David Rakel, MD
Director and Associate Professor
University of Wisconsin School of Medicine and Public Health
Balancing the GI Ecosystem
The Enterocyte:
Regenerate every 3-5 days!
Helps: Probiotics, Tea Sweet pepper, black pepper Glutamine, zinc
Hurts: fatty foods, stress, casein, +/- Gluten
Lessons from Vibrio Cholera
Increases zonula occludens toxin which weakens tight junctions and allows the flow of water into the intestinal lumen.
Rx to Watch: Larazotide
Gliadin and AT-1002 increase intestinal permeability
Gopalakrishnan, S., et al. "Larazotide acetate regulates epithelial tight
junctions in vitro and in vivo." Peptides 35(1): 86-94. 2012
The Gut Associated Lymphoid
Tissue (GALT)
>60% of total immune activity
Utilizes the majority of the body’s IgA
production
Has 10
10Lymphoctyes per meter of
bowel
You are more prokaryotic (foreign
cells) than eukaryotic (self-DNA)
10% Human Cells, 90% Bacteria
100 Trillion bacteria = 3 lbs of
body weight.
You are a symbiotic
“super-organism!”
……
6
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, food intolerance, Infection, Stress
Positive Balance Negative Balance
Peace: Balance of sympathetic & Para-sympathetic tone
Stress: ½Sympathetic tone
Proper Acidity
(pH 1-3) ½or ¾Acidity Healthy Mucous Layer Poor Mucous Layer
Low bacterial growth High bacterial growth Intact gut-immune barrier ½Intestinal Permeability
½bacterial growth & balanced flora
Imbalanced bacterial growth (dysbiosis)
Regular evacuation Irregular evacuation
Am J Clin Nutr2003;78:675–83.7
Maternal Acid Suppression
Swedish Medical Birth Registry
860,215 Children
Acid suppression (PPI or H2 blocker) =
½
51% Asthma Incidence
Dehlink E, et al. Clin & Exp Allergy. 39(2); 2008
Acid Activates Pepsin
PH=1.8-3.2 Pepsinogen Protein Active Pepsin Protease Inactive Pepsin Protease PH=>4.5Amino Acids Intact Protein Immune Response
5 days of
PPI=
PH>4.0
Rebound Dyspepsia W/ D/C of PPI
Niklasson A, et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: A double-blind placebo-controlled trial. Am J Gastroenterol advance online publication 23 March 2010.
Eosinophilic Esophagitis
Elimination Diets
Food Intolerance:
The Usual Suspects
**Most prevalent in infants and children
Dairy (Cow’s Milk Protein)** Wheat (Gluten)**
Peanut**
Corn (including corn syrup) Eggs** Citrus Soy** Beef Refined sugar Food additives
Tartrazine (Yellow dye #5) Aspartame
•Validity of IgG testing still
under question
•Allergen-specific IgG may
block IgE mediated
anaphylaxis in vivo and
protect against severe
allergic reaction
How to Stop a PPI
Slow taper off PPI
Get energy moving down and out with: Acupuncture (Aliment Pharmacol Ther
2007;26(10):1333-1344) Aerobic Exercise
Improve diet (consider elimination diet) DGL (De-Glycyrrhizanated Licorice) Slippery Elm, 1 tsp in water 2-4x/day Sucralfate (Carafate) 1 gm w/ meals, qhs Melatonin if symptoms Ïat night Consider: Iberogast…..
Promise? Iberogast®…
Proprietary blend of the following herbal extracts:German chamomile (Matricaria recutita) Clowns mustard (Iberis amara) Angelica (Angelica archangelica) Caraway (Carum carvi) Milk thistle (Silybum marianum) Lemon balm (Melissa officinalis) Celandine (Chelidonium majus) Licorice (Glycyrrhiza glabra) Peppermint (Mentha x piperita)
1 mL orally three times daily over a period of 4-weeks significantly reduces severity of acid reflux, epigastric pain, cramping, nausea, and vomiting compared to placebo.
Melzer J, et al. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther 2004:20:1279-87.
Clown’s Mustard
Developmental Programming
Process whereby an environmental factor
acting during a sensitive developmental
period has an effect that may persist
throughout life
Gut Bacteria influence….
GI Barrier Function/Immunity
Hooper, et al. Science. 292 (2001)
Cortisol/ACTH
Sudo, et al. J Physiol 558 (2004)
Vagal Nerve Signaling
Wang et al. World J Gastro. 8 (2002)
Serotonin levels (
Ï
by 2.8x)
Wikoff, et al. PNAS. 106 (2009)
Brain Development/Behavior
Heijtz, et al. PNAS.108 (2011)
Method of Birth…..
Vagina
Abdomen
Inoculates GI tract with healthy flora Less Atopy (asthma, eczema)
Not exposed to vaginal flora
More atopy (asthma, eczema)
Less Bifidogenic flora
More IgE mediated cow’s milk allergy Sanchez-Valverde F, et al. Allergy 2009: 64:884-889
Method of feeding…
Breast
Bottle
Prebiotics (FOS) = ½Bifidobacteria & Lactobacillli = ½IgA (Mucosal defense) Balance of Th1=Th2 Enterococci, Enterobacteria & Clostridia = Imbalance of humoral response ½Th2 = Atopy Taylor S, Breast Feeding: Vol 4 (1) 2009. Intestinal Permeability in Pre-term Infants: Breast vs Formula Feeding.3 Strikes and your Atopic!
①
GBS + (Peripartum Abx)
②
Cesarean Section
③
Bottle Fed
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.
Pre-biotics in Infant Formula
Formula vs Pre-biotic Formula vs Breast Milk Atopy:
9.7%
5.7%
5.7%
NNT= 24
1,130 Healthy newborns at low risk for atopy
Followed for one year
Gruber, et al. J Allergy Clin Immunol 2010; 126(4)
Abx Early in Life = Asthma
Bottom Line
The risk of developing asthma in childhood is weakly related to early treatment with antibiotics and is also linked to prenatal exposure. (LOE = 2b)
Reference
Murk W, et al. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: A systematic review. Pediatrics 2011; 127(6)
Gut Bacteria & Obesity
Birth-7 yrs: Stools sampled at 6, 12 mths. Obese Children = ¾Bifidobacteria Gut flora predicted obesity
Kalliomaki M, J Clin Nutr. 87(3):2008
General Rule:
Obese: ¾Bifidobacteria, Bacteroidetes
½Firmicutes
Backhed F et al. The Gut Microbiota as an
Environmental factor that Regulates Fat Storage. Proc Natl Acad Sci. 101(44). 2004
Germ Free Mice
Conventional Germinated Mice •½Fat Mass by 60% • Developed Insulin Resistance within 2 weeks.
High fat meal and plasma endotoxin
Am J Clin Nutr 2007;86:1286 –92
One treatment option:
Exercise
Change diet:
Ð
Saturated Fat, Sugar
Prebiotics:
Soluble fiber: Inulin, guar gum
Conjugated Linoleic Acid (CLA) 4 gms daily
Probiotics:
Bifidobacteria
Lactobacillus rhamnosis PL60 Stool transplant form your thin cousin?
Adolescence: Abx & IBD Risk
38,603 British Kids with AcneNon-Users
Users
(>30days)
Margolis D, et al. Am. J. Gastroenterol. 105:2610-6, 2010. Shaw SY, et al. Association Between the Use of Antibiotics and New Diagnoses of Crohn's Disease and Ulcerative Colitis. Am J Gastroenterol. 2011
0.14%
0.26%
Adolescence: Abx & IBD Risk
38,603 British Kids with AcneNon-Users
Users
(>30days)
1)Margolis D, et al. Am. J. Gastroenterol. 105:2610-6, 2010. 2)Shaw SY, et al. Association Between the Use of Antibiotics and New Diagnoses of Crohn's Disease and Ulcerative Colitis. Am J Gastroenterol. 2011
0.14%
0.26%
Those given the most
Abx had up to 50%
higher risk of
developing Crohn’s
Dz within 2-5 years!
An evolving GI environment..
Eat on the run New proteins (Wheat, Dairy, pasteurization)
½Sugar, ETOH ¾ 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
Blood Intestine Blood Intestine Healthy Intestine Increased Permeability Systemic Inflammatory response Ab Ab TTG IgA Antigen Exposure Inflammatory Cell Recruitment ROS Release Epithelial Damage ½Intestinal Permeability Brain-Gut Stress (Mast Cells) H+
Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: An interface between health and disease. J Gastroenterol Hepatol. 2003; 18(5):479-497.
Histamine Serotonin ¾Glutathione in Liver Calprotectin Altered Intestinal Permeability Poor Dietary Choices
Stress & Emotions
Infection Chronic Abx/Steroids Systemic Disease Toxic Exposure Food Intolerance Malnutrition Dysbiosis Toxic Overload Elevated Total Toxic & Antigenic
Burden
Low Stomach Acid
Systemic Disease
½
Intestinal Permeability - Pathophysiolog
IBS Summary
Ever since that illness, Abx or sentinel event=IBS:
4 R approach Chronic IBS:
#1Mind-body tools (hypnosis, CBT) Exercise
Trial of elimination diet Fiber (Guar Gum, Psyllium)
Peppermint Oil: 0.2-0.4 ml enteric coated capsules TID
Cromolyn (Gatrocrom) 400 mg TID
Best if + response to elimination diet
