anaq.zonulin english feb 15, 2016 (1) 3 - fluids iq part i.pdf · abstract...

Zonulin

Lucie Blouin IFMCP ND.A CN Mth K.in

Syllabus

•  DIDIH •  Explana+on of the “Zonulin” biomarker •  Detec+ng inflamma+on •  Detec+ng chronic inflamma+on •  The drying membrane •  Protocols

©copyright Lucie Blouin

TUBE&DIGESTIF&DIGESTIVE TRACT

Maldiges+on •  Inadequate Mas+ca+on •  Hypochlorhydria •  Pancrea+c insufficiency •  Bile insufficiency •  Enzymes

©2015 The Institute for Functional Medicine

MaldigestionMaldigestion• Inadequate mastication

• Hypochlorhydria

• Pancreatic insufficiency

• Enzymes

• Bile insufficiency

Maldigestion Clinical Characteristics

� Steatorrhia � Abdominal discomfort � Flatulence � Nutrient malabsorption � Edema � Bleeding � Weight loss � Decreased Growth (infants)

Origin � Mucosal dysfunction � Dysbiosis � Pancreatic enzyme

insufficiency � Bile insufficiency

Maldigestion

Stomach Func+ons

•  AcAvaAon of pepsinogen in pepsin: – Result of acid hydrolysis through hydrochloric acid

•  Start of protein digesAon process •  DestrucAon of microbial intruders •  Mineral absorpAon:

– Calcium, iron, magnesium, copper and zinc –  Increases with stomach acidity

Hydrochloric Acid (HCL) � Poor protein absorption � Vitamin B12 Deficiency �  Iron Deficiency � Ferritin Deficiency � H. Pylori Infection

� Pepsin: 90-180 mg � Betaine hydrochloride & Pepsin:

650 mg & 45 mg � Bromelain: 500-1500 mg/day � Gentian root: 10 mg/day � Zinc (L-Carnosine): 75-150 mg


Causes

•  Age

•  Stress

•  Fasting

•  Infections: Viral / bacterial

•  Antacids (abuse)

•  PPI (Protein Pump Inhibitors)

•  H2 blockers

Acidity Supporter

•  Betaine HCL

•  Umeboshi (pickled plums)

•  Digestive enzymes (pH)

•  Swedish Elixir

•  Gentian root

•  Stress management

•  Apple cider vinegar

•  Acupuncture

Apricots (Ume) Japanese (Prunus mune)

•  < H.Pylori & Active Gastritis

•  Cardiovascular protection

•  Extract MK615 – < Periodontal Disease

– Anti-inflammatory

–  Induces apoptosis

Int J Mol Sci. 2011;12(4);2088-2099;Exp Ther Med.2010 July1(4) 569-574 Med.Hypothesis 2015 aug3 Breast J. 2007 Jan-feb,13(1) 44-9.Asian pac j can pre. 2005

Gluten / Stomach Gluten Composi+on Gluten Degrada+on

Prolamine & Gliadin in wheat rich in Proline & Glutamine, 2 amino acids (AA) very difficult to digest. They are non-‐essenAal AAs since the body can synthesize them. Precisely this high content of proline and glutamine in gluten which prevents complete protein degrada8on by diges8ve enzymes.

2 Protein FracAons: Alcohol soluble Prolamines Alcohol Insolubles Glutenins. FracAons differ with cereal type. Wheat: Gliadins & Glutenins. ComposiAon: 100s of components. Depending on geneAc variaAon, each wheat variety is idenAfiable by these storage proteins, which is virtually its specific fingerprint.

http://www.drschaer-institute.com/fr/nutrition/digestion-du-gluten-1105.html

Pharmacological Approach

1.  Enzymes that break down gluten 2.  Vaccines (desensiAzaAon) 3.  MedicaAons that aYempt to prevent disease

(Celiac) 4.  MedicaAon which binds to the molecule

(gluten) hYp://celiacdisease.about.com/od/CeliacDiseaseDrugs/a/Celiac-‐Disease-‐Drugs-‐In-‐Development.htm

Gluten Gliadin Fragments Zonulin

Inactive Zonuline

Intestinal Disruption

Fasano 2011

Β Cell Disruption

AT1001=Larazotide

Reestablish Intes+nal Barrier Func+on

Larazo+de (Acetate) Zonulin Inhibitor

Prevents: -‐ The loss of intes+nal barrier func+on -‐ Appearance of auto-‐an+bodies and the onset of disease

Abstract Celiac disease is a T cell-‐driven intolerance to wheat gluten. The gluten derived T cell epitopes are proline-‐rich and thereby highly resistant to proteolyAc degradaAon within the gastrointesAnal tract. Oral supplementaAon with prolyl oligopepAdases has therefore been proposed as a potenAal therapeuAc approach. The enzymes studied, however, have limitaAons as they are irreversibly inacAvated by pepsin and acidic pH, both present in the stomach. As a consequence, these enzymes will fail to degrade gluten before it reaches the small intesAne, the site where gluten induces inflammatory T cell responses that lead to celiac disease. We have now determined the usefulness of a newly idenAfied prolyl endoprotease from Aspergillus niger for this purpose. Gluten and its pepAc/trypAc digest were treated with prolyl endoprotease and the destrucAon of the T cell epitopes was tested using mass spectrometry, T cell proliferaAon assays, ELISA, rpHPLC, SDS-‐PAGE and Western bloang. We observed that the A. niger prolyl endoprotease works opAmally at pH 4-‐5, remains stable at pH 2 and is completely resistant to digesAon with pepsin. Moreover, the A. niger derived enzyme efficiently degraded all tested T cell sAmulatory pepAdes as well as intact gluten molecules. On average the endoprotease from A. niger degraded gluten pepAdes 60 Ames faster than a prolyl oligopepAdase. Together these results indicate that the enzyme from A. niger efficiently degrades gluten proteins. Future studies are required to determine if the prolyl endoprotease can be used as an oral supplement to reduce gluten intake in paAents. Key words: celiac disease, gluten, prolyl endoprotease G-‐00034-‐2006.R1

2006: American Physiological Society.

Oral supplements of prolyl oligopepAdases proposed as therapeuAc approach to reduce gluten effect.

LimitaAon: Enzyme irreversibly inacAvated by Pepsin

& acid pH of stomach

Result: Failure to degrade gluten prior to entry into the small intes+ne

v New discovery of the prolyl endoprotease found in ASPERGILLUS NIGER

v Works opAmally at pH 4-‐5 & stable at pH 2 v Resistant to digesAon by pepsin v Degrades gluten protein 60X faster then a prolyl oligopepAdase

Aspergillus

Aspergillus: - Form of filamentous "imperfect fungi”. - Used in the food & biotechnology industry for:

- Fermentation - Enzyme production

- Organic acid production - Antimicrobial production

Diges+ve enzymes derived from Aspergillus Plant Enzyme Products Protease 800 60,000 HUT Protease 6.0 20,000 HUT Protease 3.0 20 SAPU Lipase 3000 FIP Amylase 24,000 DU Glucoamylase 30 AGU Lactase 1600 ALU Invertase 900 SU Cellulase 800 CU Hemicellulase 200 HCU Beta-‐glucanase 20 BGU Phytase 10 FTU Alpha-‐galacosidase 102 GalU

Combine 2 Amylase -‐ Never less than 24,000 U/G Neutral Protease -‐ Never less than 6,000 U/G Lactase -‐ Never less than 4,000 U/G Cellulase -‐ Never less than 340 U/G

Liz Lipsi PHD 2015

Enzymes/Gluten 400mg -‐  AcAve Acidic Protease 70,000 HUT -‐  Amylase 15,000 D.U. -‐  Glucoamylase 16 A.G.U. -‐  AcAve pepAdase (DPP IV-‐LH,DPPIV-‐LL,DPP IV-‐FP) 50,000 HUT -‐  ProbioAc mixture 400 millions -‐  -‐B.brevis,L.casei,L-‐lacAs,l.thmosus,B.lacAs,L.helveAcus

Specific Bacteria / Gluten Protease 350mg/18000 FCC PC

Ø Gluten specific bacteria/protease 50 mg / 5700 FCC PC Ø Protease/acAve acid 10 mg/1980 FCC HUT Ø Protease/ acAve alkaline 10mg/5100 FCC HUT

1500 Protease HUT 1000 Exo-‐pepAdase SAPU 250 ProbioAc combinaAon 250 DPPIV S.Boulardii 10 BCFU 15 mg rice grain Capsule of vegetable

Liz Lipsi PHD 2015

Background & Aims: Celiac sprue is a mulAfactorial disease characterized by an inflammatory response to ingested gluten in the small intesAne. ProteolyAcally resistant, proline-‐ and glutamine-‐rich gluten pepAdes from wheat, rye, and barley persist in the intesAnal lumen and elicit an immune response in geneAcally suscepAble persons. We invesAgated a new combinaAon enzyme product, consisAng of a glutamine-‐specific endoprotease (EP-‐B2 from barley) and a prolyl endopepAdase (SC PEP from Sphingomonas capsulata), for its ability to digest gluten under gastric condiAons. Methods: The ability of this combinaAon enzyme to digest and detoxify whole-‐wheat bread gluten was invesAgated. In vitro and in vivo (rat) experimental systems were developed to simulate human gastric digesAon, and the resulAng material was analyzed by high-‐performance liquid chromatography, enzyme-‐linked immunoabsorbent assay, and paAent-‐derived T-‐cell proliferaAon assays. Results: The analysis revealed that EP-‐B2 extensively proteolyzes complex gluten proteins in bread, whereas SC PEP rapidly detoxifies the residual oligopepAde products of EP-‐B2 digesAon. In vitro dose variaAon data suggests that an approximate 1:1 weight raAo of the 2 enzymes should maximize their synergisAc potenAal. The efficacy of this 2-‐enzyme glutenase was verified in a rat model of gastric gluten digesAon. Conclusions: By combining 2 enzymes with gastric acAvity and complementary substrate specificity, it should be possible to increase the safe threshold of ingested gluten, thereby amelioraAng the burden of a highly restricted diet for paAents with celiac sprue.

CombinaAon Enzyme Therapy for Gastric DigesAon of Dietary Gluten in PaAents With Celiac Sprue

Gastroenterology. August 2007, Volume 133, issue 2 ,pg 472-‐480

Study explains that enzyme therapy improves the condition in individuals

suffering from Celiac disease

PancreaAc Enzyme Insufficiency

•  Abdominal pain •  Weight loss •  Glucose intolerance •  Fat in the stool •  MalabsorpAon •  MalnutriAon •  Vitamin deficiency

•  Pale stool •  Foul stool •  Large stool •  BloaAng •  Excessive flatulence •  Candida

Causes

•  Microvilli Damage •  Toxicity •  Stress •  Nutrient deficiency •  pH unbalance •  Inhibitors / food •  OxidaAon / Free Radicals •  Alcohol (abuse)


What Contributes to Enzyme Deficiency?

• Damaged microvilli

• Toxicity

• Stress

• Nutritional insufficiency

• Imbalanced pH

• Inhibitors in food

• Free radical oxidation

• Alcohol abuse

Diseases Associated with Enzymes

•  Chronic pancreaAAs •  CysAc fibrosis •  Celiac disease •  Stomach ulcers •  PancreaAc duct obstrucAon

•  Autoimmune CondiAons •  Crohn's Disease •  Anemia •  Bone loss Disease •  Neurological CondiAons •  Etc ..

Al-‐Kaade S, Exocrine PancreaAc insuffiency,Medscape;& hYp://www.idenAfy.com/hcp

Herbs / EnzymaAc SAmulators

•  > Amylases : Ginger & Curcumin •  é Lipases > 80% : Curcumin •  > Enzymes: Disaccharidases (sucrase,lactase,maltase)

> 300%: Coriander, onions •  > Increases at least one enzyme disaccharidase: -‐ ginger, fennel, curcumin,

-‐ asafoeAda (powder), capsaicin (pepper) piperine (molecule / mushroom)

Enzyme / lactase

•  Enzyme lactase 3450 FCC units 690 mg in maltodextrine base

•  Composed of enzymes 199mg (mixture of lactase, protease,lipase,

invertase) •  Invertase *

•  Lactase 250 mg (3750 FCC units) •  Plant Protease 60 mg (8 protease BCU)

•  Lipase 60 mg (900 esterase BCU& 450 lipase BCU)

•  Bromeline 50 mg (60 GDU)

•  Plant Renine 0.1mg (0.22 IMCU)

* See next image

•  Glycoside hydrolase, which catalyzes the hydrolysis of food grade sucrose (sugar) into fructose and glucose

•  Mixture called inverted sugar, hence the name •  Present in lining of the small intesAne •  Role: Hydrolysis of dietary sucrose (sugar) •  In bees, used to convert nectar into honey.

Invertase

PancreaAn, animal derived (take with food)

Fork : 500-‐2500 units/kg/meal

-‐PancreaAn 6x 500mg -‐Protease 156,000 USP -‐Amylase 156,000 USP -‐Lipase 24,906 USP

PancreaAne 8X 125mg 1 pill -‐Protease 25,000 USP -‐Amylase 25,000 USP -‐Lipase 2,000 USP

PancreaAn 4X 500mg, 1 pill -‐Protease 50,000 USP -‐Amylase 50,000 USP -‐Lipase 4,000 USP

Enzyme Func+on Protease (proteoly+c)

•  Protein digesAon •  Supports the stomach and pancreas •  Prevent food poisoning •  Improves food allergy problems •  Increases food movement •  Supports the immune system •  Reduces inflammaAon •  Etc.


Protease (Proteolytic) Enzymes

• Bromelain (from pineapple) providing 120 GDU 150 mg

• Papain (from papaya) providing 150,000 USP units 75 mg

• Pancreatin 4X providing 5000 USP units 50 mg

• Rutin 50 mg• Trypsin 50 mg

Bromelain (pineapple) GDU 120 150 mg Papain (papaya) 150,000 USP units 75 mg PancreaAn 4x 5000 USP units 50 mg RuAn 50 mg Trypsin 50 mg D.Luckazer 2015

Bromelain: 250-‐500 mg -‐  Aqer eaAng, helps digesAon -‐  Between meals, < l’inflamma+on

-‐  Papain: 100-‐250mg

Proteoly+c Enzymes

Liz Lipsi PHD 2015

Vésicule-Biliaire- Gall Bladder

Functions - Emulsify fat - Remove cholesterol - Eliminate xenobiotics (drugs, heavy metals, etc) Removal of the gallbladder may cause deficiencies Liz Lipsi PHD 2015

Gall Bladder Insufficieny

Incomplete Digestion Steatorrhea Diarrhea

Steatorrhea: Excess fat in the stool

Ø Chronic pancreatitis

Ø Celiac disease

Ø Crohn's disease

Ø Post-gastrectomy

Ø Cholestasis

Ø Gardiase (parasite)

Ø  Dandelion Root (Taraxacum officianale) 2-‐4 g 3x/day, aqer food 5ml in 1:1 Extract (liquid)

Ø Taurine: 500-‐1000 mg, with food Ø Limonene: 1000 mg/ standardized extract (short term) Ø Bile salt extract (ox bile): 500-‐1000 mg, aqer food

Liz Lipsi PHD 2015

Radis (rouge,blanc,raifort) Pissenlit Chicorée & autres aliments verts amers ArAchaud

Vésicule&Biliaire&

•  Choline&:&300mg/&jr&(minimum)&•  Inositol:&4&grammes&/jr&•  LOCarniDne:&500O1500mg&/jr&•  Commiphora&mukul&(Guggul)&500mg&&3/jr&&&&&IntéracDons:&&&&&&DilDazem&(vasodilatateur)&&&&&Propranolo&(bêtabloquant)&

Liz Lipsi 2015 , B. Rakowski 2011, L. Blouin 2012

Gall Bladder

Choline: 300 mg/day (minimum) Inositol: 4 grams/day

L-Carnitine: 500-1500 mg/day Commiphora mukul (guggul): 500mg, 3/day

Interactions

Diltiazem (vasodilator)

Propranolol (beta-blocker)

Choline………. 300 -‐ 600 mg Inositole ……. 150 -‐ 450 mg L-‐Methionine 100 -‐ 300 mg (Green Tea) Beets Root 440 -‐ 1320 mg

Dr.R Rowntree 2015

INTESTINAL PERMEABILITY “Leaky Gut”


Mucosal Immunology | VOLUME 3 NUMBER 3 | MAY 2010

The increased intestinal permeability is an early biological change that often precedes the onset

of autoimmune diseases.

Such increased permeability could be due to environmental factors (such as infection, toxic molecules, food allergens) that possibly initiate

the disease.

Dr. G.Mullin MD 2015

Leaky Gut: Pathophysiology Poor Dietary Choices

Stress & Emotions Food Allergy

Infection

Lectins

Systemic Disease

Low Stomach Acid

Toxic Exposure

Poor dietary choices

Malnutrition

Dysbiosis

Toxic Overload

Elevated Total Toxic & Antigen Burden

Systemic Disease

Changed Intestinal

Permeability

Enzymatic Deficiencies

Condi+ons related to Intes+nal Permeability

•  Food intolerance •  Acute pancreaAAs •  Migraines •  Cholelithiasis •  Diabetes (Type 1) •  Celiac disease •  Psoariasis, eczema, etc . •  Hashimoto’s ThyrodiAs

•  Chronic faAgue syndrome •  Crohn’s disease •  SIBO •  Irritable bowel syndrome •  Alcoholism •  Protozoal diseases

Condi+ons associated with Increased Intes+nal Permeability


Other Conditions Associated with Increased Intestinal Permeability

• Food Intolerance

• Acute pancreatitis

• Migraines

• Cholelithiasis

81

•  Food intolerance? •  Acute pancreaAAs? •  Migraines? •  Cholelithiasis?

Dr GérardE Mullin MD 2015


Modified from Mucosal Immunology (Vol 1) 3rd edition, Elsevier Academic Press, Burlington, MA; 2005:page 6

BARRIERS�TO�MACROMOLECULAR�ABSORPTIONBarrier to macromolecule absorp+on

Healthy Gut

Healthy Villi/Good Absorption

Healthy Tight

Junctions

IntesDn&sain&

Villosité&Sain&AbsorpDon&

JoncDons&serrées&

Sain&

e

Healthy Intestine

Healthy Villi & Absorption

Tight JuncAons

Healthy

Vésicule&Biliaire&

•  Choline&:&300mg/&jr&(minimum)&•  Inositol:&4&grammes&/jr&•  LOCarniDne:&500O1500mg&/jr&•  Commiphora&mukul&(Guggul)&500mg&&3/jr&&&&&IntéracDons:&&&&&&DilDazem&(vasodilatateur)&&&&&Propranolo&(bêtabloquant)&

Pancréas&

Pancréas-PancréaDn&&

&5000O24000&USP&&

lipase&

amylase&

protéase&

Insuffisance&des&enzymes&pancréaDques&

•  Douleur&abdominal&•  Perte&de&poids&•  Gras&dans&les&selles&•  Intolérance&au&glucose&•  MalabsorpDon&•  MalnutriDon&•  Déficiences&en&vitamines&

•  Selle&pâle&•  Selle&nauséabonde&•  Selle&volumineuse&•  Ballonnement&•  Excès&de&flatulence&•  Candida&

L’intesDn&

Perméabilité-intes)nale-

Diète&appauvrie&Stress&&&émoDons&

InfecDon&

LecDnes&

Maladies&systémiques&

hypochloridrie&

ExposiDon&toxique&

Surcharge&de&toxicité&

Dysbiose&

MalnutriDon&

Allergies&alimentaires&

Toxicité&Totale&Élevée&&

Maladies&systémiques&&

Déficiences&enzymaDques&

Pathophysiologie&

CondiDons&reliés&à&la&perméabilité&intesDnale&

•  Intolérance&alimentaire&•  PancréaDte&aigu&•  Migraines&•  Cholélithiase&•  Diabète&Type&1&•  Maladie&coeliaque&•  Psoriasis&,eczéma&etc..&•  Hashimoto&

•  Syndrome&de&la&faDgue&chronique&

•  Maladie&de&Crohn’s&•  SIBO&&•  Syndrome&&de&l’intesDn&irritable&

•  Alcoolisme&•  InfecDons&protozoaires&

©2013 The Institute for Functional Medicine©2013 The Institute for Functional Medicine

Healthy Gut


Healthy Tight

Junctions

IntesDn&sain&

Villosité&Sain&AbsorpDon&

JoncDons&serrées&

Sain&


Altered Intestinal Permeability and Malabsorption

Damaged Villi/ Poor Absorption

DamagedCell Junctions

Perméabilité&de&l’intesDn&&&malabsorpDon&

Microvilli&Endommagé&Mauvaise&&AbsorpDon&

Endommagement&des&joncDons&

ZO&

sIgA&

Intestinal Permeability & Malabsorption

Damaged Junctions

Damaged Microvilli: Malabsorption


Secretory IntesAnale Immunoglobulin A

•  Dysbiosis •  SIBO (Small IntesAnal Bacterial Overgrowth) •  Chronic stress •  Crohn’s disease •  Celiac disease •  Autoimmune disease

sIgA


Immunoglobuline&A&sécrétoire&/intesDn&

•  La&producDon&de&l’immunoglobuline&A&sécrétoire&augmente(en(présence(dangereuse(d’an0gène(tel(que:(bactéries,parasites,&candida,virus,&protéines&allergènes,&cellule&anormale&d’anDgène.&

•  sIgA&dans&les&selles&démontrent&une&acDvité&posiDves&d’intrues&

Vitamine&A&

•  Vit&A&(tout&les&transOréDnol)&de&la&nourriture&est&converDt&en&acide&transOréDnoïque&(AR)O&sa&forme&acDveO&dans&l’intesDn&(&les&macrophages&et&les&cellules&dendriDques)&

•  AR&promouvoit&le&bon&foncDonnement&la&produc0on(du(sIgA(et&balance&la&différenDaDon&entre&les&cytokines&TH1/TH2&&TH7&

•  Vit A (all trans-retinol) in food is converted to trans-retinoic acid (RA) - its active form - in the intestine.

•  RA promotes good production of sigA and balances the differentiation of the cytokines TH1/TH2 & TH7

Vitamine&A-

•  Augmente&la&réponse&immunitaire&envers&les&pathogènes&

•  Augmente&les&lymphocytesOT&en&lien&avec&l’intolérance&

&

•  Increases the immune response to pathogens •  Increases T lymphocytes linked to intolerance

•  Breast Feeding •  Protein purified whey •  S.Boulardii •  Vitamin A •  L-‐Glutamine •  Medium chain triglycerides •  Arabinogalactan (Oqen associated with Echinacea or probioAcs)

Increasing sIgA

Tamarack American Larch


Naturally occurring medium chain triglycerides (MCT) -‐ in cow's milk (buYer -‐ 9%) -‐ in goat’s milk -‐ in coconut oil. This vegetable oil is the richest in TCM (60%)!

Triglycerides

GHEE sIgA

RÉTABLIR&LA&MUQUEUSE&INTESTINALE&

•  VITAMINE&A&OU&BETA&CAROTÈNE&•  ZINC&&•  ALOÉ&VERA&•  CHLOROPHYLLE&•  B9&•  ESSENCE&DE&CANNELLE&•  K2&(ménaquinone7)&180&mcg&

sIgA&


Healthy Gut


Healthy Tight

Junctions

©2013 The Institute for Functional Medicine©2013 The Institute for Functional Medicine© 2006 -FAAFM

Rétablir&les&joncDons&Re-establish the Junctions

anaq.zonulin english feb 15, 2016 (1) 3 - fluids iq part i.pdf · abstract...

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