Foundation for Integrated Medicine NUTRITIONAL MEDICINE AND GASTROINTESTINAL PATHOLOGY Leo Galland,...

Foundation for Integrated Medicine

NUTRITIONAL MEDICINE AND GASTROINTESTINAL

PATHOLOGYLeo Galland, M.D.


www.mdheal.org


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


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.


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


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


Intestinal dysbiosis, altered permeability, food intolerance and detoxification are inter-

connected parts of the same puzzle


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)


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%


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


NUTRIENTS SYNTHESIZED BY NORMAL GUT FLORA

• Biotin• Cobalamin• Folic acid• Pantothenic acid• Pyridoxine• Riboflavin• Vitamin K• Butyric acid• Amino acids


GUT MICROBIAL DETOXIFICATION

• Demethylate methylmercury

• Degrade N-nitrosamines

• Degrade polycyclic aromatic hydrocarbons

• Degrade aflatoxin B1 (limited)

• Hydrolyze guanidinosuccinic acid


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


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


POTENTIAL ADVERSE EFFECTS OF NORMAL GUT FLORA

• Deactivate trypsin, chymotrypsin and intestinal disaccharidases, producing maldigestion

• Produce ammonia

• Consume Vitamin B12

• Deconjugate bile salts


POTENTIAL ADVERSE EFFECTS OF NORMAL GUT FLORA

(continued)

• Increase enterohepatic recirculation of estrogens

• Activate pro-carcinogens

• Stimulate dysfunctional immune responses


BACTERIAL ENZYMES OF TOXICOLOGICAL SIGNIFICANCE TO THE HOST

ENZYME SAMPLE SUBSTRATE EFFECT

B-glucosidase Cycasin amydgalin Tumor promotion

B-glucuronidase Glucuronidides Recirculate estrogen, methemoglobin

Nitrate reductase Nitrate Nitrite production

Nitroreductase Nitrobenzene Tumor induction by nitrosamines

Azo reductase Brown FK Vacuolar myopathy

Urease Urea Ammonia toxicity

Methylmercury

demethylase

Methylmercury Reduction in neurotoxicity


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


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


AMINES PRODUCED BY GI FLORA

• Inactivated by hepatic MAO– tyramine– octopamine– histamine– cadaverine– putrespecine– Piperidine


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


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


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


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)


PRODUCTS OF MICROBIAL CHO FERMENTATION IN GUT

• SCFAs

• Propanol

• Acetaldehyde

• Formic acid

• CO2

• Butylene glycol

• Ethanol

• Butanol

• D-lactic acid

• Hydrogen

• Acetone


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


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


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


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


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


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


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


DYSBIOSIS IS ECOLOGIC IMBALANCE

Disease or dysfunction produced by the interaction between the host and its “normal” flora, organisms of low intrinsic virulence.


DYSBIOSIS-ASSOCIATED DISEASES

• Cancer: colon/breast• Inflammatory bowel

disease• Irritable bowel syndrome• Chronic fatigue

syndromes• Rheumatoid arthritis• Spondyloarthropathies

• Acne• Psoriasis• Eczema• Food

allergy/intolerance• Malabsorption

syndromes


DYSBIOSIS CAUSES DISEASE BY TWO MECHANISMS

• Microbial enzymes act upon intestinal contents to produce noxious substances

• Microbial components stimulate dysfunctional immune responses


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



• 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



(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



(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


SMALL BOWEL BACTERIAL OVERGROWTH

• produces a different pattern of dysbiosis, associated with carbohydrate/fiber intolerance, bloating, altered bowel habit, fatigue and maldigestion


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• 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


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


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


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


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


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%


Foods Provoking IBS

• Wheat 60%• Milk 44%• Corn 44%• Cheese 39%• Oats 34%• Coffee 33%• Rye 30%• Eggs 26%

• Tea 25%• Butter 25%• Yogurt 24%• Citrus 24%• Barley 24%• Chocolate 22%• Nuts 22%• Preservatives 20%


Foods Provoking IBS

• Potatoes 20%• Cabbage 19%• Sprouts 18%• Peas 17%• Beef 16%• Carrots 15%• Lettuce 15%• Rice 15%

• Pork 14%• Broccoli 14%• Soy 13%• Chicken 13%• Spinach 13%• Yeast 12%• Lamb 11%• Sugar 12%


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 commonHunter et al,Topics in Gastroenterology, 1985


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)


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

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


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


KLEBSIELLA AND ANKYLOSING SPONDYLITIS (AS)

MOLECULAR MIMICRY

• Klebsiella antigens cross-react with HLA-B27

• Initiates inflammatory cascade

– Leads to reactive arthritis


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


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


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.



• 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



• 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.


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


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


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


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


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


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”.



• 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)



• 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


NOMENCLATURE• CHRONIC CANDIDIASIS• CANDIDA SENSITIZATION SYNDROME• POLYSYSTEMIC CHRONIC CANDIDIASIS• YEAST SYNDROME• YEAST PROBLEM• YEAST DISEASE• CANDIDA• “THIS PROBLEM”

CANDIDA-RELATED COMPLEX (CRC)


CRC: SYMPTOMS• MUCOSAL INFECTION• FATIGUE• DEPRESSION• PMS• G.I. DISTURBANCES• POOR CONCENTRATION/MEMORY• ALLERGIC REACTIONS• ORGAN SPECIFIC SKIN RASH, ECZEMA, URTICARIA

HEADACHEOTHER


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


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


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-


CRC: RETROSPECTIVE STUDY

YEAST SEEN IN RECTAL SWABSPRE-TREATMENT SMEAR (CALFLOR STAIN)

0-trace 0

+ 4

++/+++ 36

POST-TREATMENT SMEAR (CALFLOR STAIN)

0-trace 28

+ 0

++/+++ 3


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)


• 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


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


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


MECHANISM OF SYSTEMIC EFFECTS OF INTESTINAL

PARASITES

• Increased intestinal permeability

• Immune sensitization/suppression

• Malabsorption


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


INTESTINAL PARASITES CAUSING PARASITIC RHEUMATISM

• Giardia lamblia

• Entamoeba histolytica

• Endolimax nana

• Taenia Saginata

• Schiostosoma mansoni

• Ascaris lumbricoides

• Strongyloides stercoralis


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


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


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


BENEFITS OF BACILLUS LATERSPORUS

• 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 diarrhea

• Helps reverse C difficile colitis


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


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)

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


ACTIVE TRANSPORT

• Monosaccharides

• Amino acids, peptides

• Sodium, zinc, copper, iron, calcium

• Vitamins


NUTRIENT ABSORPTION BY DIFFUSION

• Magnesium

• Free fatty acids

• Monoglycerides, lysolecithin


ENDOCYTOSIS

• Micelles

• Macromolecules

• Antigens

• Microbes


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


INCREASED TRANS-CELLULAR

PERMEABILITY

• Results from impairment of mucosal metabolism

• Represents a breakdown in the normal activity known as “Gut Antigen Sampling”


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 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


DIET ALTERS INTESTINAL PERMEABILITY

• Fasting:–Controls: Increased I.P.–R.A.: Decreases I.P.

Continued


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

Continued


• Mucosal Inflammation

–Food allergy

–“Idiopathic”


EFFECTS OF INCREASED PERMEABILITY

• Antigen Overload

–Sensitization

–Immune suppression

• Toxic Overload

–Hepatic stress

• Sepsis


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 often improves 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


THE FOUR VICIOUS CYCLES OF THE LEAKY GUT

• Food Allergy

• Malnutrition

• Dysbiosis

• Hepatic Distress


CYCLE ONE: 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


• 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)


• After ingesting food allergens, lactulose/mannitol (L/M) ratios rose significantly

• Taking sodium cromoglycate prevented the rise in L/M ratios

Continued


CYCLE TWO: MALNUTRITION

• Most nutrients require active transport

• Factors which increase I.P. may hinder active transport

• Resulting malnutrition disrupts intracellular adhesion


CYCLE THREE: DYSBIOSIS

• Bacterial proteases disrupt cellular adhesion molecules

• Increased I.P. leads to bacterial sensitization

• Bacterial sensitization causes leukocyte migration which increases permeability


CYCLE FOUR: HEPATIC DISTRESS

Increased permeability causes:

• Toxic stimulation of mono-oxygenases

• Increased free radical generation

• Damage to hepatocytes and bile ducts


• Biliary excretion of reactive oxygen species

• Reflux of toxic bile into pancreatic ducts

–Loss of factors

–Pancreatic insufficiency

• Toxic bile enteropathy


HEPATIC COST OF INCREASED PERMEABILITY

• Kupffer’s Cell Paralysis• Stimulation of Mono-Oxygenases• Depletion of substrates for

conjugation–GSH, Glycine

Continued


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


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


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



• 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



• 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



• 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 0.107Advised 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.


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


• 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


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)


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


DIETARY SUPPLEMENTSSTAGE 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


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


STAGE II SUPPLEMENTS

• glutamine 3000 mg/day

• Aloe vera mucopolysaccharide concentrate (ace mannan) 4 grams/day


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


SYMPTOM SCORES

0

10

20

30

40

50

60

INITIAL FINAL

1234567891011121314


SEDIMENTATION RATE

0

10

20

30

40

50

60

70

80

90

INITIAL FINAL

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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)


SERUM ALBUMEN

• Mean serum albumen increased

• initial: 32 G/L (range 24 to 38)

• final 41 (range 28 to 46)


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)


CASE REPORT

• 28 year old male, sick for 3 years, disabled

• prednisone 40 mg, azathioprine 100 mg/day

• fever 40 degrees C, bloody diarrhea 6 times/day, 30 pound weight loss, ESR 90, albumen 26 g/L, oxalic acid excretion 164 mg/day


CASE REPORT

• Stage I diet for 3 weeks led to complete clearing of symptoms

• Addition of stage I supplements and maintenance of diet led to ESR of 5, albumen of 4.2, weight gain of 15 pounds over 60 days

• all medications discontinued


CASE REPORT

• 1-year follow-up: maintenance of clinical remission, lactulose/mannitol ratio = 0.026, oxalic acid excretion of 32 mg/day

• complete remission of all parameters for 3 years


Food Allergy

Leo Galland M.D.



HOW PREVALENT IS FOOD ALLERGY/INTOLERANCE?

• 33% of 1000 teachers (56% response rate) reported avoidance specific foods because of “unpleasant” physiological reactions.

• A poll of 5000 US physicians on prevalence of food allergy (14% response rate): 0-80% (mean 10%)


Immunologic Mechanisms of Food Intolerance

• Type I (IgE mediated, TH2 promoted)

• Type II (IgG and complement mediated, cytotoxic, TH1 promoted)

• Type III (IgG immune complex mediated, TH1 promoted)

• Type IV (cell-mediated, TH1 promoted)


Non-immunologic Mechanisms of Food Intolerance

• Digestive (e.g., lactase deficiency)

• Pharmacologic (e.g., caffeine, ethanol)

• Biochemical (histamine, tyramine, salicylates, sulphites, MSG)

• Non-specific mast cell degranulation

• Lectin-mediated glycoprotein agglutination


Poor Sulphoxidation and Food Allergy (Scadding 1988)

• 74 adults with non-IgE food allergy diagnosed by elimination and challenge

• 78% slow carbocisteine sulfoxidizers vs 33% of controls (p<0.005)

• Carbon oxidation (debrisoquine): normal• Theory: altered metabolism of food

chemicals toxic/immunogenic metabolites by novel pathways


FOOD ALLERGY/INTOLERANCE: WELL-DOCUMENTED MANIFESTATIONS

• Atopic Eczema• Allergic Rhinitis, Asthma• Anaphylaxis, Angioedema,

Urticaria• Oral Allergy Syndrome

(Ortolani)• Aphthous Ulceration• Alveolitis, Hemosiderosis• Infantile Colic• Vomiting, Diarrhea,

Abdominal Pain• Irritable Bowel Syndrome• Hematochyzia, Colitis

• Pediatric Enteropathies• Celiac Disease• Protein-losing Enteropathy• Failure to thrive• Crohn’s Disease

(exacerbation)• Migraine headches• Migraine-associated Epilepsy• ADHD• Nephrotic Syndrome• Allergic Arthritis• Rheumatoid Arthritis

(exacerbation)


FOOD ALLERGY IN PEDIATRIC ATOPIC ECZEMA

• 25-60% are food reactive• Increased gut permeability

– at baseline– after food challenges– blocked by cromolyn

• Histamine release• Circulating immune complexes• Multi-system reactivity in 2/3

– 49% gastrointestinal– 23% rhinitic– 17% asthmatic

• Poor correlation between food responses and prick tests, RAST: milk, egg, citrus, additives, nuts, fish, wheat, tomatoes, lamb, chicken, soy


FOOD ALLERGY IN PERENNIAL RHINITIS

(Ortolani et al)

210 patients over 1 year

3-week oligoantigenic diet

52 improved (24.8%)

28 IgE mediated (13.3%), based upon correlation with RAST, skin testing

24 no correlation


FOOD ALLERGY IN RECURRENT APHTHOUS

STOMATITIS

• Cytotoxic lymphocytes/antibodies

• Histamine release to foods (23/60)

• 30% correlation of HR and ulcers

• Gluten, milk, food additives


FOOD ALLERGY IN HYPERKINETIC SYNDROME

(Egger et al, Lancet 1985)

76 children seen on referral

(60 boys, 16 girls)

age 2-15 (mean 7.3)

37 from dysfunctional families

4 weeks’ oligoantigenic diet

2 meats, 2 starch sources, 2 fruits,

1 vegetable, calcium, multivitamin


RESPONSE TO OLIGOANTIGENIC DIET IN HYPERKINETIC SYNDROME

Pre-diet DietTotal number 76 76

Hyperactivity: Normal 0 21 Mild 6 28 Moderate 31 19 Severe 39 8Conners’ score 24 12Antisocial acts 32 13Headache 48 9Seizures 14 1Abdominal pain 54 8Limb pain 33 6Eczema, rash 29 9Aphthous ulcers 15 5Atopic (prick test) 30 (39%)


Summary of Egger’s Results

• Open trial: 82% of children responded favorably to the oligoantigenic diet

• DBPCT: 28 participated, with rating of response by parents, a neurologist and a psychologist

• DBPCT: 51-74% of the food intolerances confirmed


FOODS PROVOKING HYPERACTIVITY IN DOUBLE-BLIND, PLACEBO-CONTROL TRIAL

% REACTIVE Additives 79

Soy 73

Milk 64

Chocolate 59

Grapes 50

Wheat 49

Oranges 45

Cheese 40

Eggs 39

Peanuts 32

Corn 29

Fish 23

Oats 23

Melon 21

Tomato 20


Cognitive-Emotional Symptoms and Food Allergy (King, 1981)

• DBPCT: 30 adults, 28 food extracts, sub-lingual, multiple measures, 2 judges

• Symptoms associated with allergen exposure: anxiety, depression, brain fog, irritability, detachment, euphoria; pruritus, cold hands, myalgia, nasal congestion, tinnitus, fatigue, headache

• Occurrence p=0.001, Severity p=0.002


FOOD ALLERGY IN PEDIATRIC MIGRAINE (Egger, 1983)

88 children, oligoantigenic diet

93% cleared by 2 weeks

90% relapsed on open challenge

40 of these, DBPC TRIAL

26 confirmed (4 reacted to placebo, 8 reacted to neither)

Atopy 55%, 46% hyper, 16% seizures

Milk, egg, chocolate, orange, wheat

benzoate, cheese, tomato, tartrazine, rye, fish,

pork, beef, corn, soy, tea


MIGRAINE-ASSOCIATED SYMPTOMS AND FOOD INTOLERANCE

88 PATIENTS

Pre-diet Diet

Abdominal pain,

diarrhea 61 8

Hyperactivity 41 5

Limb pain 41 7

Rhinitis 34 15

RAS 15 2

Vaginal discharge 11 1

Asthma 7 3

Eczema 6 3

27/40 provoked by DBPC food trial

10/40 provoked by placebo also

3/40 provoked by neither


EVIDENCE FOR ALTERED IMMUNE ACTIVATION IN RESPONSE

TO FOODS IN MIGRAINE(Marteletti 1991, Acta Neurologica)

• Increased circulating immune complexes• Increased activated T cells and total T cells• Increased plasma IL-2 levels• Effective prophylaxis with oral sodium

cromoglycate


Food Allergy in Idiopathic Nephrotic Syndrome

• Basophile histamine release test +

- 65% of 34 patients

- 5% of 19 controls

wheat, beef, milk, egg, pork

• 26 patients with refractory nephrosis

- 6 remitted on oligoantigenic diet


TM, a 26 old woman with massive proteinuria, anasarca

• Prior: aesthetician, applying artificial nails, developed asthma, multiple inhalant allergies, provoked by allergy immunotherapy

• Severe anasarca emergency hospitalization, furosemide, steroids

• Proteinuria 4 gm/day, serum albumen 1.3 gm/L, marked hyperlipidemia, normal biopsy

• Required prednisone 20 mg/day maintenance


TM, a 26 old woman with massive proteinuria, anasarca

• Initial evaluation: Cushingoid, 3+ proteinuria• Method: modified fast, supported by a rice-

based, oligoantigenic food supplement, tapering down prednisone and daily examination of urine protein by dipstick

• Result: clearing of proteinuria in 7 days, return of proteinuria within 24 hours of ingesting hen’s eggs

• Total remission for 7 years, avoids eggs


Food Intolerance and Rheumatoid Arthritis

• 5-46% of patients in various studies have exacerbation of symptoms provoked by specific foods, mostly wheat, milk, tomatoes, various additives, some confirmed with DBPC trials

• An 18-year open study of foods provoking pain in 100 patients found that certain spices and food additives were commonest agents


GLUTEN INTOLERANCE IS PREVALENT AND PROTEAN

• Gliadin antibodies were found in 30/53 patients with neurological disease of unknown cause (73% had abnormal small bowel biopsies)

Hadjivassiliou et al, Lancet 347: 369-371 (1996)

• IgG and IgA gliadin antibodies occur in 2% of Italian school children

Catassi et al, Lancet 343: 200-203 (1994)


Cow’s Milk Allergy and IDDM

• Children with IDDM have IgG against a peptide fraction of bovine serum albumen that cross-react with a pancreatic beta-cell surface protein

• Adults with recent-onset IDDM show excessive T-cell proliferation in response to beta-casein, compared to normal and auto-immune controls


DIAGNOSIS OF FOOD ALLERGY• History

– atopic disease– multisystem complaints– fluctuations– provocations - rough skin, red ears, geographic tongue

• Skin tests, IgE (total/food specific)• Dietary elimination/challenge

– symptom change– gut permeability change


D-XYLOSE ABSORPTION DECREASES AFTER FOOD ALLERGEN CONSUMPTION

• In children with cow’s milk protein enteropathy (diarrhea, pain), 1 hour blood d-xylose was significantly higher on a milk-free diet than 4 days after starting a milk-containing diet

Morin et at, Lancet i: 1102-1104 (1979)


Elimination Diets

• Elemental

• Oligoantigenic

• Avoid commonest allergens: milk, wheat, corn, soy, eggs, citrus, nuts, fish

• Gluten and/or casein-free

• Yeast and mold-free

• Low-salicylate


Technique of Food Elimination

• Obtain baseline measure of target symptoms or signs

• Complete avoidance of all food/drink containing test components for 5-14 days

• Instruct patients/parents in foods that can or should be eaten and in monitoring of symptoms


Food Challenge Techniques

• If there is no change in target parameters, return to usual diet en bloc and observe for exacerbation

• If improvement is observed, introduce foods singly, one every 1-2 days, 2-6 challenges for each food; delayed reactions are common

• If symptoms occur, hold challenges until clear• Avoid suspected symptom provokers• Re-challenge with these after completion


TREATMENT OF FOOD ALLERGY

• Symptomatic pharmacotherapy

• Dietary avoidance

• Pre-prandial cromolyn 800-1600 mg/day

• Intestinal repair

• Probiotics

• Counseling: nutritional, psychological

• Induction of oral tolerance


Detoxification

Leo Galland M.D.



OUR BODIES DETOXIFY

• Exogenous, foreign substances

• Endogenous, internally created substances


ENDOGENOUS SUBSTANCES

• Gut toxins– bacteria– parasites– yeast

• Hormones• Bile acids• Metabolic intermediates


EXOGENOUS SUBSTANCES

• Xenobiotics– herbicides– pesticides

• Air pollutants– auto exhaust– tobacco smoke

• Pharmaceuticals


DETOXIFICATION TRANSFORMS MOLECULES

• FunctionalizationPhase I

• ConjugationPhase II


MAJOR SITES OF ENZYMATIC DETOXIFICATION

• Liver

– most important organ

• Lung, intestine, kidney & skin

– demonstrable detox capability


LIVER DETOXIFICATION

• PHASE ONE: OXYGENATION

• PHASE TWO: CONJUGATION


PHASE ONE ENZYMES

• Cytochrome P450 system (20-30 enzymes)

• Use oxygen to alter molecules

• By-products include free oxygen radicals

• End products may be more dangerous than the initial chemicals


PHASE ONE ACTIVITY

• Increased in tobacco smokers• Increased or decreased by medications• Increased by char-broiled meats and

high intake of alcohol, BHT or vegetable oils

• Variably influenced by phytochemicals, especially flavonoids

• Decreased in vegans


PHASE ONE INDUCERS

• cabbage, broccoli, brussel sprouts (indole-3-carbinol)

• oranges and tangerines (limonene)

• caraway and dill seeds (limonene)


PHASE ONE INHIBITORS

• grapefruit (naringenin)

• turmeric (curcumin)

• capsicum (capsaicin)

• cloves (eugenol)

• onions (quercetin)


• ZINC DEFICIENCY DISRUPTS PHASE ONE ACTIVITY, SHIFTING ENZYME PATTERNS TO INCREASE THE PRODUCTION OF CANCER PROMOTERS


PHASE TWO:CONJUGATION

• sulfate

• amino acids: glycine, taurine, glutamine, ornithine, arginine

• glutathione

• methylation

• glucuronic acid


PHASE TWO INHIBITION

• nutritional deficiency

• toxin exposures that exhaust supplies of substrates or co-factors

• example: acetaminophen, alcohol and low protein intake deplete glutathione, which is needed for acetaminophen detoxification


PHASE TWO STIMULATION

• cabbage, broccoli, cauliflower, brussel sprouts, kale (glucosinolates)

• garlic oil, rosemary, soy• citrus peel, dill and caraway oils

(limonene)• curcumin• S-adenosyl methionine (SAM)• milk thistle (silymarins)


Glucosinolates Must Be Hydrolyzed by the Enzyme Myrosinase

• Glucosinolates (>70 types) are separated from myrosinase in plants, not sprouts

• Crushing the plant before cooking liberates the active phytochemical

• Sulforaphane releases nuclear respiratory factor-2 (Nrf2), induces glutathione S-transferase


Glucosinolates Must Be Hydrolyzed by the Enzyme Myrosinase

• Indole-3-carbinol is converted to diindolyl methane (DIM) by acid conjugation in the stomach

• DIM stimulates CYPA1/1A2, which alters estrone metabolism to reduce estrogenic activity and inhibit growth of breast cancers


PHASE TWO GENETICS

• Genetic variation in the activity of different Phase two enzymes in the liver, brain or intestines may account for disease susceptibility:

• colon cancer

• breast cancer

• Parkinson’s disease


ANTIOXIDANT BENEFITS

• protect DNA and cell or organelle membranes from free radical damage

• elevate levels of glutathione• stimulate immune responses• increase activity of tumor suppressor

genes• inhibit activity of enzymes needed for

tumor growth


ANTIOXIDANT PROTECTION

• vitamins E and C

• carotenoids (carotene, lycopene, lutein)

• flavonoids

• selenium

• glutathione

• lipoic acid


PLANT FUNCTIONS OF FLAVONOIDS

• Production stimulated by lack of light

• Stress: microbes, heavy metals, ozone, sulfur dioxide, pH changes

• Inhibit photo-oxidation and microbial growth


CLASSES OF FLAVONOIDS

• Glycosides– rutin, hesperidin

• Aglycones– flavonols (quercetin)– anthocyanidins (catechin)

• Proanthocyanidins– dimers, trimers of anthocyanidins

• Tannins– polymeric anthocyanidins


FLAVONOID EFFECTS ON MAMMALIAN CELLS

• Potent anti-oxidants

–quench free radicals

–chelate transition metals

• Inhibit oxygenases: PG synthetase

–5-lipoxygenase

• Alter activity of ION pumps


METHYLATION

• protects DNA from mutation• depends upon methionine (SAM), folic

acid, vitamin B12• enhanced by dimethylglycine (DMG),

choline, betaine• CAVEAT: methylation inactivates

genes; aberrant methylation may inactivate tumor suppressor genes


THE INTESTINES AND DETOXIFICATION

• absorption and excretion of toxins

• second largest volume of detox enzymes

• intestinal toxicity stresses the liver


DETOXIFYING AGENTS

• dietary fiber (beans, grains)

• antioxidants (vegetables, seeds, fruit)

• Phase Two inducers (crucifers)

• glutathione enhancers (selenium...)

• methylation enhancers (folic acid...)

• spices (turmeric, rosemary)

• herbs (milk thistle, Ginkgo biloba)


AB, 6 year old girl with psoriasis

• Prior to age 3: infantile colic, rarely ill• Age 3: otitis media associated with guttate

psoriasis, treated with steroids and dovenex • Naturopath: avoid junk food, use flax oil and

primrose oil progressively worse• On a 50% fruit and vegetable diet, nightshade

free dramatic improvement, leaving few tiny patches on arms


AB, 6 year old girl with psoriasis

• Her psoriasis controlling diet-Breakfast: Granola, soy milk, water-Lunch: Whole wheat bread, tuna, cheese, almond butter, fruit conserves, water-Dinner: Chicken, salmon, noodles, brown rice, salad, vegetables-Snacks: fruits and vegetables

Foundation for Integrated Medicine NUTRITIONAL MEDICINE AND GASTROINTESTINAL PATHOLOGY Leo Galland,...

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