Transcript nutritional medicine and gastrointestinal pathology

NUTRITIONAL MEDICINE
AND GASTROINTESTINAL
PATHOLOGY
Leo Galland, M.D.
Foundation for Integrated Medicine
www.mdheal.org
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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 microenvironment
• The intestinal microenvironment has an
important influence on the pathophysiology of
many different diseases
• Diets don’t treat diseases, they treat patients
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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.
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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
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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
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Intestinal dysbiosis, altered
permeability, food intolerance
and detoxification are interconnected parts of the same
puzzle
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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)
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COMPOSITION OF
NORMAL STOOL FLORA
Eubacterium, 26 spp
Bacteroides, 20 spp
Bifidobacterium, 8 spp
Peptostreptoccus
Fusobacterium, 5 spp
Ruminoccus, 11 spp
Lactobacillus, 7 spp
Streptococci
Clostridia
Enterobacteriacae
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25.5%
22.6%
11.5%
8.9%
7.7%
4.5%
2.4%
1.6%
0.6%
0.5%
BENEFITS OF
NORMAL GUT FLORA
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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
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NUTRIENTS SYNTHESIZED
BY NORMAL GUT FLORA
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Biotin
Cobalamin
Folic acid
Pantothenic acid
Pyridoxine
Riboflavin
Vitamin K
Butyric acid
Amino acids
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GUT MICROBIAL
DETOXIFICATION
• Demethylate methylmercury
• Degrade N-nitrosamines
• Degrade polycyclic aromatic
hydrocarbons
• Degrade aflatoxin B1 (limited)
• Hydrolyze guanidinosuccinic acid
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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
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HOW NORMAL GI FLORA
PROTECTS AGAINST
GI PATHOGENS
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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
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POTENTIAL ADVERSE EFFECTS
OF NORMAL GUT FLORA
• Deactivate trypsin, chymotrypsin and
intestinal disaccharidases, producing
maldigestion
• Produce ammonia
• Consume Vitamin B12
• Deconjugate bile salts
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POTENTIAL ADVERSE EFFECTS
OF NORMAL GUT FLORA
(continued)
• Increase enterohepatic recirculation of
estrogens
• Activate pro-carcinogens
• Stimulate dysfunctional immune
responses
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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
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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
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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
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AMINES PRODUCED
BY GI FLORA
• Inactivated by hepatic MAO
– tyramine
– octopamine
– histamine
– cadaverine
– putrespecine
– Piperidine
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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
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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
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ESTROGEN METABOLISM
AND GI MICROFLORA
• conjugation
• deconjugation
biliary excretion
increased
entero-hepatic
recirculation
–
increased blood and urine
estrogen
– Western diet: higher plasma estrogen,
lower stool estrogen
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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)
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PRODUCTS OF MICROBIAL
CHO FERMENTATION IN GUT
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SCFAs
Propanol
Acetaldehyde
Formic acid
CO2
Butylene glycol
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Ethanol
Butanol
D-lactic acid
Hydrogen
Acetone
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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
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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
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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
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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
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DIETARY EFFECTS ON GI FLORA
(continued)
• D-glucaric acid inhibits Bglucuronidase; 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
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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
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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
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DYSBIOSIS IS
ECOLOGIC IMBALANCE
Disease or dysfunction
produced by the
interaction between the
host and its “normal”
flora, organisms of low
intrinsic virulence.
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DYSBIOSIS-ASSOCIATED
DISEASES
• Cancer: colon/breast
• Inflammatory bowel
disease
• Irritable bowel syndrome
• Chronic fatigue
syndromes
• Rheumatoid arthritis
• Spondyloarthropathies
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Acne
Psoriasis
Eczema
Food
allergy/intolerance
• Malabsorption
syndromes
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DYSBIOSIS CAUSES DISEASE
BY TWO MECHANISMS
• Microbial enzymes act upon
intestinal contents to produce
noxious substances
• Microbial components stimulate
dysfunctional immune responses
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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
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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: Betaglucuronidase, nitro-reductase, 7-alphadehydroxylase;
– Lactobacilli lower these when fed to
omnivores and prevent colon cancer in
rats given dimethylhydrazine
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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
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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
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DIETARY PREVENTION OF
COLONIC DYSBIOSIS
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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
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SMALL BOWEL BACTERIAL
OVERGROWTH
• produces a different pattern of
dysbiosis, associated with
carbohydrate/fiber intolerance,
bloating, altered bowel habit,
fatigue and maldigestion
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CAUSES OF UPPER GI
BACTERIAL OVERGROWTH
• Achlorhydria/hypochlorhydria
• Surgical
resection/blind loops
• Stasis from
abnormal motility
• Strictures
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Fistulas
Diverticulosis
Immune deficiency
Intestinal
giardiasis
• Tropical sprue
• Malnutrition
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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
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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
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EFFECTS OF UPPER GI
BACTERIAL OVERGROWTH
(continued)
• Mucosal damage by bacterial
enzymes
– Loss of brush border
• Endotoxemia/antigenemia
• Liver damage
• Joint disease
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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
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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
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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
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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
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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
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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
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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
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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%
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Foods Provoking IBS
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Wheat
Milk
Corn
Cheese
Oats
Coffee
Rye30%
Eggs
60%
44%
44%
39%
34%
33%
26%
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Tea
Butter
Yogurt
Citrus
Barley
Chocolate
Nuts
Preservatives
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25%
25%
24%
24%
24%
22%
22%
20%
Foods Provoking IBS
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Potatoes 20%
Cabbage 19%
Sprouts 18%
Peas
17%
Beef
16%
Carrots 15%
Lettuce 15%
Rice
15%
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Pork
Broccoli
Soy
Chicken
Spinach
Yeast
Lamb
Sugar
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14%
14%
13%
13%
13%
12%
11%
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 common
Hunter et al,Topics in Gastroenterology, 1985
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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)
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IMMUNE SENSITIZATION
AND DYSBIOSIS
• Immune responses to intestinal
microorganisms may provoke
inflammatory and auto-immune
disorders
• Specific: bacterial antigens mimic autoantigens
• Non-specific: polyclonal activation,
RES hyperstimulation, APC activation
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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
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KLEBSIELLA AND ANKYLOSING
SPONDYLITIS (AS)
MOLECULAR MIMICRY
• Klebsiella antigens cross-react with
HLA-B27
• Initiates inflammatory cascade
– Leads to reactive arthritis
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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
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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
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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.
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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
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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.
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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 crossreact with HLA-DR4
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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
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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
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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
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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
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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
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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”.
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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 38106)
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AS, 31 year old woman with
angioedema
• Treatment:
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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
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NOMENCLATURE
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CHRONIC CANDIDIASIS
CANDIDA SENSITIZATION SYNDROME
POLYSYSTEMIC CHRONIC CANDIDIASIS
YEAST SYNDROME
YEAST PROBLEM
YEAST DISEASE
CANDIDA
“THIS PROBLEM”
CANDIDA-RELATED COMPLEX (CRC)
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CRC: SYMPTOMS
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MUCOSAL INFECTION
FATIGUE
DEPRESSION
PMS
G.I. DISTURBANCES
POOR CONCENTRATION/MEMORY
ALLERGIC REACTIONS
ORGAN SPECIFIC
SKIN RASH, ECZEMA, URTICARIA
HEADACHE
OTHER
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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
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CRC IS RELATED TO THE HOSTYEAST 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
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COMPARISON STUDY
87 PATIENTS: 42 CRC+/45 CRCPOSITIVE RECTAL YEAST CULTURE (41)
10 CRC+/31CRCNEGATIVE RECTAL YEAST CULTURE (46)
32 CRC+/14 CRCPOSITIVE SMEAR (37)
32 CRC+/5 CRCNEGATIVE SMEAR (9)
0 CRC+/9CRCFoundation for Integrated Medicine
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
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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 PRETREATMENT SMEARS & CULTURES)
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• 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
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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 probiotic supplements
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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
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MECHANISM OF SYSTEMIC
EFFECTS OF INTESTINAL
PARASITES
• Increased intestinal permeability
• Immune sensitization/suppression
• Malabsorption
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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
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INTESTINAL PARASITES CAUSING
PARASITIC RHEUMATISM
•
•
•
•
•
•
•
Giardia lamblia
Entamoeba histolytica
Endolimax nana
Taenia Saginata
Schiostosoma mansoni
Ascaris lumbricoides
Strongyloides stercoralis
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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
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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
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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)
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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
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BENEFITS OF
BACILLUS LATERSPORUS
• Laterosporamine: antibiotic
–Suppress auto-antibody formation
–Suppress murine lupus nephritis
• Spergualin: anti-tumor, antibiotic
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BENEFITS OF
SACCHAROMYCES BOULARDII
• Stimulates production of sIgA
• Protects against antibiotic diarrhea
• Helps reverse C difficile colitis
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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 Nhydroxyl aryl amines
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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)
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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.”
Ann NY Acad Sci 915 (2000), p xi
MECHANISMS WHICH SUPPORT
NORMAL INTESTINAL
PERMEABILITY
•
•
•
•
•
Intestinal mucus
Secretory IgA
Mucosal epithelium
Intramural macrophages
Intramural lymphocytes
– intra-epithelial
– in Peyer’s patches
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TWO TYPES OF
EPITHELIAL PERMEABILITY
• Trans-Cellular
• Para-Cellular
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TRANS-CELLULAR
PERMEABILITY
• The principal route for
the absorption of
solutes, fluid and
macromolecules
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ACTIVE TRANSPORT
• Monosaccharides
• Amino acids, peptides
• Sodium, zinc, copper, iron,
calcium
• Vitamins
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NUTRIENT ABSORPTION
BY DIFFUSION
• Magnesium
• Free fatty acids
• Monoglycerides,
lysolecithin
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ENDOCYTOSIS
•
•
•
•
Micelles
Macromolecules
Antigens
Microbes
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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
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INCREASED
TRANS-CELLULAR
PERMEABILITY
• Results from impairment of
mucosal metabolism
• Represents a breakdown in the
normal activity known as “Gut
Antigen Sampling”
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PARA-CELLULAR PERMEABILITY
IS LIMITED BY CELL ADHERANCE
MOLECULES (CAMs)
• Tight junctions contain claudins
• Adherens junctions and
desmosomes contain cadherins
• Contraction of the cytoskeleton
opens junctions (glucose
absorption is a stimulus)
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CAUSES OF INCREASED
PARA-CELLULAR
PERMEABILITY
• Infectious agents
–Parasites
–Bacteria
–Viruses
–Yeasts
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Continued
CAUSES OF INCREASED
PARA-CELLULAR PERMEABILITY
• Enterotoxins
– Ethanol
– NSAIDs
– Cytotoxic drugs
• Dysoxia
– Ischemia
– Reactive oxygen species
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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 cholinesterase activity is weak
-The effect is blocked by atropine
-It may depend upon vagal activation of
mast cells
• Similar effects occur in humans
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DIET ALTERS INTESTINAL
PERMEABILITY
• Fasting:
–Controls: Increased I.P.
–R.A.: Decreases I.P.
Continued
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• Increased I.P. induced by:
–Low-fiber diets
–Carrageenan
–Pectin/guar gum
–Castor oil
–Alcohol
–Allergens
Continued
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• Mucosal Inflammation
–Food allergy
–“Idiopathic”
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EFFECTS OF
INCREASED PERMEABILITY
• Antigen Overload
–Sensitization
–Immune suppression
• Toxic Overload
–Hepatic stress
• Sepsis
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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.
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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.
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LEAKY GUT SYNDROMES
• Enteritis, colitis
Infectious/inflammatory
• Arthritis, chronic
inflammatory
• Food allergic
disorders
• AIDS
• CFIDS
• MCS
• Chronic pancreatic
disease
• Chronic noninfectious hepatitis
• Acne
• psoriasis
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THE FOUR VICIOUS CYCLES
OF THE LEAKY GUT
•
•
•
•
Food Allergy
Malnutrition
Dysbiosis
Hepatic Distress
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CYCLE ONE: FOOD ALLERGY
• Increased baseline
permeability
• Marked increase after
challenge
• Increase blocked by
sodium cromoglycate
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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
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• “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
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• 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)
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• After ingesting food allergens,
lactulose/mannitol (L/M) ratios
rose significantly
• Taking sodium cromoglycate
prevented the rise in L/M ratios
Continued
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CYCLE TWO: MALNUTRITION
• Most nutrients require active
transport
• Factors which increase I.P. may
hinder active transport
• Resulting malnutrition disrupts
intracellular adhesion
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CYCLE THREE: DYSBIOSIS
• Bacterial proteases disrupt
cellular adhesion molecules
• Increased I.P. leads to bacterial
sensitization
• Bacterial sensitization causes
leukocyte migration which
increases permeability
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CYCLE FOUR:
HEPATIC DISTRESS
Increased permeability causes:
• Toxic stimulation of monooxygenases
• Increased free radical generation
• Damage to hepatocytes and bile
ducts
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• Biliary excretion of reactive
oxygen species
• Reflux of toxic bile into
pancreatic ducts
–Loss of factors
–Pancreatic insufficiency
• Toxic bile enteropathy
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HEPATIC COST OF
INCREASED PERMEABILITY
• Kupffer’s Cell Paralysis
• Stimulation of Mono-Oxygenases
• Depletion of substrates for
conjugation
–GSH, Glycine
Continued
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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
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HYPER-PERMEABILITY
IN RHEUMATOID ARTHRITIS
(continued)
• I.P. is further increased
• Systemic inflammation
exacerbates
• Metronidazole and minocycline
break the cycle
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TREATMENT OF
HYPER-PERMEABILITY
• Avoid enterotoxins
• Treat intestinal infection/bacterial
overgrowth with antimicrobials
• Diet: high nutrient density
– non-irritating
– allergen-free
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HELPING TO REPAIR THE
DAMAGED INTESTINE
• Glutamine
• Essential fatty acids
• Antioxidants
– Glutathione
– Bioflavonoids
– Vitamin E
– Gamma-oryzanol
• Epidermal growth factor
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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
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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
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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
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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.
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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
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• For patients in remission, the
rate of relapse correlates with
I.P. measured prospectively
Wyatt J et al, Intestinal Permeability and the
Prediction of Relapse in Crohn’s Disease,
Lancet 341:1437-1439, 1993
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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)
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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
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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
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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
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STAGE II SUPPLEMENTS
• glutamine 3000 mg/day
• Aloe vera mucopolysaccharide
concentrate (ace mannan) 4 grams/day
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CLINICAL RESPONSES
• complete clinical remission
• reduction in symptom scores
range 90% to 40%, mean 65%
• response to Stage I diet
• response to yeast/mold diet
• response to milk elimination diet
• required elimination of nuts
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6
14
11
5
5
4
SYMPTOM SCORES
60
50
40
30
20
10
0
INITIAL
FINAL
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
SEDIMENTATION RATE
90
80
70
60
50
40
30
20
10
0
INITIAL
FINAL
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
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)
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SERUM ALBUMEN
• Mean serum albumen increased
• initial: 32 G/L (range 24 to 38)
• final 41 (range 28 to 46)
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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)
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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
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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
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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
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Food Allergy
Leo Galland M.D.
Foundation for Integrated
Medicine
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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%)
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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)
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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
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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
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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)
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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
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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
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24 noFoundation
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
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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
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RESPONSE TO OLIGOANTIGENIC
DIET IN HYPERKINETIC SYNDROME
Total number
Hyperactivity:
Normal
Mild
Moderate
Severe
Conners’ score
Antisocial acts
Headache
Seizures
Abdominal pain
Limb pain
Eczema, rash
Aphthous ulcers
Atopic (prick test)
Pre-diet
76
0
6
31
39
24
32
48
14
54
33
29
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15 Medicine
30 (39%)
Diet
76
21
28
19
8
12
13
9
1
8
6
9
5
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
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FOODS PROVOKING HYPERACTIVITY IN
DOUBLE-BLIND, PLACEBO-CONTROL TRIAL
% REACTIVE
Additives
Soy
Milk
Chocolate
Grapes
Wheat
Oranges
Cheese
Eggs
Peanuts
Corn
Fish
Oats
Melon
Tomato
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79
73
64
59
50
49
45
40
39
32
29
23
23
21
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
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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
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MIGRAINE-ASSOCIATED SYMPTOMS
AND FOOD INTOLERANCE
88 PATIENTS
Pre-diet
Diet
Abdominal pain,
diarrhea
Hyperactivity
Limb pain
Rhinitis
RAS
Vaginal discharge
Asthma
Eczema
61
41
41
34
15
11
7
6
27/40 provoked by DBPC food trial
10/40 provoked by placebo also
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3/40 provoked by neither
8
5
7
15
2
1
3
3
EVIDENCE FOR ALTERED IMMUNE
ACTIVATION IN RESPONSE
TO FOODS IN MIGRAINE
(Marteletti 1991, Acta Neurologica)
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Increased circulating immune complexes
Increased activated T cells and total T cells
Increased plasma IL-2 levels
Effective prophylaxis with oral sodium
cromoglycate
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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
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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
Foundation for Integrated Medicine
TM, a 26 old woman with massive
proteinuria, anasarca
• Initial evaluation: Cushingoid, 3+ proteinuria
• Method: modified fast, supported by a ricebased, 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
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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
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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)
Foundation for Integrated Medicine
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
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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
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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)
Foundation for Integrated Medicine
Foundation for Integrated Medicine
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
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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
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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
Foundation for Integrated Medicine
TREATMENT OF FOOD ALLERGY
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Symptomatic pharmacotherapy
Dietary avoidance
Pre-prandial cromolyn 800-1600 mg/day
Intestinal repair
Probiotics
Counseling: nutritional, psychological
Induction of oral tolerance
Foundation for Integrated Medicine
Detoxification
Leo Galland M.D.
Foundation for Integrated
Medicine
Foundation for Integrated Medicine
OUR BODIES DETOXIFY
• Exogenous, foreign
substances
• Endogenous, internally
created substances
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ENDOGENOUS
SUBSTANCES
• Gut toxins
– bacteria
– parasites
– yeast
• Hormones
• Bile acids
• Metabolic intermediates
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EXOGENOUS
SUBSTANCES
• Xenobiotics
– herbicides
– pesticides
• Air pollutants
– auto exhaust
– tobacco smoke
• Pharmaceuticals
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DETOXIFICATION
TRANSFORMS MOLECULES
• Functionalization
Phase I
• Conjugation
Phase II
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MAJOR SITES OF
ENZYMATIC DETOXIFICATION
• Liver
– most important organ
• Lung, intestine, kidney & skin
– demonstrable detox capability
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LIVER DETOXIFICATION
• PHASE ONE: OXYGENATION
• PHASE TWO: CONJUGATION
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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
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Foundation for Integrated Medicine
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
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PHASE ONE INDUCERS
• cabbage, broccoli, brussel sprouts
(indole-3-carbinol)
• oranges and tangerines (limonene)
• caraway and dill seeds (limonene)
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PHASE ONE INHIBITORS
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grapefruit (naringenin)
turmeric (curcumin)
capsicum (capsaicin)
cloves (eugenol)
onions (quercetin)
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• ZINC DEFICIENCY DISRUPTS
PHASE ONE ACTIVITY, SHIFTING
ENZYME PATTERNS TO
INCREASE THE PRODUCTION
OF CANCER PROMOTERS
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PHASE TWO:CONJUGATION
• sulfate
• amino acids: glycine, taurine, glutamine,
ornithine, arginine
• glutathione
• methylation
• glucuronic acid
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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
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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)
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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
Foundation for Integrated Medicine
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
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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
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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
Foundation for Integrated Medicine
ANTIOXIDANT
PROTECTION
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vitamins E and C
carotenoids (carotene, lycopene, lutein)
flavonoids
selenium
glutathione
lipoic acid
Foundation for Integrated Medicine
Foundation for Integrated Medicine
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
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CLASSES OF FLAVONOIDS
• Glycosides
– rutin, hesperidin
• Aglycones
– flavonols (quercetin)
– anthocyanidins (catechin)
• Proanthocyanidins
– dimers, trimers of anthocyanidins
• Tannins
– polymeric anthocyanidins
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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
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Foundation for Integrated Medicine
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Foundation for Integrated Medicine
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
Foundation for Integrated Medicine
THE INTESTINES
AND DETOXIFICATION
• absorption and excretion of toxins
• second largest volume of detox
enzymes
• intestinal toxicity stresses the liver
Foundation for Integrated Medicine
DETOXIFYING AGENTS
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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)
Foundation for Integrated Medicine
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
Foundation for Integrated Medicine
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