1	NUTRITIONAL MEDICINE AND GASTROINTESTINAL PATHOLOGY Leo Galland, M.D. Foundation for Integrated Medicine www.mdheal.org
2	WHY SPEND A HALF DAY TALKING ABOUT THE GUT? The small bowel is where digestion and absorption of nutrients occurs The food we eat creates the intestinal micro-environment The intestinal microenvironment has an important influence on the pathophysiology of many different diseases Diets don’t treat diseases, they treat patients
3	BEYOND DIGESTION The gut is a sensory organ. Protozoa know their environments by ingestion. The gut is a neuroendocrine organ. Every neurotransmitter found in the brain is also found 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.
4	BEYOND DIGESTION The gut contents are an inner world that is “outside” the cellular body. Its surface is a frontier with an area 100 meters square 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
5	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
6
7
8
9	Intestinal dysbiosis, altered permeability, food intolerance and detoxification are inter-connected parts of the same puzzle
10	MUCOSAL BACTERIA ARE USUALLY NOT ISOLATED FROM STOOL Colon: Anaerobic spirochetes, fusiform bacteria Ileum: Coccobacilli Stomach: Lactobacilli, yeasts Oral: Anaerobes (Corynebacteria, Actinomyces, Bacteroides, Spirochaetes, Fusobacteria and Aerobes: Streptococcus and Lactobacillus)
11	COMPOSITION OF NORMAL STOOL FLORA Eubacterium, 26 spp 25.5% Bacteroides, 20 spp 22.6% Bifidobacterium, 8 spp 11.5% Peptostreptoccus 8.9% Fusobacterium, 5 spp 7.7% Ruminoccus, 11 spp 4.5% Lactobacillus, 7 spp 2.4% Streptococci 1.6% Clostridia 0.6% Enterobacteriacae 0.5%
12	BENEFITS OF NORMAL GUT FLORA Synthesize vitamins Synthesize short chain fatty acids Metabolize xenobiotics/toxins Prevent colonization by pathogens Stimulate normal immune system maturation Convert dietary flavonoids to active aglycones
13	NUTRIENTS SYNTHESIZED BY NORMAL GUT FLORA Biotin Cobalamin Folic acid Pantothenic acid Pyridoxine Riboflavin Vitamin K Butyric acid Amino acids
14	GUT MICROBIAL DETOXIFICATION Demethylate methylmercury Degrade N-nitrosamines Degrade polycyclic aromatic hydrocarbons Degrade aflatoxin B1 (limited) Hydrolyze guanidinosuccinic acid
15	IMMUNOLOGICAL EFFECTS OF NORMAL GI MICROFLORA Stimulate RES activity Increase number of immunocompetent cells Increase immunoglobulin synthesis Increase complement levels May stimulate dysfunctional immune responses
16	HOW NORMAL GI FLORA PROTECTS AGAINST GI PATHOGENS Synthesis of short chain fatty acids Synthesis of antibiotics Competition for nutrients Induction of a low re-dox potential Deconjugation of bile acids Blockage of adherance receptors Degradation of bacterial toxins
17	POTENTIAL ADVERSE EFFECTS OF NORMAL GUT FLORA Deactivate trypsin, chymotrypsin and intestinal disaccharidases, producing maldigestion Produce ammonia Consume Vitamin B12 Deconjugate bile salts
18	POTENTIAL ADVERSE EFFECTS OF NORMAL GUT FLORA (continued) Increase enterohepatic recirculation of estrogens Activate pro-carcinogens Stimulate dysfunctional immune responses
19	BACTERIAL ENZYMES OF TOXICOLOGICAL SIGNIFICANCE TO THE HOST
20	TOXIC METABOLITES OF GI FLORA Ammonia from hydrolysis of urea Amines from amino acid decarboxylation Phenols from dietary tryptophan Secondary bile acids Recycled estrogens Nitrites from nitrates N-nitrosamines from nitrates/nitrites
21	AMMONIA Produced by urease from urea in gut Klebsiella, Proteus, Bacteroides, Bifidobacteria Inhibits oxidative metabolism in brain Reduced by low protein diets, by substituting dairy for meat (flora changes) Low colonic pH reverses absorption Rapid transit inhibits absorption
22	AMINES PRODUCED BY GI FLORA Inactivated by hepatic MAO tyramine octopamine histamine cadaverine putrespecine Piperidine
23	NITROSAMINES From nitrates/nitrites & secondary amines lecithin, choline dimethylamine lysine piperidine arginine pyrrolidine Water, vegetables, cured meats, cheese may contain nitrates, absorbed in jejunum Hypochlorhydria increases formation
24	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
25	ESTROGEN METABOLISM AND GI MICROFLORA conjugation biliary excretion deconjugation increased entero-hepatic recirculation increased blood and urine estrogen Western diet: higher plasma estrogen, lower stool estrogen
26	TRYPTOPHAN METABOLISM BY GI MICROFLORA tryptophanase indole, absorbed by colon mucosa, potential carcinogen GI flora quinaldic acid, 8-OH quinaldic: bladder carcinogens Aerobes: E. Coli, Proteus spp Anaerobes: Bacteroides fragilis, ss. Thetaiotamicron (increased with stress)
27	PRODUCTS OF MICROBIAL CHO FERMENTATION IN GUT Ethanol Butanol D-lactic acid Hydrogen Acetone SCFAs Propanol Acetaldehyde Formic acid CO2 Butylene glycol
28	EFFECTS OF SHORT CHAIN FATTY ACIDS Butyrate: anti-neoplastic, reduces growth of human cancer cells Propionate: inhibits gluconeogenesis Acetate: stimulates salt and water absorption All: anti-bacterial, anti-fungal lower pH = reduced DCA and less NH4 absorption stimulate growth of mucosal cells
29	FACTORS AFFECTING GI FLORA GI secretions: type, volume, content Enzymes, cells, mucus, pH, re-dox Diet Fiber, fat, protein, CHO Motility and transit time Host immunity Emotional distress
30	DIETARY EFFECTS ON GI FLORA High Fat: Bacteroides up, Lactobacilli and Enterococci down Vegetarian: anaerobes down Cellulose: lower yeasts, Staph, Proteus and Clostridia; also total bacterial count and levels of bacterial enzymes
31	DIETARY EFFECTS ON GI FLORA (continued) Galactomannans (guar gum & locust bean gum), carboxymethylcellulose: increase bacterial bio-mass and enzyme levels Unrefined CHO vs refined: increase bacterial content of ileostomy fluid Wheat bran: reduces methylmercury toxicity by increasing demethylation by GI flora
32	DIETARY EFFECTS ON GI FLORA (continued) D-glucaric acid inhibits B-glucuronidase; found in crucifers, citrus, cherry and human urine Low fiber diets increase bacterial translocation Pectins with high methoxy content: increase nitroreductase activity; may increase B-glucuronidase
33	SUMMARY OF DIET AND GI FLORA High meat diets induce enzymes that may promote carcinogenesis and the formation of indoles and ammonia High soluble fiber and complex carbohydrate increases fermentation Insoluble fiber decreases carcinogenic enzyme concentrations Phytochemicals may inhibit bacterial enzymes
34	STRESS AND GI MICROFLORA ACTH injection increases jejunal E. coli Cosmonauts lose Bifidobacteria and Lactobacillus before take-off Fear and anger selectively increase Bacteroides fragilis spp, Thetaiotamicron; this increases colonic tryptophanase, which increases skatole and indole production on high meat diets
35	DYSBIOSIS IS ECOLOGIC IMBALANCE Disease or dysfunction produced by the interaction between the host and its “normal” flora, organisms of low intrinsic virulence.
36	DYSBIOSIS-ASSOCIATED DISEASES Acne Psoriasis Eczema Food allergy/intolerance Malabsorption syndromes Cancer: colon/breast Inflammatory bowel disease Irritable bowel syndrome Chronic fatigue syndromes Rheumatoid arthritis Spondyloarthropathies
37	DYSBIOSIS CAUSES DISEASE BY TWO MECHANISMS Microbial enzymes act upon intestinal contents to produce noxious substances Microbial components stimulate dysfunctional immune responses
38	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
39	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
40	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
41	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
42	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
43	SMALL BOWEL BACTERIAL OVERGROWTH produces a different pattern of dysbiosis, associated with carbohydrate/fiber intolerance, bloating, altered bowel habit, fatigue and maldigestion
44	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
45	EFFECTS OF UPPER GI BACTERIAL OVERGROWTH Vitamin B12 deficiency Bile salt dehydroxylation Impairs formation of micelles Formation of hydroxy fatty acids Bile salt deconjugation Increase colonic water secretion Inhibit monosacchardide transport
46	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
47	EFFECTS OF UPPER GI BACTERIAL OVERGROWTH (continued) Mucosal damage by bacterial enzymes Loss of brush border Endotoxemia/antigenemia Liver damage Joint disease
48	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
49	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
50	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
51	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
52	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
53	IRRITABLE BOWEL SYNDROME IS ASSOCIATED WITH SPECIFIC FOOD INTOLERANCE Specific food intolerance, present in 48% of patients with diarrhea and pain, is associated with unstable fecal flora, high aerobe:anaerobe ratios and high stool PGE2 levels Alun Jones et al, Lancet, 1982
54	The Addenbrooke’s Hospital Exclusion Diet for IBS 1-2 meats: lamb, turkey, fish, chicken, beef 1 fruit: pears, pineapple, banana, apple Rice, water Commonest diet was lamb, pears, rice
55	Outcome of Exclusion Diet in 182 IBS Patients No improvement after 7 days: 38 (21%) Improved after 7 days: 144 (79%) -Provoking foods identified, established dietary control of IBS: 122 (67%) -Intolerant of one food 5% -Intolerant of 2-5 foods 28% -Intolerant of 6-10 foods 35% -Intolerant of > 10 foods 32%
56	Foods Provoking IBS Tea 25% Butter 25% Yogurt 24% Citrus 24% Barley 24% Chocolate 22% Nuts 22% Preservatives 20% Wheat 60% Milk 44% Corn 44% Cheese 39% Oats 34% Coffee 33% Rye 30% Eggs 26%
57	Foods Provoking IBS Pork 14% Broccoli 14% Soy 13% Chicken 13% Spinach 13% Yeast 12% Lamb 11% Sugar 12% Potatoes 20% Cabbage 19% Sprouts 18% Peas 17% Beef 16% Carrots 15% Lettuce 15% Rice 15%
58	Food Intolerance in IBS Is not Associated with Atopy Only 10% of patients were atopic 40% could relate onset of symptoms to: -A course of antibiotics (11%) -A bout of gastroenteritis (12%) -Abdominal or pelvic surgery (15%) Unstable fecal flora was common Hunter et al,Topics in Gastroenterology, 1985
59	IBS with Food Intolerance Is Associated with Excess Fermentation, Corrected by Diet 6 patients, 6 controls, whole body chamber Total body hydrogen production greater with IBS, fell with exclusion diet. (No grains except rice, no dairy or beef, restrict yeast, citrus, caffeine, tap water) King et al, Lancet 352: 1187-1189 (1998)
60
61	IMMUNE SENSITIZATION AND DYSBIOSIS Immune responses to intestinal microorganisms may provoke inflammatory and auto-immune disorders Specific: bacterial antigens mimic auto-antigens Non-specific: polyclonal activation, RES hyperstimulation, APC activation
62	MOLECULAR MIMICRY (Cross Reactivity) MECHANISM Microbes colonize positive individuals Cross-reactivity with bacterial antigens leads to secondary immune damage Antibodies against microbes bind to cells carrying HLA antigens Increased cytotoxic damage Inflammation from complement or cytokine cascades
63	INTESTINAL INFLAMMATION AND SPONDYLOARTHOPATHIES sIgA is increased in AS (suggest enteritis) Sub-clinical ileitis occurs in many pts with primary spondyloarthropathies 10-20% of IBD patients get AS Bowel infections often precede reactive arthritis Silent carriage of Salmonella can precipitate reactive arthritis
64	KLEBSIELLA AND ANKYLOSING SPONDYLITIS (AS) MOLECULAR MIMICRY Klebsiella antigens cross-react with HLA-B27 Initiates inflammatory cascade Leads to reactive arthritis
65	KLEBSIELLA AND ANKYLOSING SPONDYLITIS (AS) (continued) THE EBRINGER RESEARCH 96% of AS patients have HLA-B27 gene Many AS patients grow Klebsiella on stool culture AS pts have higher serum IgA against Klebsiella than controls
66	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
67	VS, 41 year old male event planner with hip, knee and back pain and fatigue Prior history: chronic rhinitis, hypercholesterolemia, Lyme disease 1993 and 1994, hypothyroidism 1994 Past several years: persistent tightness in back, persistent pain in calves,hips, knees, poor response to physical therapy, fluctuating fatigue, poor sleep, dizziness, alternating constipation and diarrhea. Food: single, lives alone,eats out all the time, sweets. Family history: Crohn’s disease, hyperlipidemia, hypertension. Mother had been ill with ASVD and breast cancer most of his life.
68	VS, 41 year old male event planner with hip, knee and back pain and fatigue Physical exam: -Nodular thyroid -Decreased range of motion of hips and LS spine, diminished straight leg raising bilaterally, no joint tenderness, scattered tender points of lower extremities Lab: - HLA B27 + -ANA + 1:40 speckled -Normal X-rays of SI joints, spine -E. histolytica in stool
69	VS, 41 year old male event planner with hip, knee and back pain and fatigue Treatment: -Ebringer diet (eliminate grains, sucrose, lactose) -Doxycycline, paromomycin Initial response: - “I can’t prepare my own food.” - Hip and knee pain markedly improved. - Lost 20 lbs. Further response: “My friends can’t believe that I’m cooking for myself.” “My friends can’t believe how good I look.” “My physical therapist can’t believe how flexible I am.” 90% pain-free, modifies diet to his life style.
70	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
71	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
72	SKIN DISEASES AND THE GI FLORA Cystic acne: endotoxemia Atopic eczema: dramatic reduction of Lactobacilli, Bifidobacteria, Enterococci; increased Candida, Clostridia, Staph aureus, Proteus, Klebsiella, atypical coliforms Psoriasis, scalp seborrhea: intestinal yeasts
73	DYSBIOSIS MAY INVOLVE YEASTS AND PROTOZOA Yeasts are normal inhabitants of the alimentary canal and are glucose fermenters Yeasts are powerful chemical factories Yeasts are highly antigenic -90% of people have type 4 immunity -10% of people have type 1 immunity -type 3 immunity was found in asthmatics Yeast polysaccharides exert immune activating (zymosan) and immune suppressing (mannan) activity
74	GUT FERMENTATION AND YEAST (Hunnisett et al, J Nutr Med 1990) 61% of chronically ill polysymptomatic patients developed measurable ethanol in blood after ingesting 6 gm glucose Mean rise of 2.5 mg/dl, range from 1 to 7
75	TREATMENT RESULTS SUGGEST YEAST AS A CAUSE OF FERMENTATION AND SYMPTOMS Low sugar diet cleared 42% Diet + nystatin cleared 86% 116/149 clinically better Diet + tetracycline cleared 21%, worsened 35% 2/22 clinically better
76	AS, 31 year old woman with angioedema Prior: Recurrent yeast vaginitis, SAR 1999: OCP for one year, tetracycline for acne for one month edema of face, feet, fingers, hives. Oral steroids. 2000-2001: edema, urticaria, fatigue, brain fog—50% of time. Antihistamines ineffective. Diuretics prn. Allergy evaluation: neg. Self-started a yeast elimination diet: “less moody, a bit less swollen”.
77	AS, 31 year old woman with angioedema Physical exam: mild acne with scarring, peri-orbital swelling, angioedema of left palm, distended abdomen with LLQ tenderness, normal genitalia Intradermal C. albicans antigen: marked delayed reaction, starting after 6 hours, lasting for several days with diffuse erythema, edema and tenderness of forearm, healing with scaling of skin Lab: impaired lymphocyte proliferative response to C. albicans (1.2, ref>3), low plasma zinc (597 mcg.dL, ref 600-1300), borderline retinol 39 mcg/dL (ref 38-106)
78	AS, 31 year old woman with angioedema Treatment: Continue diet Zinc 25 mg/day Vitamin A 10,000 IU/day Lactobacillus plantarum 10 billion units/day Nystatin 3 million units p.o. tid. Initial response was more swelling, lip edema Raised dose to 13 million units/day diuresis, followed by clearing of edema and increased energy
79	NOMENCLATURE CHRONIC CANDIDIASIS CANDIDA SENSITIZATION SYNDROME POLYSYSTEMIC CHRONIC CANDIDIASIS YEAST SYNDROME YEAST PROBLEM YEAST DISEASE CANDIDA “THIS PROBLEM” CANDIDA-RELATED COMPLEX (CRC)
80	CRC: SYMPTOMS MUCOSAL INFECTION FATIGUE DEPRESSION PMS G.I. DISTURBANCES POOR CONCENTRATION/MEMORY ALLERGIC REACTIONS ORGAN SPECIFIC SKIN RASH, ECZEMA, URTICARIA HEADACHE OTHER
81	INTESTINAL YEASTS MAY CAUSE SYMPTOMS BY 3 MECHANISMS Tissue invasion (oral, esophageal, intestinal thrush) Fermentation of sugars (production of ethanol, arabinitol and other toxins) Sensitization (asthma, urticaria, allergic vaginitis, IBS, Crohn’s disease, psoriasis). Cross-sensitization with food yeast may occur
82	CRC IS RELATED TO THE HOST-YEAST INTERACTION Rectal cultures of patients who respond to anti-fungal drugs are less likely to grow yeasts than those of a normal population These patients produce mucosal factors that are abnormally active at inhibiting yeast growth
83
84
85
86	COMPARISON STUDY 87 PATIENTS: 42 CRC+/45 CRC- POSITIVE RECTAL YEAST CULTURE (41) 10 CRC+/31CRC- NEGATIVE RECTAL YEAST CULTURE (46) 32 CRC+/14 CRC- POSITIVE SMEAR (37) 32 CRC+/5 CRC- NEGATIVE SMEAR (9) 0 CRC+/9CRC-
87	CRC: RETROSPECTIVE STUDY YEAST SEEN IN RECTAL SWABS PRE-TREATMENT SMEAR (CALFLOR STAIN) 0-trace 0 + 4 ++/+++ 36 POST-TREATMENT SMEAR (CALFLOR STAIN) 0-trace 28 + 0 ++/+++ 3
88	CRC: RETROSPECTIVE STUDY MICROBIOLOGY OF RECTAL SWABS PRE-TREATMENT CULTURES (BIGGY AGAR) POSITIVE 11 NEGATIVE 32 31 PATIENTS WITH CRC HAD A RECTAL SMEAR THAT WAS ++/+++ AND A SIMULTANEOUS RECTAL CULTURE THAT WAS NEGATIVE (78% OF TOTAL WITH PRE-TREATMENT SMEARS & CULTURES)
89	"Patients with CRC who had..." Patients with CRC who had strongly positive rectal mucus smears and negative rectal cultures had something in their mucus that inhibited the growth of Candida albicans in culture
90
91
92	TREATMENT OF YEAST DYSBIOSIS INVOLVES DIET AND MEDICATION Sugar restriction Avoidance of dietary yeasts (fermented foods, dried fruits, fruit juices, bread) Anti-fungal medication (may provoke a Herxheimer-type response before symptoms improve) Restoration of normal bacterial flora with pro-biotic supplements
93	THE SPECTRUM OF DISEASE INDUCED BY INTESTINAL PARASITES Diarrhea, dysentery, enteritis, colitis “Non-specific” chronic GI complaints UGI bacterial overgrowth Extra-intestinal tissue invasion Malabsorption syndrome Immune supression Allergy (urticaria, atopic reactivity) Food intolerance Fatigue Rheumatologic syndromes
94	MECHANISM OF SYSTEMIC EFFECTS OF INTESTINAL PARASITES Increased intestinal permeability Immune sensitization/suppression Malabsorption
95	PARASITIC RHEUMATISM Inflammatory arthropathy Elevated ESR Inconsistent eosinophilia Inefficacy of anti-inflammatory drugs Demonstration of parasitic infection Prompt response to anti-parasitic treatment Immune complex formation
96	INTESTINAL PARASITES CAUSING PARASITIC RHEUMATISM Giardia lamblia Entamoeba histolytica Endolimax nana Taenia Saginata Schiostosoma mansoni Ascaris lumbricoides Strongyloides stercoralis
97	A UNIQUE ROLE FOR INTESTINAL HELMINTHS Stimulate development of TH-2 cells and down-regulate TH-1 cells Stimulate production of the anti-inflammatory cytokine IL-10 Lack of helminths may account for the increasing prevalence of inflammatory disorders in the developed world, both atopic and mediated by TH-1 autoimmunity
98	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
99	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)
100	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
101	BENEFITS OF BACILLUS LATERSPORUS Laterosporamine: antibiotic Suppress auto-antibody formation Suppress murine lupus nephritis Spergualin: anti-tumor, antibiotic
102	BENEFITS OF SACCHAROMYCES BOULARDII Stimulates production of sIgA Protects against antibiotic diarrhea Helps reverse C difficile colitis
103	E. COLI: BENEFICIAL EFFECTS Prevents infection of animals with Cholera, Shigella, Pseudomonas and staph aureus (no effect on Candida or Salmonella) Degrades N-nitrosamines and polycyclic aromatic amines and N-hydroxyl aryl amines
104	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)
105	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.”
106	MECHANISMS WHICH SUPPORT NORMAL INTESTINAL PERMEABILITY Intestinal mucus Secretory IgA Mucosal epithelium Intramural macrophages Intramural lymphocytes intra-epithelial in Peyer’s patches
107	TWO TYPES OF EPITHELIAL PERMEABILITY Trans-Cellular Para-Cellular
108
109	TRANS-CELLULAR PERMEABILITY The principal route for the absorption of solutes, fluid and macromolecules
110	ACTIVE TRANSPORT Monosaccharides Amino acids, peptides Sodium, zinc, copper, iron, calcium Vitamins
111	NUTRIENT ABSORPTION BY DIFFUSION Magnesium Free fatty acids Monoglycerides, lysolecithin
112	ENDOCYTOSIS Micelles Macromolecules Antigens Microbes
113	INTESTINAL ANTIGEN TRANSPORT IS A PHYSIOLOGICAL PROCESS M-Cells Particulate/insoluble antigens Overlie Peyer’s Patches Response is mostly CD4 Enterocytes Soluble antigen Response is mostly CD-8
114
115
116	INCREASED TRANS-CELLULAR PERMEABILITY Results from impairment of mucosal metabolism Represents a breakdown in the normal activity known as “Gut Antigen Sampling”
117	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)
118
119	CAUSES OF INCREASED PARA-CELLULAR PERMEABILITY Infectious agents Parasites Bacteria Viruses Yeasts Continued
120	CAUSES OF INCREASED PARA-CELLULAR PERMEABILITY Enterotoxins Ethanol NSAIDs Cytotoxic drugs Dysoxia Ischemia Reactive oxygen species
121	PSYCHOLOGICAL STRESS CAN INCREASE GUT PERMEABILITY THROUGH A CHOLINERGIC MECHANISM Rats: cold stress increases both para-cellular permeability and endocytosis. -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
122	DIET ALTERS INTESTINAL PERMEABILITY Fasting: Controls: Increased I.P. R.A.: Decreases I.P. Continued
123	"Increased I.P" Increased I.P. induced by: Low-fiber diets Carrageenan Pectin/guar gum Castor oil Alcohol Allergens Continued
124	"Mucosal Inflammation" Mucosal Inflammation Food allergy “Idiopathic”
125	EFFECTS OF INCREASED PERMEABILITY Antigen Overload Sensitization Immune suppression Toxic Overload Hepatic stress Sepsis
126	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.
127	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 often improves the associated disease.
128	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
129	THE FOUR VICIOUS CYCLES OF THE LEAKY GUT Food Allergy Malnutrition Dysbiosis Hepatic Distress
130	CYCLE ONE: FOOD ALLERGY Increased baseline permeability Marked increase after challenge Increase blocked by sodium cromoglycate
131	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
132	"“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
133	"17 children with IBS" 17 children with IBS 9 with with food-induced alterations of intestinal permeability All 9 were completely cured with diet (7 diet alone, 2 diet plus oral cromolyn before meals)
134	"After ingesting food allergens" After ingesting food allergens, lactulose/mannitol (L/M) ratios rose significantly Taking sodium cromoglycate prevented the rise in L/M ratios Continued
135
136
137	CYCLE TWO: MALNUTRITION Most nutrients require active transport Factors which increase I.P. may hinder active transport Resulting malnutrition disrupts intracellular adhesion
138	CYCLE THREE: DYSBIOSIS Bacterial proteases disrupt cellular adhesion molecules Increased I.P. leads to bacterial sensitization Bacterial sensitization causes leukocyte migration which increases permeability
139
140	CYCLE FOUR: HEPATIC DISTRESS Increased permeability causes: Toxic stimulation of mono-oxygenases Increased free radical generation Damage to hepatocytes and bile ducts
141	"Biliary excretion of reactive oxygen..." Biliary excretion of reactive oxygen species Reflux of toxic bile into pancreatic ducts Loss of factors Pancreatic insufficiency Toxic bile enteropathy
142	HEPATIC COST OF INCREASED PERMEABILITY Kupffer’s Cell Paralysis Stimulation of Mono-Oxygenases Depletion of substrates for conjugation GSH, Glycine Continued
143	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
144	HYPER-PERMEABILITY IN RHEUMATOID ARTHRITIS (continued) I.P. is further increased Systemic inflammation exacerbates Metronidazole and minocycline break the cycle
145	TREATMENT OF HYPER-PERMEABILITY Avoid enterotoxins Treat intestinal infection/bacterial overgrowth with antimicrobials Diet: high nutrient density non-irritating allergen-free
146	HELPING TO REPAIR THE DAMAGED INTESTINE Glutamine Essential fatty acids Antioxidants Glutathione Bioflavonoids Vitamin E Gamma-oryzanol Epidermal growth factor
147	A.F., a 6 year old girl with fever of unknown origin Prior history: vesicoureteric reflux and recurrent UTI; used co-trimoxazole from 12 to 36 months of age and it cleared. Age 5 developed cycling fever with daily temperature spikes to 105 F, lasting 5 days and recurring every 10 to 21 days. Appendectomy (normal appendix) followed by 2 months of metronidazole in September 1998. Microscopic colitis was found in transverse colon, not though to be Crohn’s or ulcerative colitis. Fevers continued but with decreased severity and frequency
148	A.F., a 6 year old girl with fever of unknown origin Parents started a diet eliminating sugar, junk food, wheat and milk products, with improvement: -Fevers occurring every 5 to 7 weeks, lasting only 3 days, spiking only to 102 F. In between fevers, patient appears very healthy. ESR 38 with fever Seen in July 1999. ESR 16 (afebrile) intestinal permeability: low mannitol excretion (3%), high lactulose/mannitol ratio (0.313) IgG to casein in blood, not to gluten
149	A.F., a 6 year old girl with fever of unknown origin Treatment: -casein-free diet -L-glutamine 3.7 gm bid -microcrystalline cellulose 3.7 gm bid -N-acetyl-glucosamine 185 mg bid - Ulmus rubra bark (slippery elm) 110 mg bid -Methylsulfonylmethane (MSM) 160 mg bid -Aloe vera extract (30% MPS) 1 tsp qd Mixed together in apple sauce
150	A.F., a 6 year old girl with fever of unknown origin Initial response: -“Radiant and happy, energy better than in her whole life” - No fever until April, 2000, following Easter festivities: -Temp 102 F, lasting 2 days, recurred 3 weeks later. -Intestinal permeability: low mannitol excretion (3%), lactulose/mannitol ratio improved at 0.107 Advised to follow casein-free diet 100% for at least a month Further response: -No fever during subsequent year -Normal intestinal permeability by 10/00. Mannitol excretion 12%, lactulose mannitol ratio 0.04. -Glutamine, NAG, MSM, slippery elm, aloe discontinued. -Able to tolerate casein when away from home.
151	INTESTINAL PERMEABILITY AND CROHN’S DISEASE Patients have increased I.P. First degree relatives have high I.P. Patients have abnormal reactivity of mucosal lymphocytes to normal gut flora and Candida antigens
152	"For patients in remission" 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
153
154
155	NUTRITIONAL THERAPY FOR CROHN’S DISEASE 20 patients, age 21 to 59, ill 6 mo to 12 yrs followed for 6 months to 8 years symptoms scored: diarrhea, abdominal pain, fever, fatigue, blood/mucus in stool, weight lab tests scored: hemoglobin, ESR, albumen, intestinal permeability (lactulose/mannitol fractional excretion)
156	THE SPECIFIC CARBOHYDRATE DIET EAT fruits, vegetables, meat, fish, poultry, eggs, nut flours and butters, most legumes, eggs, some hard cheeses and yogurts AVOID all grains, disaccharides (lactose and sucrose), soy, potatoes
157	DIETARY SUPPLEMENTS STAGE I Fish oil, delayed release, supplying 875 mg of eicosapentaenoic acid (EPA)/ day vitamin E 400 mg/day zinc 20 mg/ day selenium 200 mcg/day folic acid 800 mcg/day
158	STAGE II DIET OPTIONS complete milk avoidance yeast/mold elimination diet avoidance of nuts and nut flours addition of non-glutinous starch (e.g., rice and potatoes) As modifications to the Specific Carbohydrate Diet
159	STAGE II SUPPLEMENTS glutamine 3000 mg/day Aloe vera mucopolysaccharide concentrate (ace mannan) 4 grams/day
160	CLINICAL RESPONSES complete clinical remission 6 reduction in symptom scores 14 range 90% to 40%, mean 65% response to Stage I diet 11 response to yeast/mold diet 5 response to milk elimination diet 5 required elimination of nuts 4
161	SYMPTOM SCORES
162	SEDIMENTATION RATE
163	INTESTINAL PERMEABILITY Lactulose/mannitol ratio, ref range is 0.01 to 0.06 measured in 13 patients decreased in 84% initial mean 0.275 (range 0.024 to 0.645) final mean 0.074 (range 0.018 to 0.186)
164	SERUM ALBUMEN Mean serum albumen increased initial: 32 G/L (range 24 to 38) final 41 (range 28 to 46)
165	MEDICATION USE ASA derivatives (16 patients), mean dose decreased 33% prednisone (6 patients), mean dose decreased from 17 mg/day (range 10 to 40) to 5 mg/day (range 0 to 7.5) azathioprine (3 patients), mean dose decreased from 100 mg/day to 33 mg/day (range 0 to 50)
166