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 gastroparesis Gumurdulu 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.COLI AND 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	CAUSES OF UPPER GI BACTERIAL OVERGROWTH Fistulas Diverticulosis Immune deficiency Intestinal giardiasis Tropical sprue Malnutrition Achlorhydria/hypo-chlorhydria Surgical resection/blind loops Stasis from abnormal motility Strictures
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
51	CELIAC DISEASE (CD) IS PREVALENT AND PROTEAN Overall prevalence of celiac disease (CD) in US was 1:133. Among patients with chronic GI symptoms it was 1:57. Fasano et al, Arch Int Med 2003; 163: 286-92. Commonest symptoms of CD patients in the US are fatigue (82%), abdominal pain (73%), bloating (72%) and anemia (63%). Half deny diarrhea or weight loss and 62% are normal- or overweight. Zipser et al.Dig Dis Sci 2003; 48: 761-4.
52	THE DIAGNOSIS OF CD IS USUALLY MISSED Almost 1% of children in Finland have CD (biopsy proven), but only 25% of these had been evaluated for CD based on clinical presentation. Maki et al, NEJM 2003; 348: 2517-24. IgG and IgA gliadin antibodies occur in 2% of Italian school children Catassi et al, Lancet 343: 200-203 (1994) Reliance on a single serological marker (gliadin-IgA, anti-TGA, anti-EMA) underestimates CD prevalence Shamir et al, Am J Gastroenterol 2002; 97: 2589-94.
53	CD Is Associated with Neuropsychiatric Disorders Gliadin or endomysial antibodies and villous atrophy were found in 16-19% of Swedish children with Down syndrome, none of whom had clinical CD. Carlsson et al, Pediatrics 1998; 101: 272-5. Gliadin antibodies were found in 30/53 patients with neurological disease of unknown cause (73% had abnormal small bowel biopsies) Hadjivassiliou et al, Lancet 1996; 347: 369-71 CD is associated with subclinical thyroid disease, panic and major depressive disorders Carta et al. J Psychosom Res 2002; 53:789-93
54	Pathogenesis of Celiac Disease Genetic predisposition: HLA DQ2 Gliadin peptides bind to tissue transglutaminase (TGA), the CD auto-antigen, activating cytotoxic (CD8+)T cells of the adaptive immune system Gliadin peptides also induce macrophages of the innate immune system to produce IL-15, which is essential for priming the adaptive immune response. Maiuri et al, Lancet 2003; 362: 30-37. Gliadin may stimulate innate GI immunity
55	Gut Flora and Expression of Celiac Disease Phenotype Bacterial prolyl endopeptidase deaminates the critical gliadin peptides, preventing TGA binding Shan L, et al Science 2002;297:2275-9 C albicans hyphal wall protein-1 binds to TGA, permitting C albicans mucosal adherence. TGA-yeast bonding may stimulate formation of anti-TGA and anti-endomysial antibodies. C albicans may cause symptoms of celiac disease in patients not responding to a gluten-free diet. Anti-yeast treatment might relieve these symptoms. Nieuwenhuizen, et al, Lancet 2003;361:2152-4.
56	EPITHELIAL PERMEABILITY REGULATES TRANSPORT OF WATER, SOLUTES AND PARTICULATE MATTER “The intestinal epithelium is the site of vectorial transport…between the intestinal lumen and the circulation. The net effect of transport is regulated by the tightness (or leakiness) of the barrier and vice versa. Both transport and barrier functions are physiologically regulated, and both can be dramatically altered under disease conditions.”
57	MECHANISMS WHICH SUPPORT NORMAL INTESTINAL PERMEABILITY Intestinal mucus Secretory IgA Mucosal epithelium Intramural macrophages Intramural lymphocytes intra-epithelial in Peyer’s patches
58	TWO TYPES OF EPITHELIAL PERMEABILITY Trans-Cellular Para-Cellular
59	TRANS-CELLULAR PERMEABILITY The principal route for the absorption of solutes, fluid and macromolecules
60	PARA-CELLULAR PERMEABILITY IS LIMITED BY CELL ADHERANCE MOLECULES (CAMs) Tight junctions contain claudins Adherens junctions and desmosomes contain cadherins Contraction of the cytoskeleton opens junctions (glucose absorption is a stimulus)
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62	CAUSES OF INCREASED PARA-CELLULAR PERMEABILITY Infectious agents Parasites Bacteria Viruses Yeasts Continued
63	CAUSES OF INCREASED PARA-CELLULAR PERMEABILITY Enterotoxins Ethanol NSAIDs* Cytotoxic drugs Dysoxia Ischemia Reactive oxygen species
64	PSYCHOLOGICAL STRESS CAN INCREASE GUT PERMEABILITY THROUGH A CHOLINERGIC MECHANISM Rats: cold stress increases para-cellular permeability. -This effect is greater when cholin- esterase activity is weak -The effect is blocked by atropine -It may depend upon vagal activation of mast cells Similar effects occur in humans
65	DIET ALTERS INTESTINAL PERMEABILITY Fasting: Controls: Increased I.P. R.A.: Decreases I.P. Mucosal Inflammation increases I.P. Food allergy “Idiopathic”(celiac disease) Continued
66	"Increased I.P" Increased I.P. induced by: Low-fiber diets Carrageenan Pectin/guar gum Castor oil Alcohol Allergens Continued
67	INTESTINAL PERMEABILITY IS MEASURED BY PROBES ABSORBED AND EXCRETED UNCHANGED BY THE KIDNEYS Probes used for small bowel permeability include Cr51-EDTA, PEGs and the ratio of lactulose to mannitol. Colonic permeability can only be measured if the probe is administered by enema.
68	INCREASED INTESTINAL PERMEABILITY (LEAKY GUT) IS NOT A DISEASE OR SYNDROME It contributes to the pathophysiology of many different diseases. Improvement of the related disease usually improves the leaky gut. Decreased intestinal permeability may improve the associated disease.
69	LEAKY GUT SYNDROMES CFIDS MCS Chronic pancreatic disease Chronic non-infectious hepatitis Acne Psoriasis Enteritis, colitis Infectious/inflam-matory Arthritis, chronic inflammatory Food allergic disorders AIDS
70	Intestinal Permeability and Food Allergy Increased baseline permeability Marked increase after challenge Increase blocked by sodium cromoglycate
71	ABNORMAL INTESTINAL PERMEABILITY IN FOOD ALLERGY 42% of children with eczema had reduced jejunal villus:crypt ratios (malabsorption) Increased PEG-4K absorption (leakiness) Increased PEG absorption blocked by cromolyn pre-treatment Increased fasting lactulose absorption in adults with food allergy (eczema, hives); further increase with offending food blocked by cromolyn 300mg
72	"“Evaluation of I.P" “Evaluation of I.P… provides an effective means of diagnosing food allergy” Barau E and Dupont C, Modifications of Intestinal Permeability during Food Provocation Procedures in Pediatric Irritable Bowel Syndrome, J Pediatr Gastroenterol Nutr, 11:72-77, 1990 Continued
73	INTESTINAL PERMEABILITY AND CROHN’S DISEASE Patients have increased I.P. First degree relatives have high I.P. and excessive increase in I.P. when exposed to aspirin Patients have abnormal reactivity of mucosal lymphocytes to normal gut flora and Candida antigens
74	INTESTINAL PERMEABILITY AND CROHN’S DISEASE For patients in remission, the rate of relapse correlates with I.P. measured prospectively Wyatt J et al, Intestinal Permeability and the Prediction of Relapse in Crohn’s Disease, Lancet 341:1437-1439, 1993
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77	HYPER-PERMEABILITY IN RHEUMATOID ARTHRITIS NSAIDs increase intestinal permeability Increased I.P. allows sensitization to gut flora Bacterial sensitization causes enteritis and formation of circulating immune complexes
78	HYPER-PERMEABILITY IN RHEUMATOID ARTHRITIS (continued) I.P. is further increased Systemic inflammation exacerbates Metronidazole and minocycline break the cycle
79	PROTEUS AND RHEUMATOID ARTHRITIS (RA) Frequency of HLA-DR4 in RA patients: 50 to 75%. Those without HLA-DR4 usually have DR-4 + mothers. Controls: 20% HLA-DR4 positive RA patients often have elevated serum IgG titers to Proteus spp that cross-react with HLA-DR4
80	Proteus, RA and Diet RA patients in England, Spain and Norway have higher anti-Proteus IgG than controls Anti-Proteus IgG correlates with disease activity and C-reactive protein levels Fasting, followed by a one year gluten-free vegan diet improves symptoms and indices of disease activity, only in patients whose Proteus antibodies decrease and who show a change in fecal bacterial fatty acid profiles. E coli antibodies are not affected
81	TREATMENT OF HYPER-PERMEABILITY Avoid enterotoxins Treat intestinal infection/bacterial overgrowth with antimicrobials Diet: high nutrient density non-irritating allergen-free
82	HELPING TO REPAIR THE DAMAGED INTESTINE Glutamine Essential fatty acids Antioxidants Glutathione Bioflavonoids Vitamin E Gamma-oryzanol Epidermal growth factor Colostrum