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Overview Things to remember about the
Triggers and Treatments in gut
Inflammatory Bowel Disease Discuss the pathogenesis of
25 – 30 ft long
25 – 30 ft long
Inflammatory Bowel Disease (IBD)
100 sq yds of surface area
100 sq yds of surface area
Clarify our understanding of likely
Gut lumen is not inside’ the body
Gut lumen is not ‘inside’ the body
triggers and mediators in IBD Dynamic physiologic organ
Dynamic physiologic organ
Review potential therapeutic options in
Primary functions:
Primary functions:
Dan Lukaczer ND
IBD
Digestion & absorption of nutrients
Institute for Functional Medicine
August 22, 2007
August 22, 2007 Barrier to differentiate friend from foe
Webinar Metabolism & detoxification
GUT Function: Gut Activities
A Simplified Approach
Immune Function
Immune Function Ingestion - Digestion -
Absorption - Assimilation
-
GUT Defense
“Defense & Repair”
“Defense & Repair”
Host -Bacteria Mutualism - The
Host- The Mechanisms:
Endocrine Function
Endocrine Function Undiscovered Organ
“Communication”
“Communication”
Barriers to Access,
Immune Balance: Inflammation
and Oral Tolerance Oral Tolerance &
Enteric Nervous System (ENS) - Immune Activation
Detoxification & the Second Brain
Nutrition &
Nutrition &
Digestion Elimination
Elimination Elimination
Detoxification & Elimination
“In”
“In” “Out”
“Out”
Epithelial Cells
Mucins
Physical barrier
Physical barrier trans-
Selective trans-cellular
absorption
Semi-permeable secretion
Semi-
Tight junctions: desmosones
Prevent adhesion of foreign (cell adhesion proteins) bind
microbes adjacent cells together and
Prevent absorption of prevent paracellular
absorption.
macromolecules
Gap junctions: proteinaceous
tubes that allow materials to
pass between cells.
Enzymes and other Digestive
Secretions
enzymes- Amylase,
Salivary enzymes- Amylase,
Lysozyme
Lysozyme
Gastric HCL, Pepsin
Pancreatic enzymes
Bile acids
Intestinal brush border
Enzymes
Gastrointestinal Flora:
The ‘Undiscovered Organ’
Vast and complex ecosystem
Over 400 species identified: 30-40
species comprising up to 99% of the
total population
10x the number of cells as human body
100x the genomic material
Metabolic activity greater then the liver
2-3 pounds of microbiota
Location of Microbes in the Types of Microbes In the GI
Stimulates the intestinal immune GI Tract
system Tract
Metabolic Functions of Microbiota Metabolic Functions of Microbiota
At birth - digestive tract of
Mucus production Undigested dietary humans is sterile. Passive anti-microbial mechanisms:
Short chain fatty fiber breakdown Colonized by microbes prevent adhesion of pathogenic bacteria
within the first few days of by physically competing for binding sites
acids metabolism Gas production life. (displacement)
Primary bile acid Fermentation At first, predominantly
deconjugation bifidobacteria (breast-fed alter local microenvironment through the
Production of infants). production of organic acids to make it
Vitamin absorption phenols more inhospitable for other microbes.
With the introduction of
Fats, TG, cholesterol Breakdown of starch other foods, a diverse
regulation & oligosaccharides microbial population Active anti-microbial mechanisms:
develops in the
. . . & Detoxification gastrointestinal tract. Lactobacillus and Bifidobacteria species
secrete anti-microbial substances active
against a wide variety of microbes.
Metabolic Functions of Microbiota Gut Associated Lymphoid Tissue
(GALT)
Immunological mechanisms Immunological defense
Enhance serum and intestinal IgA Largest lymph organ in the body: 50-70%
response of the immune system and
Increase B cell frequency in peripheral immunoglobulin producing cells are
blood located within the GI tract
Increase phagocytosis of E coli (a Populated by T cells, B cells, plasma cells,
general marker of increased immune activated TH cells and macrophages in
response) loose clusters
Secretory IgA (sIgA)
Predominant immunoglobulin
released onto the surface of the GI
mucosa.
Binds to and neutralizes microbes
and other antigens before they can
cross the mucosal barrier.
Accumulations of lymphocytes or solitary lymph
follicles found scattered beneath the epithelium in
Peyer’s patches
IgA Secretion Oral Tolerance & Immune
Activation
The first critical step is differentiation
non-self.
between self and non-self.
Mucosal immune development requires
environmental contact with commensal
microflora and infections
The Hygiene Hypothesis Evidence for the Hygiene Hypothesis
• Increased allergy results from in
decreased exposure to infections ‘ Hygiene Hypothesis’
Hypothesis’ has been tested in
early life (small family size, clean infants with a family history of atopic
environment) allergy who received a Lactobacillus
• Some research suggest better living
conditions in childhood associated with
probiotic.
increased risk of IBD later in life 50% drop in atopy at 2 and again at 5
• Suggestion is there is sub-optimal
sub-
stimulation of the sIgA-dependent
sIgA- dependent
year follow -up compared to controls.
mucosal barrier function Conclusion: reduced microbial load in
• Mechanisms include altering TH1/TH2
balance and induction of T regulator
infancy has led to an increasing
incidence of allergy.
cells
Brandtzaeg P. Ann NY Acad Sci. 2002;964:14- 45.
Experimental inflammation occurs as a result
of excessive effector T-cell function or Gut in Balance
deficient regulatory T-cell function
There is a constant state of balanced
There is a constant state of balanced
chronic inflammation present in the
gastrointestinal tract.
This physiologic inflammation is essential
This
for the maturing of the immune system
and development of the normal
morphology of the intestinal mucosa.
Nature Reviews Immunology 2003;3:524
Genetic Propensity and Inflammation Gut on Fire Gut on Fire
MAMPs and TLRs MAMPs and TLRs
Microbe-
Microbe- associated molecular patterns TLRs are expressed both in epithelial
TLRs are expressed both in epithelial
(MAMPs) are highly conserved cells and in phagocytic cells, thus
cells and in phagocytic cells, thus
structures of pathogenic and functioning as sensors of microbial
functioning as sensors of microbial
commensal bacteria and are recognized infection. They are critical to initiation
infection. They are critical to initiation
pattern-
by pattern- recognition receptors, such of inflammatory and immune defense
of inflammatory and immune defense
Toll-like
as Toll-like receptors (TLRs). responses.
responses.
TLRs act as gates [tolls] for controlling Crohn’s
Crohn’s Disease more commonly has
the immune system. the NOD2 portion of TLR altered,
the NOD2 portion of TLR altered,
leading to an increase in the NF- κ
leading to an increase in the NF- B
Sartor RB. ACG 2003. Baltimore, MD.
induced inflammation.
induced inflammation.
Sartor RB. ACG 2003. Baltimore, MD.
Inflammation or
Inflammation or
Balance
Balance gene-
Conclusions: Critical gene-
Antecedents
Genes
Genes environment interactions
(genetics, experiences, past illnesses,
Cytokines
Cytokines
Gut flora plays a crucial role in maturation
Gut flora plays a crucial role in maturation occupational exposure, nutrition, lifestyle)
Immune
Immune
Response
Response of the immune system.
of the immune system.
Environment
Environment Bacterial species (commensal &
Bacterial species (commensal &
Triggers Feed-forward
Infections or
Infections or pathogenic) have different abilities to
pathogenic) have different abilities to cycle
Dysbiosis
Dysbiosis cause inflammation.
cause inflammation. (microbes, allergens, trauma, toxins, etc.)
Normal Flora
Normal Flora
Food Antigens
Food Antigens Genetic backgrounds…
Genetic backgrounds…
Probiotics
Mediators
Probiotics may have different dominant antigenic stimuli
Prebiotics
Prebiotics (food & flora) (psycho social stress, cytokines,
may selectively respond to different antibiotic, prostanoids, nitric oxide, kinins,
hormones, neurotransmitters,
probiotic, and prebiotic therapies free radicals)
What May Cause Dysregulation of What May Cause Dysregulation of Consequences of
the GUT Environment? the GUT Environment? GUT Dysregulation
(Triggers and Mediators) (Triggers and Mediators) Immunologically mediated localized
inflammatory responses
Nutrient insufficiencies Diminished HCL secretion
Breach of mucosal integrity
Medications (NSAIDs, cytotoxic Diminished enzyme secretion
Portal circulation flooded with antigenic
agents, antibiotics, antacids) Diminished bile secretion macromolecules resulting in detoxification
Infectious agents: viruses, Food allergies pathway stress
bacteria, protozoa, helminthes-
Psycho/Emotional stress Increase in circulating immune complexes—
Intestinal dysbiosis activation of the complement cascade and other
Travel pathways.
Ethanol
Hypoxia, exposure to extreme Chronic (and local) inflammation may impact
Localized free radical production
altitude HPA axis
Altered Mucosal Integrity Consequences of CROSS REACTIVITY MODEL
GUT Dysregulation “Leaky Gut” and Autoimmunity
Poor Dietary Choices
Poor Dietary Choices Food Allergy
Stress & Emotions
Molecular mimicry – Antigens may possess similar
Stress & Emotions Immune reaction occurs B cells form antibodies
antigenic determinants as human tissue. by T & B lymphocytes
Infection
Infection Malnutrition B Cell
Altered Translocation of microbial components may
Altered
Lectins
Lectins Intestinal result in antibody production and cross reactivity. T Cell
Elevated Total
Permeability Toxic & Antigenic
Toxic & Antigenic Antigen B Cell
Burden
Burden
Example: Klebsiella and ankylosing spondylitis.
Systemic Disease
Systemic Disease Dysbiosis
Many other intestinal microbes have been Transmigration of bacteria Antibodies confuse self
Low Stomach Acid
Low Stomach Acid or food antigen through (cartilage) with other (bacteria,
implicated in systemic disease: Salmonella, leaky gut virus, microbe))
Toxic Exposure
Toxic Exposure Toxic Overload Shigella, Campylobacter, Yersinia, Proteus . Immune reaction occurs, resulting in pain,
swelling, tissue damage Knee Joint
Systemic Disease
Leaky gut
Triggers: nutrient insufficiency, medication,
Association between Systemic dysbiosis, parasite, food reaction, surgery, etc
Localized Inflammatory Bowel Disease
Symptoms and IBD Disturbance of
irritation/
GI flora
inflammation
Evidence for a strong association Local reaction/localized symptoms Pathogenesis
Pathogenesis
between arthralgias and
spondyloarthropathies and IBD has Physical disruption of Triggers and mediators
Triggers and mediators
mucosal barrier Potential therapeutic options
been provided by several clinical and
epidemiological studies. Increased mucosal permeability
The role of bacterial flora and Food protein
Bacterial/yeast/protozoa
pathogenic microorganisms present in /toxin translocation translocation
the intestinal lumen may induce these
Portal and systemic overload
joint diseases in patients with IBD.
Immunologically mediated reactions (and perpetuation)
Karimi O, Pena AS. Rev Esp Enferm Dig. 2005 Aug;97(8):570-4.
Distant Signs and Symptoms:Systemic illness
Genetics of IBD Ethnicity and IBD Autoimmunity and IBD
(15-
Familial occurrence (15 -20% patients
have affected relative) Autoimmune reactions can occur when
Genetic influence is lower in ulcerative there is a genetic susceptibility for the
colitis than in Crohn’ s disease host immune system to recognize, and
(potentially) misinterpret an environmental
Human gene testing antigen presented to the body (e.g., within
Nucleotide- binding oligomerization
- the GI tract).
domain For this to happen:
Nod2 (CARD15) mutations on chromosome The host must be exposed to the antigen.
16 The antigen must be presented to the mucosal
Nod1 (CARD4) immune system following its paracellular
Basu, D; Am J Gastroenterology 100:2254 -2261, 2005 passage through a compromised intestinal
Genetic influence manifested in ethnic permeability.
prevalence
Animal Models, Bacteria and the
Lessons from Animal Models Pathogenesis of Chronic Immune
Pathogenesis of Chronic Immune Role of Bacteria in IBD
Mediated Intestinal Inflammation
Mediated Intestinal Inflammation
• Immune-manipulated mice do not
Immune-manipulated mice do not
develop colitis when germ-
develop colitis when germ-free.
• Certain animal strains induce colitis
Certain animal strains induce colitis
more than others.
more than others.
• No single strain will induce colitis
No single strain will induce colitis
consistently in all models.
consistently in all models.
• Host genetic background influences
Host genetic background influences
disease severity.
disease severity.
ETIOLOGIC HYPOTHESES The Hygiene Hypothesis Evidence for the Hygiene Hypothesis
Etiologic Hypothesis
• Increased allergy results from in
decreased exposure to infections Hygiene Hypothesis’ has been tested in
‘Hygiene Hypothesis’ has been tested in
early life (small family size, clean infants with a family history of atopic
environment) allergy who received a Lactobacillus
• Some research suggest better living
conditions in childhood associated with
probiotic.
increased risk of IBD later in life in atopy at 2 and again at 5
50% drop in atopy at 2 and again at 5
• Suggestion is there is sub- optimal
stimulation of the sIgA- dependent
sIgA-
sub- follow-up compared to controls.
year follow-up compared to controls.
Conclusion: reduced microbial load in
mucosal barrier function
• Mechanisms include altering TH1/TH2
balance and induction of T regulator
infancy has led to an increasing
incidence of allergy.
cells
Brandtzaeg P. Ann NY Acad Sci. 2002;964:14-45.
Gene-Environment Interaction
Gene-
Conclusions on Etiology of IBD
IBD probably represents an
interaction between host genetic
susceptibility, commensal flora,
and a dysregulated host immune
response.
It is likely also a consequence of a
defective mucosal barrier to
luminal antigens.
The flora and immune response
are mediated by a variety of
environmental factors.
Altered Bacterial Milieu Intestinal Permeability
Bacterial etiology has long been
Considerable evidence supports
postulated, however research has the presence of increased
never confirmed a specific intestinal permeability (IP) in
responsible agent. Crohn's disease.
Triggers and Mediators in
It is now thought that normal IP increases in patients with
Inflammatory Bowel enteric flora, possibly triggered by Crohn's disease proportional to
an initial change in the disease activity.
Disease gastrointestinal milieu, (i.e.,
It is not entirely clear if IP is a
dysbiosis, infection etc.) plays a trigger for dysfunction, a mediator,
key role in the development of IBD. or a consequence of inflammation.
Guarner F, et. al. Best Pract Res Clin Gastroenterol. 2003 Takeuchi K et. al. Novartis Found Symp. 2004;263:151 -8; discussion
Oct;17(5):793-804. 159-63, 211-8
Healthy Gut Leaky Gut Leaky Gut - Pathophysiology
Poor Dietary Choices
Poor Dietary Choices Food Allergy
Food Allergy
Stress & Emotions
Infection Malnutrition
Malnutrition
Healthy Villi/ Altered
Good Damaged
Lectins Intestinal Elevated Total
Elevated Total
Absorption Villi / Poor
Permeability
Permeability Toxic & Antigenic
Absorption
Systemic Disease Dysbiosis
Dysbiosis Burden
Low Stomach Acid
Healthy Cell
Healthy Cell
Healthy Cell
Junctions Damaged Cell
Damaged Cell Toxic Exposure
Junctions
Junctions Toxic Overload
Junctions Systemic Disease
Microbes and Microbial Diet: Protein and Alcohol Protein and Sulfide
Components
Components Hydrogen sulfide is a luminally acting,
Activate bacterially derived cell poison that has
Consumption of meat, particularly red been implicated in ulcerative colitis.
Intestinal immune and processed meat, protein and
Sulfide generation in the colon is
cells alcohol were associated with higher probably driven by dietary
rate of relapse. sulfur-
components such as sulfur-containing
Secrete inflammatory
products High sulphur or sulphate intakes were amino acids and inorganic sulfur (e.g.,
Cytokines also associated with relapse and may sulfite).
Reactive oxygen species
Reactive oxygen species offer an explanation for the observed Dietary protein from meat is an
Eicosinoids
Eicosinoids increased likelihood of relapse. important substrate for sulfide
generation by bacteria in the human
Develop
large intestine.
Jowett SL, et. al. Gut. 2004 Oct;53(10):1479-84.
Magee EA, et al. Am J Clin Nutr. 2000 Dec;72(6):1488-94.
Local mucosal damage
Diet: Sugar and Fat Decreased Short Chain Fatty Acids Oxidative Stress
A high sucrose consumption was
A high sucrose consumption was
SCFA, in particular butyrate, are a major Blood total antioxidant capacity is
Blood total antioxidant capacity is
associated with an increased risk for IBD
associated with an increased risk for IBD source of energy for colonocytes.
while fructose intake was negatively
while fructose intake was negatively Additionally, they play a central role on significantly reduced in IBD
significantly reduced in IBD
associated with risk for IBD. Similar trends
associated with risk for IBD. Similar trends the physiology and metabolism of the patients compared with controls,
patients compared with controls,
were noted in UC and CD.
were noted in UC and CD. colon. irrespective of disease activity.
irrespective of disease activity.
A high fat intake was associated with an
A high fat intake was associated with an
Several studies have reported that IBD
increased risk for UC; this was particularly
increased risk for UC; this was particularly is associated with impairment in SCFA The decreased antioxidant
The decreased antioxidant
marked for animal fat.
marked for animal fat. production. defenses may be a primary
defenses may be a primary
a higher consumption of sweets was
a higher consumption of sweets was
The effect of prebiotics on cell phenomenon severely
phenomenon severely
positively associated with UC risk, whereas
positively associated with UC risk, whereas proliferation, differentiation, apoptosis, compromising the mucosa and
compromising the mucosa and
the consumption of sugars, sweeteners,
the consumption of sugars, sweeteners, mucin production, immune function, therefore increase the
therefore increase the
sweets, fats and oils and fish and shellfish
sweets, fats and oils and fish and shellfish and chemokine expression seem to be
were positively associated with CD risk.
were positively associated with CD risk. largely mediated by SCFA. susceptibility to oxidative tissue
susceptibility to oxidative tissue
SCFA concentrations in the intestinal damage.
damage.
Reif S et. al. Gut. 1997 Jun;40(6):754 -60. .
60. lumen vary markedly with diet.
Feb;11(2):154-
Wakai K et. al. Inflamm Bowel Dis. 2005 Feb;11(2):154-63.
Sep;49(9):1433-
Koutroubakis IE et. al. Dig Dis Sci. 2004 Sep;49(9):1433-7.
Sanderson IR J Nutr. 2004 Sep;134(9):2450S-2454S
Psychological Stress Antecedents
(Predisposing factors)
Genetic propensity (NOD/CARD15)
Inadequate immunological stimulation
Levels of depressive symptoms Western diet (fat, sugar, protein)
are positively associated with
future changes in Crohn ’s disease.
Crohn’ s disease. Potential Therapeutic
Triggers
Psychological factors such as a (Activation)
Feed-forward Options in Inflammatory
depressive mood associated with cycle
anxiety may exert a negative
(Infection, Dysbiosis, other toxins?)
Bowel Disease
influence on the course of Crohn’ s
and UC. Mediators
(Perpetuation)
Mittermaier C et. al. Psychosom Med. 2004 Jan-Feb;66(1):79-84. Dysbiosis, Depression/anxiety, Decreased SCFA,
Mardini HE et. Al. Dig Dis Sci. 2004 Mar;49(3):492-7. Increased IP, low antioxidant reserves/increased free
radicals, Inflammatory cytokines/prostanoids)
Elemental and Exclusion Diets Elemental Diet Mechanisms Elemental Diets
The mechanism by which elemental diets Total enteral nutrition (TEN) was
Total enteral nutrition or purified liquid exert their positive effect is unclear. compared to partial enteral nutrition
diets (elemental diets) with food
exclusion can induce remission in Amino acids used as the sole nitrogen (PEN) in children with active Crohn's
Crohn’
patients with active Crohn’ s disease source may be a major contributor. In animal disease for six weeks. The PEN group
often comparable to steroids studies, the addition of dietary proteins was encouraged to eat an unrestricted
result in intestinal damage. diet while those receiving TEN were
However, food exclusion is difficult to In patients with Crohn's disease intestinal
maintain long term with palatability, not allowed to eat.
permeability (using measurement of
solid-
inability to stay on a solid-free diet for ingested non- metabolic monosacharide and
non- Only TEN led to a reduction in
weeks, and social inconvenience as disaccharides) is elevated before elemental diarrhea, an increase in hemoglobin
major compliance issues diet therapy and drops following therapy, and albumin, and a fall in platelets and
Unfortunately, exclusion diet studies suggesting elemental diets improve IP and ESR.
have been sparse and inconclusive. may be related to symptomatic improvement Johnson T et al. Gut. 2006 Mar;55(3):356-61. Epub 2005 Sep 14
Iwata M et. al. Nippon Shokakibyo Gakkai Zasshi. 2001 Jun;98(6):636-43.
Elemental Diets and Type of Fat Exclusion Diet Studies Exclusion Diet Studies
Dietary fat has been suggested to determine
the therapeutic effect of enteral diets in
Only one trial with UC: 18 subjects Crohn’
Research in Crohn’s has been
Crohn's disease. were randomized into active (diet
Patients with active Crohn's disease were
inconclusive.
exclusion) or control groups and
randomised to receive an enteral diet high Remission rates in CD patients on
in oleate (79%) and low in linoleate (6.5%) followed for 6 weeks.
(PEN1), high in linoleate (45%) and low in
Diet group displayed significantly
elimination diet do not appear to
oleate (28%) (PEN2), or (c) oral prednisone be significantly better than those
and a conventional ward diet. fewer symptoms than did the controls.
Sigmoidoscopic findings improved in observed on unrestricted diets.
Overall remission rates were 27%, 63% and
79%, respectively. 8 subjects in the diet group compared Pearson M et al. Gut. 1993 Jun;34(6):783-7.
The type of dietary fat may be of importance with 2 of the controls.
for the primary therapeutic effect of enteral
No common foods provoked
nutrition in active Crohn's disease.
Gassull MA Gut. 2002 Aug;51(2):164 -8.
symptoms in all patients.
Candy S et. al. S Afr Med J. 1995 Nov;85(11):1176 -9.
BACTERIA Probiotics and Prebiotics Prebiotics: Germinated Barley
Foodstuff (GBF)
Anti-
Inflammatory inflammatory Probiotics: live microorganisms, Eighteen patients with mild to
Eighteen patients with mild to
moderately active UC were divided into
moderately active UC were divided into
which, when administered in two groups.
two groups.
adequate amounts, confer a health
benefit on the host. GBF- treated group (n = 11) received 20
GBF-treated group (n = 11) received 20
to 30 grams of GBF daily together with
to 30 grams of GBF daily together with
Prebiotics: non digestible food the baseline treatment.
the baseline treatment.
ingredients that beneficially affect After 4 weeks, the GBF group showed a
After 4 weeks, the GBF group showed a
the host by selectively stimulating significant decrease in clinical activity
significant decrease in clinical activity
Certain bacteria may down regulate a the growth and/or activity of one or a index scores compared with controls.
index scores compared with controls.
limited number of bacteria in the GBF increased fecal concentrations of
GBF increased fecal concentrations of
chronic immune induced intestinal colon that can improve host health. Bifidobacterium
Bifidobacterium and Eubacterium
inflammatory process. limosum .
limosum
Kanauchi O, et. al. Gastroenterol 2002; 37 Suppl 14: 67-72
Prebiotics: Germinated Barley Prebiotics: Bifidogenic growth Prebiotics: Oat bran
Foodstuff stimulator (BGS)
BGS is a prebiotic preparation 22 patients with quiescent UC were
22 patients with quiescent UC were
wenty- one patients with
T wenty-one patients with produced by Propionibacterium instructed to add 60 grams of oat
instructed to add 60 grams of oat
treated
moderately active UC treated with freudenreichii isolated from Swiss bran (corresponding to 20 g
bran (corresponding to 20 g
20-30 grams daily of GBF for 24
20-30 grams daily of GBF for 24 cheese. dietary fiber) to the daily diet for 12
dietary fiber) to the daily diet for 12
weeks. Twelve patients with mildly to weeks.
weeks.
moderately active ulcerative colitis
GBF significantly reduced clinical received orally 4.5 grams of BGS daily Fecal butyrate concentration
Fecal butyrate concentration
for 4 weeks. increased by 36% at 4 weeks.
increased by 36% at 4 weeks.
activity as compared to controls. Patients showed improvement in their
clinical activity index scores and Patients reporting abdominal pain
Patients reporting abdominal pain
GBF prolonged remission and reflux complaints at entry
endoscopic index score. and reflux complaints at entry
compared to controls . Patients showed an increase in stool showed significant improvement at
showed significant improvement at
butyrate concentrations. 12 weeks that returned to baseline
12 weeks that returned to baseline
Hanai H, et. al. Int J Mol Med 2004; 13: 643-647 Suzuki A, et. Al. Nutrition. 2006 Jan;22(1):76-81. 3 months later.
3 months later.
Hallert C Bowel Dis. 2003 Mar;9(2):116 -21.
Probiotics: E. coli Nissle1917 Probiotics: E. coli Nissle1917 Probiotics: Saccharomyces
boulardii
Non-pathogenic strain of Escherichia coli
-pathogenic strain of Escherichia coli
Double blind trial in patients with UC in Thirty- two patients with Crohn's disease
Thirty-two patients with Crohn's disease
116 patients with UC were randomized to remission who received E. coli either in clinical remission were randomly
in clinical remission were randomly
receive either mesalazine or Nissle1917
mesalazine once daily (n = 162) or mesalazine 500 treated for six months with either
treated for six months with either
mg three times daily (n = 165). mesalamine 1 g three times a day or
mesalamine 1 g three times a day or
Initial responses to treatment were mesalamine 1 g two times a day plus
mesalamine 1 g two times a day plus
Relapses in 40/110 (36.4%) patients in the
similar, with remission noted in 75% and Saccharomyces boulardii 1 g daily.
Saccharomyces boulardii 1 g daily.
E coli Nissle 1917 group and 38/112
68% of those receiving mesalaz ine and E (33.9%) in the mesalazine group. Relapses were observed in 37.5% of
Relapses were observed in 37.5% of
coli, respectively.
respectively. patients receiving mesalamine alone vs.
patients receiving mesalamine alone vs.
E coli Nissle 1917 showed efficacy and 6.25% of patients (1/16) on mesalamine
6.25% of patients (1/16) on mesalamine
73% and 67% of patients remained in safety in maintaining remission plus Saccharomyces boulardii ( however
plus Saccharomyces boulardii ( however
remission for 12 months. equivalent to the gold standard this was not statistically significant).
this was not statistically significant).
mesalazine.
Rembacken BJ, et. al. Lancet 1999; 354: 635-639
Guslandi M, et al. Dig Dis Sci. 2000 Jul;45(7):1462-4.
Kruis W -23
Kruis W , et. al. Gut. 2004 Nov;53(11):1617-23
Probiotics: Lactobacillus GG Probiotics: Lactobacillus GG
Probiotics: Saccharomyces
boulardii double- placebo-
20 patients in a double-blind, placebo -
45 patients randomized in placebo
25 patients with a mild to moderate [(1-
controlled trial of Lactobacillus GG [(1-
clinical flare-up of ulcerative colitis
controlled study to determine if
2)x 10(10) cfu vs. placebo for 3 months. Lactobacillus GG, taken for one
received S. boulardii 250 mg three times
a day for 4 weeks during ongoing
No differences were observed between year, could reduce severity or
maintenance treatment with mesalazine. the groups with regard to disease activity prevent Crohn's recurrent lesions
index. after surgery
17/24 patients who completed the study
attained clinical remission confirmed
An observational trial showed Lacto GG
decreased frequency of first episodes of
No significant differences in the
endoscopically. severity of the lesions between the
pouchitis after 3 years.
Kuisma J, et al. Aliment Pharmacol Ther. 2003 Feb 15;17(4):509-15. two groups
Guslandi M, et. al. Eur J Gastroenterol Hepatol. 2003 Jun;15(6):697-8 Gosselink MP, et. al. Dis Colon Rectum. 2004 Jun;47(6):876 -84. Epub 2004 Prantera C, et al Gut. 2002 Sep;51(3):405-9.
Apr 19.
Probiotics: Lactobacillus GG Probiotics: Lactobacillus GG Probiotics: Lactobacillus
johnsonii
187 ulcerative colitis patients with Seventy-five children with CD in remission
Seventy-five children with CD in remission
quiescent disease were randomized to were randomized to either LGG (n=39) or 98 patients who had undergone surgical
receive Lactobacillus GG 18 x 10(9) (65 placebo (n=36) and followed for up to 2 Crohn’ s disease were randomized
resection for Crohn’s disease were randomized
patients), mesalazine 2400 mg/day (60 years. to receive Lactobacillus johnsonii (4 x 10(9) or
patients) or Lactobacillus GG + The median time to relapse was 9.8 months placebo for six months.
mesalazine (62 patients) for 12 months. in the LGG group and 11.0 months in the Endoscopic scores did not differ significantly
placebo group. between groups. There were four clinical
Overall analysis showed no difference in recurrences in the LA1 group and three in the
LGG did not prolong time to relapse in
relapse rate among the three treatment children with CD when given as an adjunct placebo group.
groups. to standard therapy. L johnsonii did not have a sufficient effect in
Zocco MA, Aliment Pharmacol Ther. 2006 Jun 1;23(11):1567-74. Bousvaros A, et al. Inflamm Bowel Dis. 2005 preventing endoscopic recurrence of Crohn's
Sep;11(9):833-9. disease.
Marteau P et. al. Gut. 2006 Jun;55(6):842-7
Probiotics: Lactobacillus Probiotics: VSL#3 Probiotics: VSL#3
johnsonii
VSL#3: defined ratio of Bifidobacterium
VSL#3: defined ratio of Bifidobacterium In double blind trials, VSL#3 prevented
Seventy patients with CD were enrolled breve, Bifidobacterium longum,
breve, Bifidobacterium longum, relapse of chronic pouchitis after
prior to elective ileo-caecal resection and
caecal resection and Bifidobacterium infantis, Lactobacillus
Bifidobacterium infantis, Lactobacillus induction of remission by antibiotics.
randomly assigned after surgery to daily acidophilus, Lactobacillus plantarum,
acidophilus, Lactobacillus plantarum, Pilot studies have indicated that VSL#3
Lactobacillus casei, Lactobacillus
Lactobacillus casei, Lactobacillus maintained remission of UC in 75% of
treatment with either Lactobacillus bulgaricus and Streptococcus
bulgaricus and Streptococcus patients over 12 months.
johnsonii, 10 billion CFU, or placebo for salivarius subsp. thermophilus.
salivarius subsp. thermophilus. Patients who developed pouchitis while
12 weeks. In vitro studies showed that epithelial
In vitro studies showed that epithelial treated with placebo had low bacterial and
Endoscopic score and clinical relapse barrier function and resistance to
barrier function and resistance to high fungal diversity. Bacterial diversity
was not significantly different between Salmonella invasion could be enhanced
Salmonella invasion could be enhanced was increased and fungal diversity was
by exposure to a proteinaceous soluble
by exposure to a proteinaceous soluble reduced in patients in remission
the two treatment groups at 3 months. factor secreted by the bacteria found in
factor secreted by the bacteria found in maintained with VSL#3.
the VSL#3
the VSL#3..
et. Al.
Van Gossum A et. Al. Inflamm Bowel Dis. 2007 Feb;13(2):135-
Mimura T, et. al. Gut 2004; 53: 108-114 75
42. Madsen K, et. al. Gastroenterology 2001; 121: 580
Madsen K, et. al. Gastroenterology 2001; 121: 580 -591
Kuhbacher T, et al. Gut. 2006 Jun;55(6):833-41. Epub 2006 Jan 9.
Probiotics: VSL#3 Probiotics: VSL#3 Ulcerative Colitis and VSL#3
34 patients with active UC (non-
16 patients with quiescent IBD who responsive to conventional treatment),
suffered from arthralgia were given were given 3.6 trillion cfu of VSL#3
VSL#3 for 2 weeks. daily for six weeks.
10 of the 16 patients had a Treatment resulted in a combined
statistically significant improvement induction of remission/response rate
as documented by the Ritchie of 77% -- with no adverse events.
Articular Index.
Bacterial species in VSL#3 were
detected at the target site.
Karimi O, et. al. Drugs Today (Barc). 2005 Jul;41(7):453-9.
Bibiloni, R., et al. . Am J Gastroenterol. 2005;100:1539-1546.
Ulcerative Colitis and VSL#3 Biochemical Individuality: Issues with Probiotics
A Gut Check
“The mammalian gut microbiota Optimal dose
Optimal dose
interact extensively with the host Duration of treatment
Duration of treatment
through metabolic exchange and
co-metabolism of substrates. Selection of and differences
Selection of and differences
Appropriate consideration of between the several available
between the several available
individual human gut microbial probiotic strains
probiotic strains
activities will be a necessary part Specific mechanisms of action
Specific mechanisms of action
of future personalized health-care
paradigms.”
Nicholson JK, Holmes E, Wilson ID. Nature Reviews
Microbiology. April 2005.
Colonoscopy Images
Poll Question Omega 3 Fatty Acids Omega 3 Fatty Acids
How many of you have used the One-year, double-blind, placebo-
One-year, double-blind, placebo- Pediatric patients with Crohn's
Pediatric patients with Crohn's
following probiotics in controlled study to investigate the disease in remission were
disease in remission were
Inflammatory Bowel Disease? effects of a fish-oil preparation
fish-oil preparation randomized into two groups and
randomized into two groups and
(total of 2.7 g of n -3 fatty acids) in
n- treated for 12 months with 5- ASA
treated for 12 months with 5-
(you can choose more then one the maintenance of Crohn's + omega- 3s (eicosapentanoic acid,
+ omega-
answer) disease remission. EPA, 400 mg/g, docosahexaenoic
EPA, 400 mg/g, docosahexaenoic
After one year, 23 patients (59 acid, DHA, 200 mg/g) or 5 -ASA
acid, DHA, 200 mg/g) or 5
fish-oil group
percent) in the fish-oil group +placebo capsules.
+placebo capsules.
VSL#3
remained in remission, as The number of patients who
The number of patients who
Saccromyces Boulardi compared with 10 (26 percent) in relapsed at 1 year was significantly
relapsed at 1 year was significantly
Lacto GG the placebo group. lower in omega-3 group.
lower in omega-3 group.
Lactobacillus johnsonii Romano C, et. al. World J Gastroenterol. 2005 Dec
7;11(45):7118--21.
7;11(45):7118 21.
Belluzzi A, et al. N Engl J Med. 1996 Jun 13;334(24):1557--60.
60.
Other
Antioxidants Omega 3 fatty acids and Omega 3 Fatty acids,
Randomized controlled trial of stable Antioxidants Antioxidants and Prebiotics
but oxidatively stressed CD subjects (n Patients with UC were randomized to
= 57) supplemented with vitamins E Randomized placebo- controlled trial of
-
(800 IU) and C (1000 mg) or placebo for consume an oral supplement enriched
4 weeks. fish oil (2.7 g EPA and DHA/d; n = 31) with fish oil, fructooligosaccharides, gum
and antioxidant preparation (vitamins arabic, vitamin E, vitamin C, and
During supplementation, plasma A, C, and E and selenium) or placebo
vitamin C and alpha-tocopherol
alpha-tocopherol selenium, or a carbohydrate- based
increased and all indices of oxidative (olive oil; n = 31) for 24 weeks in placebo formula each day for 6 months.
stress decreased significantly. patients with CD.
intent-to- treat and completed
Both intent-to -treat and completed
Conclusion: patients with inactive or Fish-
Fish-oil/antioxidant arm was associated patients given supplement had a
mildly active CD can be oxidatively with lower arachidonic acid, modified significantly greater rate of decrease in
stressed and have increased peripheral blood mononuclear cell the dose of prednisone required to
requirement in antioxidant vitamins. composition and lowered production of control clinical symptoms over 6 months
PGE(2) and IFN- gamma by circulating as compared with the placebo group.
Aghdassi E, et. al. Am J Gastroenterol. 2003 Feb;98(2):348-53.
Feb;98(2):348- monocytes or macrophages.
-69.
Seidner DL et. al. Clin Gastroenterol Hepatol. 2005 Apr;3(4):358-69.
Nov;80(5):1137-44.
Trebble TM et. al. Am J Clin Nutr. 2004 Nov;80(5):1137-44.
Dehydroepiandrosterone Helminths Worms?
(DHEA)
Induction of a Th2 immune response
Induction of a Th2 immune response
Dehydroepiandrosterone sulphate by intestinal helminths diminishes Th1
by intestinal helminths diminishes Th1 Th1 Th2
concentrations are decreased in patients
with inflammatory bowel disease. responsiveness.
responsiveness.
Twenty patients with chronic active
Certain helminths induce mucosal T
Certain helminths induce mucosal T
inflammatory bowel disease (seven
Crohn's disease and 13 ulcerative colitis) cells to make Th2 and regulatory
cells to make Th2 and regulatory
took 200 mg DHEA per day orally for 8 cytokines. Helminth
cytokines. Helminth -induced mucosal
weeks.
IL4, TGFbeta, and IL10 likely are part of
IL4, TGFbeta, and IL10 likely are part of
Six Crohn's disease patients and six
ulcerative colitis patients went into the protective process.
the protective process.
remission.
Helminths affect pathways of innate
Helminths affect pathways of innate
No patient withdrew from the study
side-effects.
because of side-effects. immunity like TLR4 expression and
immunity like TLR4 expression and
function.
function.
Feb;17(3):409-
Andus T et al. Aliment Pharmacol Ther. 2003 Feb;17(3):409 -14.
Weinstock JV Ann N Y Acad Sci. 2006 Aug;1072:356-64 .
Aug;1072:356-
Hygiene hypothesis Helminths: Trichuris suis Summary and Conclusions
suis, the porcine whipworm, is genetically
T suis, the porcine whipworm, is genetically The GI tract has developed elaborate
related to T trichiura, the human whipworm.
T suis is not a natural human parasite but it mechanisms to coexist with its
has been shown experimentally to colonize commensal microflora, rapidly
humans briefly without causing disease.
respond to invading pathogens and
Twenty nine patients with active Crohn's
disease were enrolled in an open label antigens, and then returning to
study. All patients ingested 2500 live T suis homeostasis.
ova every three weeks for 24 weeks, and
disease activity was monitored. If these tightly regulated homeostatic
At week 24, 23 patients (79.3%) responded mechanisms are disturbed in a
(decrease in CDAI >100 points or CDAI <150) susceptible individual, chronic
and 21/29 (72.4%) remitted (CDAI <150).
There were no adverse events. intestinal inflammation may be
Elliott, D.E., Urban Jr., J.F., Argo, C.K., Weinstock, J.V.
FASEB Journal 2000;14:1848-1855.
induced.
Summers RW, Gut. 2005 Jan;54(1):87 -90 .
Summers RW, Gut. 2005 Jan;54(1):87 90
Summary and Conclusions Summary and Conclusions
The induction of inflammation starts
The induction of inflammation starts
Once the mucosal epithelium is
Once the mucosal epithelium is
with a breakdown of the intestinal
with a breakdown of the intestinal disrupted, luminal pathogens and
disrupted, luminal pathogens and
epithelial barrier.
epithelial barrier. antigens are able to traverse the former
antigens are able to traverse the former
barrier, infiltrating the underlying
barrier, infiltrating the underlying
Triggers of this breakdown appear
Triggers of this breakdown appear mucosal layers.
mucosal layers.
varied and may include:
varied and may include:
This enhances antigenic exposure to
This enhances antigenic exposure to
Infections: pathogenic bacteria, protozoa immune and non - immune cells located in
immune and non
or other microbes deeper mucosal compartments.
deeper mucosal compartments.
Changes in the normal gut mileau
This process results in aggravation and
This process results in aggravation and
caused by medications, diet etc. chronification of mucosal inflammation,
chronification of mucosal inflammation,
This breakdown is considered central
This breakdown is considered central which in turn further compromises the
which in turn further compromises the
and the initial step of mucosal
and the initial step of mucosal barrier function of the intestinal
barrier function of the intestinal
epithelium.
epithelium.
inflammation.
inflammation.
To register for AFMCP and receive the additional 10%
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