Download The Gut-Immune Interface

The Gut-Immune Interface
David Rakel, MD
Director, UW Integrative Medicine
Asst. Professor, Dept of Family Medicine
UW School of Medicine and Public Health
Surface Area Exposed to the
External Environment
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!
3 Main Modes of Defense
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
Method of Birth…..
Vagina
Inoculates GI tract
with healthy flora
Less Atopy (asthma,
eczema)
Abdomen
Not exposed to
vaginal flora
More atopy (asthma,
eczema)
Method of feeding…
Breast
Bottle
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
Hygiene Hypothesis
 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.
An evolving GI environment..
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 Gut
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)
Histamine
Seratonin
Antigen
Exposure
 Intestinal
Permeability
Inflammatory Cell
Recruitment
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.
Phase 2 Detoxification
Conjugation
Neutralized Toxin
Phase II System
Glutathione
Amino Acid
Methylation
Sulfation
Acetylation
Glucoronidation
Fat Soluble
Required Nutrients
Glutathione, B6
Glycine
SAMe
Cysteine, methionine, molybdenum
Acetyl-CoA
Glucuronic Acid
Toxin Prepared for Excretion
Water Soluble
Bile/Intestines
Urine/Kidneys
Increasing Glutathione
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)
 Intestinal Permeability - Pathophysiology
Poor Dietary Choices
Food Intolerance
Stress & Emotions
Infection
Chronic Abx/Steroids
Systemic Disease
Malnutrition
Altered
Intestinal
Permeability
Dysbiosis
Elevated Total
Toxic & Antigenic
Burden
Low Stomach Acid
Toxic Exposure
Toxic Overload
Systemic Disease
Key Questions to Ask….
Was there a
disruption to the
normal GI
environment?
Infection
Trauma
Antibiotics/Chemo
Chronic Stress
Surgery
Treatment
“4 R” Approach
Remove (Foods, Pathogens, Rx)
Replace (Acid, Enzymes)
Re-Inoculate (flora)
Repair (Gut Mucosa)
Remove…..
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
Mind Body
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
Mind-Body Influences (Stress)
Monkeys:
Separation of infant and
mother = fecal flora
(Lactobacilli)
Rats:
Chronic stress = 
Permeability
Cortisol results in; 
Permeability
 Mucin production
 IgA secretion
Stress induced changes
reversed with nutrition
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.
Elimination Diets
Elimination Diets
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
Food Intolerance:
The Usual Suspects (IgG)
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.
Replace…
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
Re-inoculate…
Probiotics
Prebiotics
Consider Comprehensive Diagnostic
Stool Analysis
Stool Transplant!?
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):580585.
HPI via retention enema for UC
Before
After
Borody TJ,et al. Treatment of ulcerative colitis
using fecal bacteriotherapy. J Clin
Gastroenterol. 2003; 37(1):42-47.
Repair…
Exercise
Nutrition
Supplements
Exercise: Don’t Overdo it!
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)
Sugar + Yeast =
Fiber!
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.
Sources of Viscous Fiber
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.
Zinc
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
73.3%
2. Calcium
65.1%
3. Magnesium
61.6%
4. Vitamin A
56.2%
5. Vitamin B6
53.6%
6. Iron
39.1%
7. Vitamin C
37.5%
8. Folate
33.2%
9. Thiamine
30.2%
10. Riboflavin
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
L-Glutamine
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)
Glutamine MOA
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.
Omega 3
Doc, those antibiotics you
gave me made my IBS go
away!
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
Hydrogen Breath Test
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
IBS & SBBO
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.
Treatment of SBBO
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
What Worked?
Food elimination?
Supplements?
Having a plan?
Increased sense of control?
Relationship?
All or One?
The Origins of S _ _ _ (Kaka)
Ship High I T
n
ransport
I have already said more than
I know……
For Handouts and Clinical Resources:
www.fammed.wisc.edu/integrative