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Title: Nutrition%20and%20the%20Gastrointestinal%20Ecosystem


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
  • Raynauds syndrome
  • Sjogrens 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 gt 25, 30 of
    people gt 65
  • Achlorhydria is a symptom of atrophic gastritis,
    not a normal effect of aging Hurwitz et al,
    JAMA 1997278 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 37230-3.

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 lt4
    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.
  • PPIs 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
    May13(5)643-7.
  • Kanauchi et al. J Gastroenterol.
    200338134-41.
  • Kanauchi et al, Int J Mol Med.
    200312701-4
  • Kanauchi et al. J Gastroenterol. 2002 37
    Suppl 1467-72.
  • .

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 travelers
    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), RR0,51
  • Kalliomaki et al, Lancet 357 1076-79 (2001)

34
Lactobacilli for Managing Food Allergy
  • Infants with atopic eczema and cows 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)
  • Peyers 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
  • Achlorhydria/hypo-chlorhydria
  • Surgical resection/blind loops
  • Stasis from abnormal motility
  • Strictures
  • Fistulas
  • Diverticulosis
  • Immune deficiency
  • Intestinal giardiasis
  • Tropical sprue
  • Malnutrition

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(continue
d)
  • 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(continue
d)
  • 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, Ballieres Clin Rheumatol, 1989

51
CELIAC DISEASE (CD) IS PREVALENT AND PROTEAN
  • Overall prevalence of celiac disease (CD) in US
    was 1133. Among patients with chronic GI
    symptoms it was 157.
  • 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
    53789-93

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 20022972275-9
  • 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
    20033612152-4.

56
EPITHELIAL PERMEABILITY REGULATES TRANSPORT OF
WATER, SOLUTES AND PARTICULATE MATTER
  • The intestinal epithelium is the site of
    vectorial transportbetween 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 SUPPORTNORMAL INTESTINAL
PERMEABILITY
  • Intestinal mucus
  • Secretory IgA
  • Mucosal epithelium
  • Intramural macrophages
  • Intramural lymphocytes
  • intra-epithelial
  • in Peyers 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)

61
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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. 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
  • Enteritis, colitis Infectious/inflam-matory
  • Arthritis, chronic inflammatory
  • Food allergic disorders
  • AIDS
  • CFIDS
  • MCS
  • Chronic pancreatic disease
  • Chronic non-infectious hepatitis
  • Acne
  • Psoriasis

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 villuscrypt 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 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, 1172-77,
  • 1990

  • Continued

73
INTESTINAL PERMEABILITY AND CROHNS 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 CROHNS 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 Crohns Disease, Lancet
    3411437-1439, 1993

75
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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
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