVES • Colonic hyperacidity (low stool pH) • Absence of appropriate flora • Delayed gastric emptying • Antibiotics

42. BACTERIAL OVERGROWTH IS MORE COMMON THAN SUSPECTED • 202 patients with IBS underwent hydrogen breath testing • 157 (78%) had SBBO and were treated with antibiotics • 25/47 patients had normal breath tests at follow-up • Diarrhea and abdominal pain were significantly improved by treatment

43. SBBO AND IBS: CONCLUSIONS Elimination of SBBO eliminated IBS in 12/25 of patients: 48 % of patients with IBS and abnormal breath tests who responded to antibiotics with normal breath tests no longer met Rome criteria for IBS Pimentel M et al, AM J Gastroenterol 2000

44. Small Bowel Bacterial Overgrowth and Fibromyalgia (FMS) • Lactulose breath tests: 153 patients (42 FMS, 111 IBS) and 15 healthy controls • All 42 FMS and 93 (84%) of IBS had an abnormal LBT, but only 3 (20%) of controls. • Breath hydrogen correlated with the degree of pain in FMS. Pimentel, Ann Rheum Dis 2004; 63: 450-2

45. MANAGEMENT OF UGI BACTERIAL OVERGROWTH INVOLVES DIET, ANTIBIOTICS • Low fermentation diet -restrict sugar, starch, soluble fiber • Antimicrobials (in select cases): • Metronidazole (anaerobes) • Tetracyclines (anaerobes) • Ciprofloxacin (aerobes) • Bismuth • Bentonite

46. Low Fermentation Diet • Basic diet: no wheat, sucrose, lactose • Additional restrictions -no glutinous grains -no cereal grains, potatoes -restrict fruits, juices, honey -avoid legumes -cook all vegetables

47. UGI Flora, Molecular Mimicry and Exuberant Enteric Immunity • Cross-reactivity to bacterial antigens leads to immune-mediated damage • Antibodies against microbes bind to cells carrying HLA antigens • Inflammation from complement or cytokine cascades, T cell activation

48. INTESTINAL INFLAMMATION AND SPONDYLOARTHOPATHIES • Arthritis is a frequent complication of IBD • Sub-clinical ileitis occurs in many pts with ankylosing spondylitis (AS); associated with increase sIgA • Bowel infections often precede reactive arthritis • Silent carriage of Salmonella can precipitate reactive arthritis

49. KLEBSIELLA AND ANKYLOSING SPONDYLITIS (AS) THE EBRINGER RESEARCH • 96% of AS patients have HLA-B27, cross-reacts with Klebsiella antigen • Many AS patients grow Klebsiella on stool culture • AS pts have higher serum IgA against Klebsiella than controls

50. Nutritional Therapy for Ankylosing Spondylitis • A diet free of grains and disaccharides reduced levels of Klebsiella in stool, lowered the level of anti-Klebsiella IgA and improved the symptoms of patients with AS Ebringer, Balliere’s Clin Rheumatol, 1989