David Rakel, MD
Director, UW Integrative Medicine
Asst. Professor, Dept of Family Medicine
UW School of Medicine and Public Health

Surface Area
(Sq M)
200
180
160
140
120
100
80
60
40
20
0
Skin Lungs GI

The Enterocyte:
Regenerate every 3-5 days!

Mucous Barrier (Prostaglandins, IgA)
NSAIDS, Chemotherapy, Lack of fiber,
Infection, Stress
Microflora (Probiotics, Prebiotics)
Antibiotics, Poor nutrition, Infection, Stress
Local Immune system (GALT)
Food allergy, intolerance (IgG), Infection,
Stress

Positive Balance
Peace: Balance of sympathetic
& Para-sympathetic tone
Proper Acidity
(pH 1-3)
Healthy Mucous Layer
Low bacterial growth
Intact gut-immune barrier
 bacterial growth & balanced flora
Regular evacuation
Negative Balance
Stress:

Sympathetic tone
 or

Acidity
Poor Mucous Layer
High bacterial growth

Intestinal Permeability
Imbalanced bacterial growth
(dysbiosis)
Irregular evacuation

Inoculates GI tract with healthy flora
Less Atopy (asthma, eczema)
Not exposed to vaginal flora
More atopy (asthma, eczema)

Prebiotics (FOS) =

Bifidobacteria &
Lactobacillli =

IgA (Mucosal defense)
Balance of Th1=Th2
Enterococci,
Enterobacteria &
Clostridia =
Imbalance of humoral response
 Th2 = Atopy

Am J Clin
Nutr2003;78:675 –83.7


Bifidobacteria, Lactobacilli =

IgA in Mucous = (Th1=Th2)

Intestinal Permeability = Th2 imbalance (Allergic..Atopy) or a Th1 imbalance (Autoimmune.. Crohns)

Probiotics in primary prevention of atopic disease:
A randomised placebo-controlled trial
Lancet, 2001. Vol.
357 ( 9262 )
Probiotics given prenataly and postnataly for a total of 6 months.
Lactobicillus GG reduced eczema by
50%
NNT = 4.5
Follow-up study showed that effect persisted to 5 yrs of age.

Eat on the run
New proteins (Wheat,
Dairy, pasteurization)
 Sugar,  Nutrient dense foods
Different bacteria
Less fiber
More Rx (PPI, steroids,
Abx)
Cordain L. Origens & Evolution of the Western Diet: Health Implications for the 21st
Century. Am J of Clinic Nutr. 2005

Healthy
Villi/Good
Absorption
Healthy Cell
Junctions

 Intestinal Permeability &
Malabsorption
Damaged
Villi/ Poor
Absorption
Damaged
Cell junctions

Intestine
Healthy Intestine Blood
Intestine
Increased
Permeability
Ab
Ab
Systemic
Inflammatory response
Blood

Brain-Gut Stress
(Mast Cells)
Antigen
Exposure
Inflammatory Cell
Recruitment
Histamine
Seratonin

Intestinal
Permeability
Calprotectin
ROS Release
Epithelial
Damage
H+

Glutathione in Liver
Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: An interface between health and disease. J Gastroenterol Hepatol. 2003; 18(5):479-497.

Conjugation
Phase II System
Glutathione
Amino Acid
Methylation
Sulfation
Acetylation
Glucoronidation
Neutralized Toxin
Fat Soluble
Required Nutrients
Glutathione, B
6
Glycine
SAMe
Cysteine, methionine, molybdenum
Acetyl-CoA
Glucuronic Acid
Toxin Prepared for Excretion
Bile/Intestines
Water Soluble
Urine/Kidneys

Safe with long-term use;
Vitamin C 500 mg/d
Vitamin E 800 IU/d (Mixed Tocopherols)
B-Complex Vit.
(Thiamine & B6)
Milk Thistle
Needs Further Study;
NAC
(N-Acetylcysteine aka; Mucomyst)
Glutathione
(Good in food: fruits, vegetables & fish. Or a
Mediterranean type diet)


Poor Dietary Choices
Stress & Emotions
Infection
Chronic Abx/Steroids
Food Intolerance
Malnutrition
Altered
Intestinal
Permeability
Dysbiosis Systemic Disease
Low Stomach Acid
Toxic Exposure Toxic Overload
Elevated Total
Toxic & Antigenic
Burden
Systemic Disease

Was there a disruption to the normal GI environment?
Infection
Trauma
Antibiotics/Chemo
Chronic Stress
Surgery

“4 R” Approach
Remove (Foods, Pathogens, Rx)
Replace (Acid, Enzymes)
Re-Inoculate (flora)
Repair (Gut Mucosa)

Stress (Change interpretation)
High risk foods
Gluten (wheat), dairy
What food do you crave the most?
Chronic acid suppression (PPI, H2 blocker) if able.
If able: Antibiotics, steroids

Neuropeptides from the gut influence our emotions.
Metaphor
“Gut Instinct”
“Something's eating me up inside”
“Listen to your gut”

Soderholm JD. Stress and gastrointestinal tract. II. Stress and intestinal barrier.
Am J Physiol Gastrointest Liver Physiol, 280(1), G7-G13. 2001

Monkeys:
Separation of infant and mother =  fecal flora
(Lactobacilli)
Rats:
Chronic stress = 
Permeability
Cortisol results in;

Permeability
 Mucin production

IgA secretion

Rat pups separated from mothers =

Permeability
Reversed with:
Omega-3 fatty acids
(DHA)
Arachadonic Acid
Prebiotics (FOS)
Probiotics (Lactobacillus)
Garcia-Rodenas CL, et al. Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats.
J Pediatr Gastroenterol Nutr. 2006; 43(1):16-24.

Ogle KA, Bullock JD. Children with allergic rhinitis and or bronchial asthma treated with elimination diet: A five-year follow-up. Annals of
Allergy. 44(5)273. 1980, May.
Asthma
1980 study of 322 <1 year olds w/ negative skin tests
Ate only Meat Base Formula, beef, carrots, broccoli, apricots
91% with improvement of respiratory symptom scores
51% reproduced symptoms with food challenges
Milk, eggs, chocolate, soy, legumes (peanuts), cereals, in that order

Dairy
Wheat
Corn (including corn syrup)
Eggs
Citrus
Soy
Beef
Refined sugar
Food additives
Tartrazine (Yellow dye #5)
Aspartame

Figure 2 Mean change in symptom severity scores at 12 weeks according to degree of adherence. Difference between the groups with high adherence: 101 (95% confidence interval 54, 147); ***p<0.001.
Atkinson, W et al. Gut 2004;53:1459-1464
Copyright ©2004 BMJ Publishing Group Ltd.

Acid (Betaine HCL)
Elderly
Significant indigestion
Digestive Enzymes
Short term use only
To help with malabsorption if present
Consider Lactulose/Mannitol permeability test

Lactulose (Big Sugar)
Mannitol (Small Sugar)
Results:

Mannitol

Lactulose = Normal

Lactulose and Mannitol = Malabsorption
 Mannitol  Lactulose =  Permeability

Probiotics
Prebiotics
Consider Comprehensive Diagnostic
Stool Analysis

Human Probiotic Infusion(HPI)
Aas J, Gessert CE,
Bakken JS.
Recurrent clostridium difficile colitis: Case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis.
2003; 36(5):580-
585.

Before After
Borody TJ,et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin
Gastroenterol. 2003; 37(1):42-47.

Exercise
Nutrition
Supplements

Intense running =

Intestinal
Permeability
Combining NSAIDS with Marathon running = 
Permeability
Lambert GP, et al. Gastrointestinal permeability during exercise:
Effects of aspirin and energy-containing beverages. J Appl Physiol.
2001; 90(6):2075-2080.

Change in American Diet
Rich in refined sugars and vegetable oils =
36.2% of total energy in the American Diet.
These foods are essentially void of nutrients
(empty foods..just energy)

Viscous fiber absorbs water, slows glucose absorption (lowers glycemic Index),
 cholesterol absorption.
Is needed for healthy mucous layer
Increases thermogenesis during digestion.
Prolongs digestion = satiety
Reduces insulin secretion by  glycemic index.

Consider 1/2-1 tsp TID qAC with 8 oz of Water
Guar Gum (Benefiber)
Psyllium (Metamucil)
Ground Flax seed
Konjac
Asian tubor: 5 times more potent that psyllium, guar gum & oat fiber in  cholesterol.
Caution: these agents expand like sponges and if taken with little water can cause obstruction, particularly Konjac.

HCL Acid depends on
Zinc for its secretion
Needed for IgA and immune function
Beneficial for shortening infectious diarrhea and pneumonia in kids.
Inhibits copper absorption

Percentage of all Individuals >2 yo NOT meeting 100% US Recommended Dietary
Allowances
1.
Zinc
2.
Calcium
3.
Magnesium
4.
Vitamin A
5.
Vitamin B6
6.
Iron
7.
Vitamin C
8.
Folate
9.
Thiamine
10.
Riboflavin
65.1%
73.3%
61.6%
56.2%
53.6%
39.1%
37.5%
33.2%
30.2%
30.0%
Cordain L. Origens & Evolution of the Western Diet: Health Implications for the 21st
Century. Am J of Clinic Nutr. 2005

Zinc and Endothelial Repair
10 Patients given Indomethacin to cause
 permeability
Randomized Cross-over trial
Zinc 37.5 mg resulted in 75%  in gastric and small bowel injury & 50% less villous shortening.
Indomethacin = 3-4x
 permeability vs none in those tx with Zinc
Mahmood A, Zinc carnosine, a health food supplement that stabilizes small
bowel integrity and stimulates gut repair processes. Gut. 2006

Non-essential Amino Acid
Used as energy source for rapidly growing cells
Good evidence to support use for the very sick
(intensive care, chemo &
Rx therapy)
5-10 gms BID (Powder)

Reduces Inflammation by reducing gut associated cytokine release
Wischmeyer PE. Can glutamine turn off the motor that drives systemic inflammation?
Crit Care Med. 2005; 33(5):1175-1178.
Reduces risk of gut derived septicemia in critically ill
Antioxidant, Increases Glutathione (GSH)
Enhances Heat Shock Protein (HSP) that protects enterocytes from injury.
Does not reduce permeability in those without inflammation who are nutritionally deprived
Hulsewe KW, et al. Clin Nutr. 2004; 23(5):1217-1225.

Glutamine’s Benefit in the ICU
De-Souza DA, Crit Care Med.
2005; 33(5):1125-1135.

Small Bowel Bacterial Overgrowth (SBBO)
Coliform and anaerobic bacteria normally found in the colon, grow in the small intestine.
? Chronic acid suppression
Consider in those with severe IBS

Oral administration of lactulose or glucose.
Elevated levels of bacteria ferment the sugar  hydrogen and methane gas that can be detected in exhaled gas.
If elevated, also check H.
Pylori Ab

202 w/ Rome Criteria for IBS
78% had SBBO on Hydrogen Breath Test
Those with SBBO that were eradicated with Abx had significant improvement in
Sxs
48% had resolution of Rome criteria for
IBS post treatment
Pimentel M. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel. Am J. Gastroenterol. 95(12), 3503-3506, 2000.

Low carbohydrate diet
Abx: TMP/Sulfa & Metronidazole (low dose for 2-4 weeks)
Probiotics post antibiotics, or alone if
Abx not used (Lactobacillus GG,
Culturelle )
Avoid acid suppressing agents

Food elimination?
Supplements?
Having a plan?
Increased sense of control?
Relationship?
All or One?

hip
igh
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ransport