Nutrition and the Gastrointestinal Ecosystem

Leo Galland M.D.Foundation for Integrated Medicine

www.mdheal.org

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.

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

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

Three Components of the GI Ecosystem

• Diet• Microbial flora• Mucosa

• Epithelium• Mucus layer• Immune cells• Blood vessels• Nerve endings

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)

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

Gastric Ecosystem Disruptors

• H. pylori infection

• Acid-lowering drugs

• NSAIDs

• Malnutrition (B12)

• Delayed emptying (gastroparesis)– Drugs (clonidine)– Disease (diabetes)

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

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

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

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

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

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.

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

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

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.

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

Colonic Ecosystem Disruptors

• Antibiotics

• Infection

• Unabsorbed bile acids

• Bacterial putrefaction

• Altered motility– Disease– Drugs, supplements– Stress, lifestyle

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

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

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

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

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

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

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)

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

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. .

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)

BENEFITS OF BACILLUS LATEROSPORUS

• Laterosporamine: antibiotic

–Suppress auto-antibody formation

–Suppress murine lupus nephritis

• Spergualin: anti-tumor, antibiotic

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

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)

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)

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

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)

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

CAUSES OF UPPER GI BACTERIAL OVERGROWTH

• Achlorhydria/hypo-chlorhydria

• Surgical resection/blind loops

• Stasis from abnormal motility

• Strictures

• Fistulas

• Diverticulosis

• Immune deficiency

• Intestinal giardiasis

• Tropical sprue

• Malnutrition

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

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

EFFECTS OF UPPER GI BACTERIAL OVERGROWTH

(continued)

• Mucosal damage by bacterial enzymes

– Loss of brush border

• Endotoxemia/antigenemia

• Liver damage

• Joint disease

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

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

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

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

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

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

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

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

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

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

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.

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.

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

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

Gut Flora and Expression of Celiac Disease Phenotype

• Bacterial prolyl endopeptidase deaminates the critical gliadin peptides, preventing TGA bindingShan 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.

Ann NY Acad Sci 915 (2000), p xi

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.”

MECHANISMS WHICH SUPPORTNORMAL INTESTINAL

PERMEABILITY

• Intestinal mucus• Secretory IgA• Mucosal epithelium• Intramural macrophages• Intramural lymphocytes

– intra-epithelial– in Peyer’s patches

TWO TYPES OF EPITHELIAL PERMEABILITY

• Trans-Cellular

• Para-Cellular

TRANS-CELLULAR PERMEABILITY

• The principal route for the absorption of solutes, fluid and macromolecules

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)

CAUSES OF INCREASED PARA-CELLULAR

PERMEABILITY

• Infectious agents–Parasites–Bacteria–Viruses–Yeasts

Continued

CAUSES OF INCREASED PARA-CELLULAR PERMEABILITY

• Enterotoxins

– Ethanol

– NSAIDs*

– Cytotoxic drugs

• Dysoxia

– Ischemia

– Reactive oxygen species

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

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

• Increased I.P. induced by:–Low-fiber diets–Carrageenan–Pectin/guar gum–Castor oil–Alcohol–Allergens

Continued

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.

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.

LEAKY GUT SYNDROMES

• Enteritis, colitis Infectious/inflam-matory

• Arthritis, chronic inflammatory

• Food allergic disorders

• AIDS

• CFIDS• MCS• Chronic pancreatic

disease• Chronic non-

infectious hepatitis• Acne• Psoriasis

Intestinal Permeability and Food Allergy

• Increased baseline permeability

• Marked increase after challenge

• Increase blocked by sodium cromoglycate

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

• “Evaluation of I.P… provides an effective means of diagnosing food allergy”

Barau E and Dupont C, Modificationsof Intestinal Permeability during FoodProvocation Procedures in PediatricIrritable Bowel Syndrome, J Pediatr Gastroenterol Nutr, 11:72-77,1990

Continued

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

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

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

HYPER-PERMEABILITY IN RHEUMATOID ARTHRITIS

(continued)

• I.P. is further increased

• Systemic inflammation exacerbates

• Metronidazole and minocycline break the cycle

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

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

TREATMENT OF HYPER-PERMEABILITY

• Avoid enterotoxins

• Treat intestinal infection/bacterial overgrowth with antimicrobials

• Diet: high nutrient density

– non-irritating

– allergen-free

HELPING TO REPAIR THE DAMAGED INTESTINE

• Glutamine• Essential fatty acids• Antioxidants

– Glutathione– Bioflavonoids– Vitamin E– Gamma-oryzanol

• Epidermal growth factor• Colostrum