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Strengthening the Gut Barrier Helps Prevent Overactivated Immune Systems Eric Weaver, PhD Proliant Health and Biologicals Ankeny, IA Proteins vs. Bioactive Proteins Background Antibodies/immunoglobulins: Discovered in the 1900’s, textbook science

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strengthening the gut barrier helps prevent overactivated immune systems
Strengthening the Gut Barrier Helps Prevent Overactivated Immune Systems

Eric Weaver, PhD

Proliant Health and Biologicals

Ankeny, IA

slide3

Background

  • Antibodies/immunoglobulins: Discovered in the 1900’s, textbook science
  • Immunoglobulins and other plasma proteins and peptides are essentialproteins for immunity!
    • Immunoglobulin (antibodies), sIgA, is the body’s primary means of defending the body in the oral cavity and digestive tract
    • >90% of all immunoglobulin is antibodies directed against intestinal antigens
  • Supplementation of immunoglobulin has not been feasible.
    • Technology and cost have been important factors
    • Dose is critical to the effect.
  • New processing and sourcing technologies have now made oral supplementation feasible.
plasma proteins improves growth in weaned pigs
Plasma Proteins Improves Growthin Weaned Pigs
  • Consistent improvement in young pig growth when plasma proteins are fed post-weaning.

47 trial summary

    • ADG 34%
    • ADFI 23%
    • G/F 9%
summary of plasma protein response in challenge trials

Species Organism Results Author Year

Pigs E. coli  fecal scores Borg, et al. 1999

Pigs salmonella  fecal scores Borg, et al. 1999

Pigs E. coli  ADG,  mortality Bosi, et al. 2002

Pigs E. coli  ADG,  secretory IgA Bosi, et al. 2003

Pigs E. coli  ADG IRTA 2003

Pigs E. coli  shedding Deprez, et al. 1999

Pigs E. coli  ADG,  mortality IRTA 2002

Pigs rotavirus  diarrhea Harrell, et al. 2000

Pigs PMWS  survival,  ADG EMBRAPA 2005

Calves E. coli  survival,  ADG,  scours Quigley & Drew 2000

Calves crypto  scours,  shedding Hunt, et al. 2002

Calves corona  recovery Arthington, et al. 2002

Calves E. coli  survival,  ADG,  scours Nollet, et al. 1999

Shrimp WSSV  survival,  ADG Yukinori 2001

Trout Y. ruckeri  survival,  ADG Aljaro et al. 1999

Turkeys Pasteurella  survival,  ADG Campbell, et al. 2001

Summary of Plasma Protein Response in Challenge Trials
the effect of plasma proteins on the growth of pair fed weaned pigs7
The Effect of Plasma Proteins on the Growth of Pair Fed Weaned Pigs

+31%*

+17%*

+10%*

Jiang et al., 2001

slide11

What is ImmunoLin®?

The First Purified Immunoglobulin for Use in Supplements!

  • ImmunoLin® is a natural bovine immunoglobulin product isolated from edible bovine plasma.
  • Products:
  • ImmunoLin powder (>45% IgG)
  • ImmunoLin WP (>45% IgG) – agglomerated for use in liquid
  • Muscle Factors (>20% IgG) – edible-grade serum concentrate
  • Features:
  • Edible-grade, concentrated for lower inclusion rate
  • Light color, odor – blends well with other protein sources
  • Low plate count (aerobic plate count < 10,000, typical 1,000)
  • Low endotoxin
slide12

Frequently Asked Questions and Concerns

  • Is immunoglobulin digested or broken down which makes it not efficacious?
  • How can humans benefit from another species source of immunoglobulin?
slide13

Studies of IgG Recovery After Oral Administration

* Represents % of original dose recovered in stool or an vitro sample

slide14
The Effect of Digestive Processes on the Biological Activity of Immunoglobulin Administered Orally
  • The average IgG recovery following digestion or simulated digestion in 12 published studies is 25%
    • No studies have reported 100% loss of IgG
    • Digestibility: In vivo studies indicate low relative digestibility of plasma proteins (75%-80%) when compared to milk protein (>95%).
    • IgG F(ab’)2 fragments also retain biological activity (LeFranc-Millot et al., 1995)
  • Clinical studies of bovine Ig and the large number of animal studies evaluating the efficacy of plasma proteins proves that Ig is biologically active following oral ingestion
slide15

Antigen-binding Capacity of Natural Immunoglobulin

These data indicate that antibodies against common pathogens are found in high concentrations in ImmunoLin!

immunity the gi tract and wellness
Immunity, the GI tract and Wellness
  • ..Adults have about 400 sq. meters of surface area and 2 lbs of bacteria in the GI tract so it is no wonder that the GI tract is the site where many health problems begin. It can be considered the most important immunological organ, accounting for 70% of the body’s immune cells.
effects of serum proteins on gut permeability in a cryptosporidiosis model
Effects of Serum Proteins on Gut Permeability in a Cryptosporidiosis model

Hunt et al., 2002

slide18

The Cyclical Consequences of Compromised Immunity and Barrier Function

Immune Competence

Barrier Function

factors affecting gut barrier function
Stress

Heat

Physical

Psychological

Ischemic

Trauma – burns, surgery

Nutrition and Diet

Malnutrition of the gut

Nutrient status

Vit. D, Zinc, antioxidants

Immune status

Immune activation and inflammation

Immunocompromise

Factors Affecting Gut Barrier Function
  • Exercise
  • Age
    • Young and old
  • Genetics
    • NOD2 (IBD)
  • Drugs
    • Anti-inflammatories
    • Antibiotics
  • Disease
    • Infectious
      • Bacterial, viral, protozoal
    • Non-infectious
  • Pancreatic function
slide21

10

Intestinal effects (on specific functions)

Introduction

Gut associated lymphoid tissue (GALT)

Luminal Antigens

(Food, microbes, toxins, etc)

slide22

Model of Immune Activation and Changes in Gut Barrier Function

Water secretion

Luminal Antigens (food, toxins, etc)

Changes in tight junctions and

epithelial function

vascular permeability

PP activation

inflammatory cells

infiltration

MLN activation

Systemic Immune Activation

slide23

Plasma protein concentrates attenuate the effects of S. aureus enterotoxin B on intestinal barrier function and immune system activation in an experimental model of inflammation

Moreto, M., L. Russell, J. Polo, A. Perez-Bosque, C. Garriga, J. Campbell, and J. Crenshaw

J. Nutr. 2006. Vol. 196:2838

slide24

2

MHC II

TCR

Induction of intestinal inflammation

Introduction

S. aureus enterotoxin B (SEB)

SEB

Cytokine secretion

Intestinal inflammation

T-lymphocyte

slide25

3

Inflammation model

Experimental design

Design

SEB (i.p.)

Day 30

Day 33

  • Intestinal effects:
  • Unspecific
  • neutrophil infiltration
  • vascular permeability
  • water content in feces
  • On specific functions
  • organizedintestinal immune system
  • barrier properties
  • nutrient absorption

Day 21

S

24 h

48 h

Control diet

+ SDAP / +IC

ON DIET

13-14 days

0 days

  • General / systemic effects:
  • feedconsumption and growth curve
  • analysis of hematological variables
  • concentration of serum IgA and IgG
  • spleen lymphocyte populations
slide26

Mucosal

compartment

Serosal

compartment

13

Intestinal effects (on specific functions)

Results

Dextran & HRP flux

*

(40 kDa)

Control = no challenge, standard diet

SEB = toxin i.p.

SEB-SDAP = toxin i.p. + plasma proteins in diet

SEB-IC = toxin i.p. + immunoglobulin conc.

slide27

34

B

C

*

φ

A

*

φ

*

φ

φ

Unpublished experiments

Results

Mucosal cytokine expression of pro-inflammatory cytokines

  • Pro-inflammatory cytokines
  • IL-6
  • IFN – γ
  • TNF- α
slide28

*

φ

13

*

φ

*

φ

Effects on Cytokines

Results

TNF-α

slide29

*

13

φ

*

φ

φ

φ

Effects on Cytokines

Results

IFN-γ

*

(40 kDa)

slide30

Phase IV Report

Diffuse GALT

Lamina propria lymphocytes (LPL)

Intraepithelial lymphocytes (IEL)

T lymphocytes

activated T lymphocytes

Th lymphocytes

Ts/c lymphocytes

Tγδlymphocytes

NK cells

SEB

SEB-SDAP

SEB-IC

SEB

SEB-SDAP

SEB-IC

slide31

Phase IV Report

Comparison of the effects on diffuse & organized GALT

Lamina propria lymphocytes (LPL) - 24 h

Peyer’s patches (PP) - 48 h

T lymphocytes

activated T lymphocytes

Th lymphocytes

Ts/c lymphocytes

Tγδlymphocytes

NK cells

SEB

SEB-SDAP

SEB-IC

SEB

SEB-SDAP

SEB-IC

(Phase IV Report)

(J. Nutr. 2004 134: 2667–2672)

slide32

Phase V Report

Cytokines and inflammatory mediators

IL-10

IFN-γ

TNF-α

IL-6

LTB4

Peyer’s patches

Mucosa

Serum

IFN-γ

TNF-α

IL-6

LTB4

IL-10

SEB

SEB-SDAP

SEB-IC

SEB

SEB-SDAP

SEB-IC

SEB

SEB-SDAP

SEB-IC

slide33

15

Effects of SEB, PP and IC

Conclusion

  • Conclusions:
  • SEB is a potent stimulant of the acute inflammatory response (innate immunity).
    • I.P. administration of SEB alters intestinal immune and barrier functions without causing systemic effects
  • PP/IC reduces the effects of SEB on:
    • Mast cell activation
    • Lymphocyte activation in GALT
    • Luminal water content
    • Intestinal permeability to dextran and HRP
  • PP/IC prevents the effects of SEB on pro-inflammatory cytokine

In rats challenged with SEB, PP and IC reduces over-stimulation of the immune system and improves barrier function

Proliant Health and Biologicals

papers communications
Papers & communications
  • Plasma protein supplements attenuate the activation of mucosal intestinal lymphocytes induced by S. aureus enterotoxin B in rats. 10th European Nutrition Conference, Paris, July 10-13, 2007.
  • Dietary plasma protein supplements prevent the release of mucosal proinflammatory mediators in a rat model of intestinal inflammation. 10th European Nutrition Conference, Paris, July 10-13, 2007.
  • Dietary plasma supplementation reduces S. aureus enterotoxin B-induced intestinal inflammation in weaned rats. 2008. J. Nutr. 138:533-537.
  • Oral porcine plasma proteins prevent the release of mucosal pro-inflammatory cytokines in rats challenged with S. aureus enterotoxin B. Digestive Disease Week, 2008.
hypotheses for the mechanism of action
Hypotheses for the mechanism of action

Immune stimulation by microflora or luminal antigens

Immunoglobulins

Glycoproteins

LPS/endotoxin binding proteins

Iron-binding, antiviral,

antibacterial peptides

Bacterial and viral aggregation and exclusion

Endotoxin neutralization

Bacteriostatic and viral inhibition activity

Effectiveness of barrier function

Reducing bacterial adhesion to the epithelium

Access of luminal contents to dendritic cells and macrophages

Nutrition of the epithelium

Resulting from decreased immune system activation

Immune tolerance

Biological activity of plasma supplements (Tregs, IL-10)

hypotheses for the mechanism of action36
Hypotheses for the mechanism of action

Endotoxin

Intestinal microorganisms

immune stimulation by microflora or endotoxin

Intestinal lumen

IEL

effectiveness of barrier function

Tissue destruction

Naive T-cell

APC

Lamina propria

Pro-inflammatory

Activated T-cell

immune tolerance

Cell recruitment

Granulocytes

Regulatory T-cell

Anti-inflammatory

Th1 cells

Pro-inflammatory

Th2 cells

Pro-inflammatory

Macrophages

Lymphocytes

slide37

Immune Compromise or Loss in Gut Barrier Function

Microbial Translocation and Endotoxemia

Immune Activation and Inflammation

Appetite Catabolism Insulin/IGF-I

Resistance*

Weight Loss

Lean Tissue

*O’Connor et al. 2008. Regulation of IGF-I function by proinflammatory cytokines: At the interface of immunology and endocrinology

slide38

When can oral immunoproteins be beneficial?

  • Inflammatory events: new bacterial (e.g. traveler’s diarrhea) or viral exposure, and inflammatory disease, a stimulus for loss of barrier function and over response to LPS
  • Stress: Suppresses immune response/barrier function
  • Geriatrics: Inflammation increases with age, gut barrier function declines
  • Young: Immunonaive, deprived of colostrum or breast milk, premature weaning, ENC status
  • Exercise: Increases endotoxemia and inflammatory cytokine production, increases risk of heat stress/stroke, can adversely affect training and/or performance
  • Surgery/hospitalization – increased TNF-α lowers survival
  • Gut health issues: diarrhea, ulcers (Helicobacter), and NSAIDS increase gut permeability
  • Immune deficient – disease, weaning, gut malnutrition, steroid therapy, and antibiotic use can all compromise intestinal immunity

*Ideal supplement forms: drink mixes, capsules, chewable tablets, syrups, and bars

*References available upon request

slide39

Causes and Consequences of Heat Stress-Induced

GI Barrier Dysfunction

G.P. Lambert. Exerc. Sport Sci.

Rev. 185-190, 2004.

slide40

Ideas for use in Supplements

Consumers with need for greater immunity and barrier function

1) Travelers: New exposure (air, food and water), high stress.

2) Retailers: Constant exposure to the public.

3) Stressed: No time to be sick. Stress compromises immunity.

4) Elderly: Help for an immune system that doesn’t respond. Prefer liquids or bars.

5) Children: A boost when they need it. Limits on taste, dosage form and safety issues.

6) Athletes – improve health in training and competition.

7) Susceptible: Powerful support for the immune deficient.

Delivery systems compatible with consumer and Ig:

Capsule or tablet

Individual serve packets (drink or consume as is)

Cannister of 30 d supply

Chewable tablets (500 mg per tablet), 10/roll

Dose is important!

Supplements: 2.5 - 10 grams per serving based on need!

Functional foods: 250 mg to 1,500 mg per serving

*Goals of supplements and functional foods are different. Functional foods have improved health characteristics vs traditional food products. The objective for supplements is to deliver a nutrient or bioactive ingredient at levels not normally in foods in sufficient quantities to improve health.

*References available upon request

slide41

Who can benefit?

Applications in Gastrointestinal Wellness

1) IBS/Stressed: Imbalance in the gut. “D” form affects half of this group.

2) AIDS/Immune deficient: Chronic problems with diarrhea.

3) Elderly: Help for an immune system that doesn’t respond. Combine with fiber?

4) Children: Viral GI infections are common. Combine with a immune nutrients such as zinc

5) Travelers: New exposure, high stress.

6) Recovery

Hospitalized: Need to maintain lean body mass, add to whey-based beverage

Ulcers - NSAIDS, aphthous

Antibiotics

Medications: chemotherapy

*References available upon request

slide42

Ideas for use in Supplements

Delivery systems compatible with consumer and Ig:

Capsule or tablet

Powder - individual serve packets (drink or consume as is)

Cannister containing 30 d supply

Chewable tablets (500 mg per tablet), 10/roll

Formulation considerations:

Immune support – nutrients compatible for age groups and situations

Gut health – compatible with probiotics (feed and protect)

Inflammation – all system approach that includes the gut

Dose is important!

Supplements: 2.5 - 10 grams of ImmunoLin per serving. Recommendation for adapting dose.

Functional foods: 250 mg to 1,500 mg per serving

*Goals of supplements and functional foods are different. Functional foods have improved health characteristics vs traditional food products. The objective for supplements is to deliver a nutrient or bioactive ingredient at levels not normally in foods in sufficient quantities to improve health.

*References available upon request

slide43

Current issues supporting opportunities for ImmunoLin

  • Recent studies

Gut health and inflammation – Perez-Bosque et al. J. Nutr. 2004, 2006, and 2007

HIV – lack of immunity in the gut, even with years of ART treatment – Mehandru et al. PLoS 2006; Brenchley et al., 2007

Chemotherapy damages intestinal barrier dysfunction – Song et al – Dig Dis Sci 2006

Plasma proteins assist in recovery from rotavirus-induced diarrhea – Corl et al. (2007)

  • Current issues support marketplace opportunities

Food-borne disease, travel illness, HIV, IBD, chemo- and antibiotic-induced diarrhea continue to be major health problems world-wide

  • Support of Medical Advisory Board
summary why supplementation works
Summary: Why supplementation works!!
  • Immunoglobulins are essential proteins for immunity!
    • ImmunoLin is an effective boost to sIgA, a natural constituent of the body
    • ImmunoLin provides antibodies that the body needs
  • Immunoglobulin survives digestion.
  • ImmunoLin is a powerful aid to preserving gut barrier function
  • ImmunoLin reduces the burden on the immune system
    • Nutrients in the body can be used for “productive” functions, not to fuel the immune response
  • The body’s immune system can better defend the body against “other” agents.
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