INTESTINAL INFLAMMATION AND ENTERAL NUTRITION

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INTESTINAL INFLAMMATION AND ENTERAL NUTRITION

• Dr Kevan Jacobson
• BCRI and B.C. Childrens Hospital
• Vancouver, B. C.

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Objectives

• The pathogenesis of IBD diet
• History formulations of EN
• Why is EN important in chronic disease
• Nutritional support
• Immune modulatory properties
• Are elemental diets more effective that
  non-elemental diets
• Are elemental diets as effective as steroids
• Pre probiotics

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Pathogenesis
Environmental Triggers Infectious agents Tobacco
smoke Dietary factors
Bystander
Mucosal Immune System Defective or inappropriate
Modifying Endogenous Factors Epithelial
Barrier Neuro-endocrine System
Direct target
Genetic Predisposition Candidate genes Family Hx
21 of CD,15-40 of UC (incidence 10X greater
with family hx)
Adapted from Shanahan F, Targan SR. Mechanisms of
tissue injury in IBD. In Targan SR, Shanahan F,
editors IBD from bench to bedside, Baltimore,
1994, Williams Wilkins
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EN

• Nutritional Support
• Maintains functional status
• Prevents lean tissue loss
• Induces wt gain
• Stimulates growth

• Modulation of Immune function
• Reduces oxidative stress
• Attenuates lipid peroxidation
• Reduces inflammatory mediators

Weight gain Increased energy Growth
Induces Clinical Remission
Improved wellbeing Improved quality of life
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Enteral NutritionElemental Diet

• Originally designed for astronauts in the 1960s
  to reduced stool output
• GI surgical patients
• CD
• OMorain compared steroids with ED in active CD

Omorain et al. Elemental diet as primary
treatment of acute Crohns disease a controlled
trial . BMJ 19842881859-1862
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Enteral NutritionFormulations

• ED
• AA mixture
• SED
• Peptide based diets
• PD
• Intact protein

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EN - Formulations
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Growth Chart
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(No Transcript)
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Important Dietary Factors

• PUFA (n-3)
• Vitamin D
• Vitamins A, C, E
• Glutamine

• Trace elements
• Short chain FAs
• Prebiotics
• Probiotics

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Nutritional/ Growth Impairment in IBD

• PEM in 20-25
• Reduced height velocity in up to 88
• Early growth delay has been associated with
  permanent linear stunting in 17
• Absolute height deficits reported in 10-40

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Proposed Mechanismsfor Growth Impairment

• Anorexia with inadequate caloric intake (5HT from
  PVN)
• Enteric leakage of protein
• Lack of compensatory reducing in REE as seen
  with anorexia nervosa patients
• Inflammatory mediators may interfere with
  growth plate kinetics - TNF, IL-6
• Daily corticosteroids

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Proposed Beneficial MechanismsUnderlying Effects
of EN
Adapted from Seidman et al. Nutritional
Modulation of Gut Inflammation. Nestle Nutrition
Workshop Series Clinical Performance program,
2002Vol 741-65
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Dietary Lipids
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Role of Lipid Nutrition in Health and Disease

• Total amount of dietary fat
• Composition of dietary fat

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Total Amount of Dietary Lipid

3.06 g/day 1.15
16.56 g/day
30.06 g/day 11.27
Percentage of patients achieving remission at 4
weeks
N 10
N 8
N 10
Tsujikawa T, Shiga University of Medical Science,
Japan 2003
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Composition of Dietary Lipid

• ? intake of animal protein n-6 PUFA
• ? incidence of CD in Japan
• ? Intake of MUFA, PUFA (mainly n-6 PUFA) Vit
  B6
• ? incidence of UC in the west

Shoda R, et al. Am J Clin Nutrition
199663741-745. Geerling BJ, et al. Diet as a
risk factor for the development of of UC. Am J
Gastroenterol 2000951008-1013.
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Composition of Dietary Lipid Length of
Triglyceride Chains

• MCT
• Digested into FAs by pancreatic lipase
• Absorbed directly
• Carnitine not required
• ? mucosal damage
• ? TNF-a, ? LTB4 (DNB)

• LCT (gt 14 carbons)
• Metabolized more slowly
• Require bile salts, chylomicron formation,
  absorbed into lymphatics
• Carnitine required for oxidation
• ?Impaired utilization in sepsis
• ? lymphocyte proliferation
• upregulation of a4-integrin L-selectin

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Fatty Acids

• PPAR dependent
• mechanisms

• Regulation of Lipid mediator synthesis

Modulate immune function
Modulate Inflammation
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PUFA (n-3)

• Peroxisome proliferating-activator-receptors
  (PPAR)
• Nuclear receptor superfamily (a, ß, ?)
• Immune cells enterocytes

Modulate immune function
? Inflammation ?TNF-a, IL-6, IL-1ß
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Fatty Acid Metabolism
Linolenic acid (LNA) (183n-3)
Linoleic acid (LA) (182n-6)
Sequential enzymatic conversion (primarily in the
liver)
Eicosapentaenoic acid (EPA) (205n-3)
Arachidonic acid (AA) (204n-6)

• Inhibits AA metabolism
• (competitively via same enzymatic pathway)
• Substrate for LT, PG

• Important component of membrane phospholipids
• Substrate for LT, PG, TX

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Arachidonic Acid Metabolism
Linoleic acid (diet)
AA (esterified)
Phospholipid A2
AA (free)
5-lipoxygenase pathway
Cyclooxygenase pathway
LTA4
PGH2
LTB4
PGE2
TXA2
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n-3 PUFAs
PPAR dependent mechanisms
Regulation of Lipid mediator synthesis

• Modulate Inflammation
• ? LTB4, PGE2, TXA2
• ? leucocyte function
• ? cytokine production
• ? NK cell activity
• ? Ab production
• ? MF membrane surface molecule exp

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Antioxidants
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Oxidative Stress and the GUT
Balance between oxidants antioxidants
Antioxidants Endogenous Exogenous
Oxidant Free radicals Products of metabolism
Steel from or donate an electron to neighboring
molecules
Neutralize free radicals Stabilize prevent
oxidative damage

• Modulate
• Cellular structure function
• Immune function

• Free

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Oxidative Stress and the GUT
Free Radicals
Oxidation of substrates - lipid peroxidation

• Damage of NA structure

Functional changes in epithelial cells
Modification of gene expression
Altered permeability Disordered cell
turnover Altered receptor expression Apoptosis Che
motaxis

• Free

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Beneficial Growth Effects of EN
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Elemental vs Other Liquid Diets
Griffith et al. Meta-analysis of enteral
nutrition in CD. Gastroenterology
19951081056-1067.
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EN as 10 Therapy for Active CD Comparison of
Adult Pediatric Multicenter Controlled Trials
Patients with isolated crohns colitis were
excluded from the pediatric trials.
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EN vs Steroids
Griffith et al. Meta-analysis of enteral
nutrition in CD. Gastroenterology
19951081056-1067.
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EN vs Steroids
Griffith et al. Meta-analysis of enteral
nutrition in CD. Gastroenterology
19951081056-1067.
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Disease Location Clinical Response

• Several small studies suggest that EN as 10
• therapy for colonic CD is less effective

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Relapse Rates

• 60 - 70 within 1 year of stopping EN
• Lower following steroid therapy
• However data not altogether convincing

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Supplemental Feeds/ Cyclic EN

• Cyclic EN better than low dose alternate day
  steroids in maintaining remission promoting
  linear growth
• Continuation of nocturnal NG feeds 4-5 x weekly
  as supplement to an unrestricted daytime diet
  also associated with prolonged remission
  improved growth

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The Bottom Line

• Good outcome in terms of lean body mass linear
  growth
• Good immunomodulatory properties
• Less effective than steroids
• Steroids improve appetite well-being
• Need to improve the formulation composition

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Beneficial Effects of Probiotics
Adapted from Seidman et al. Nutritional
Modulation of Gut Inflammation. Nestle Nutrition
Workshop Series Clinical Performance program,
2002Vol 741-65
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Requirements of Probiotics
Adapted from Seidman et al. Nutritional
Modulation of Gut Inflammation. Nestle Nutrition
Workshop Series Clinical Performance program,
2002Vol 741-65
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Germinated Barley Food-stuff (GBF)

• Insoluble mixture of glutamine-rich-protein
  hemicellulose-rich- dietary fibre
• Utilized by Bifidobacterium, lactobacillus
  eubacterium
• Convert substrate into lactate, acetate
  butyrate
• Attenuate inflammation
• Absorb water attenuate diarrhea

Fukuda et al. Internat J Mol Med 2002965-70.
DDS model