Can nutritional therapy be used on a
practical basis for maintenance?
Robert N. Baldassano, MD
Colman Professor of Pediatrics
University of Pennsylvania, Perelman School of Medicine
Director, Center for Pediatric IBD
The Children's Hospital of Philadelphia
I have the following financial relationships
to disclose
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•
•
•
Janssen Pharmaceuticals
Takeda Pharmaceuticals
AbbVie, Inc.
Avaxia Biologics, Inc
Products or services produced by this company are relevant to
my presentation
Nutritional Therapy
• Elusive Enteral Nutrition
is the most obvious and
ignored clue to the
effect of Diet as an
Environmental Factor
for IBD
• EEN is given for 6-8
weeks, and
then…….?????????
The Gut Microbiota in Health and Disease
Health
Therapeutic disruption of dysbiosis
•Antibiotics, Probiotics, Prebiotics
•Fecal Transplantation
•Dietary Intervention
Dysbiosis (altered
microbiota
composition
associated with
disease)
IBD
Adapted from Walker, A.W. et al.
Pharmacological Research. 2012.
Diet is associated with new onset IBD
• High dietary intakes of total fats, PUFAs, omega-6
and meat were associated with an increased risk of
CD and UC
• High fiber and fruit intakes were associated with
decreased CD risk
• High vegetable intake was associated with decreased
UC risk.
Hou JK et al. American Journal of Gastro 2011; 106:563-73
What is the Link Between Diet,
Dysbiosis, and IBD?
• Hypothesis #1 - Regular diet contains harmful
components that lead to inflammation
• Hypothesis #2 – Diet alters the gut microbiome
which lead to inflammation
• Hypothesis #3 - Diet determines the metabolic
product of gut microbes which impacts health
What is the Link Between Diet,
Dysbiosis, and IBD?
• Hypothesis #1 - Regular diet contains harmful
components that lead to inflammation
• Hypothesis #2 – Diet alters the gut microbiome
which lead to inflammation
• Hypothesis #3 - Diet determines the metabolic
product of gut microbes which impacts health
PLEASE
Pediatric Longitudinal Study of
Semi-Elemental Diet and Stool Microbiome
• Prospective cohort study of children with Crohn
disease from Philadelphia (used Peptamen), Toronto
(used Modulen) and Halifax (used Osmolite); (n=90)
– Enteral therapy with defined formula diet (38) vs.
anti-TNFα therapy (52)
– PCDAI measured at baseline and 8 weeks
– Stool for calprotectin (FCP) and microbiome
• measured at baseline, 1 week, 4 weeks, and 8 weeks
PLEASE
Greater Mucosal Healing with More
Restrictive Diet
(Induction)
62
Percentage of Patients
70
60
45
50
Partial Enteral Nutrition
40
Exclusive Enteral Nutrition
30
Anti-TNF
14
20
10
0
Calprotectin < 250
Calprotectin Concentration at Week 8 (mcg/g)
PLEASE
Greater Mucosal Healing with More
Restrictive Diet
• Similar amounts of formula intake for the Partial
EN and Exclusion EN groups
• If formula was itself “anti-inflammatory,” we would
expect that outcomes for the nutritional therapies
would be comparable.
• Conclusion
• Enteral nutritional therapy is effective due to
the exclusion of table foods.
Partial Enteral Nutrition with a Crohn's Disease
Exclusion Diet Is Effective for Induction of
Remission
Partial Enteral Nutrition (50% formula + CDED)
(N=53)
Results
A) Significant improvement in:
PCDAI, CRP, ESR, Albumin
B) 70% Remission rate
C) 7 patients refused PEN but followed CDED:
6/7 in Remission
Sigall-Boneh, et al. IBD. 20(8):1353-1360, 2014
Dietary-fat-induced taurocholic acid promotes
colitis in Il10-/- mice
Devkota et al. Nature 2012;487:104
Sartor RB. Nat. Rev. Gastro. and Hep. 2012;9:561-562
Dietary Factors and UC
• Study of 191 patients with
UC in remission
• Followed over 1 year
• 52% of patients relapsed
during this time period
• Consumption of meat,
particularly red and
processed meat increased
the likelihood of relapse
Jowett et al. Gut. 2004.
What is the Link Between Diet,
Dysbiosis, and IBD?
• Hypothesis #1 - Regular diet contains harmful
components that lead to inflammation
• Hypothesis #2 – Diet alters the gut microbiome
which lead to inflammation
• Hypothesis #3 - Diet determines the metabolic
product of gut microbes which impacts health
Enterotypes of the Human Gut
Microbiome
• Enterotypes Abundance
of one of three genera
• Bacteroides
• Prevotella
• Ruminococcus
• The basis for enterotype
clustering is unknown but
appears to be independent
of:
•
•
•
•
Bacteroides
Prevotella
Ruminococcus
Nationality
Gender
Age
Body Mass Index
(BMI).
Enterotype 1
Enterotype 2
Enterotype 3
Arumugam et al. Nature 2011;473:174-80
COMBO - Cross-Sectional Study of Diet and
Stool Microbiota
Are nutrients associated
with specific bacterial taxa?
Conclusions:
• Clustering by nutrient group
• Inverse correlation between
carbohydrates and amino
acids and fats and fiber
• Inverse correlation between
Bacteroides and Prevotella
Wu et al. Science 2011;334:105-8
Blue- Rarely Eats
Red – Often Eats
Bacterial Enterotypes and Long Term Diet
Animal Protein
Animal Fat
Blue- Rarely Eats
Red – Often Eats
The Bacteroides enterotype:
The Prevotella enterotype:
Highly associated with animal protein
and saturated fats, which suggests
meat consumption as in a Western diet
Highly associated with carbohydrates
and simple sugars, which suggests a
carbohydrate-based diet more typical of
agrarian societies
Associations seen with long term, but not with recent diet patterns
Wu G, et al. Science. 2011 Oct 7;334(6052):105-8
Dietary components regulate bacterial gene
transcription
• Important function of the
intestinal microbiome is
metabolism of glycans
(complex carbohydrates
and polysaccharides)
• Bacteroides thetaiotaomicron
• Highly abundant obligate
anaerobe in the
microbiota of most adults
• Known for its ability to
metabolize
polysaccharides
Sonnenburg et al. Science. 2005.
What is the Link Between Diet,
Dysbiosis, and IBD?
• Hypothesis #1 - Regular diet contains harmful
components that lead to inflammation which
leads to dysbiosis
• Hypothesis #2 – Diet alters the gut microbiome
• Hypothesis #3 - Diet determines the metabolic
product of gut microbes which impacts health
Diet, the Gut Microbiome, Metabolome, and Disease
Diet serves as a substrate for the microbiota to produce certain
metabolites
We are not the only organism consuming what we eat
Holmes et al. Cell Met. 2012;16:559
Conceptual Model
Susceptible Host (Genetics)
Environmental Trigger #1 Influences Steady State Gut Microbiome
(Mode of Delivery, Early Diet, Long Term Diet)
Environmental Trigger #2 Initiates Pathologic Inflammation
(Infection, Antibiotic Exposure, Starting or Stopping Smoking)
Diet Contributes to Perpetuation / Recurrence of Pathologic Inflammation
(Lack of Key Nutrients, Influencing Metabolite Production, Direct Action)
Should we be Immunosuppressing
our Patients?
Hypothesis: IBD arises from
inappropriate handling of intestinal
bacteria
Maintenance Therapy with
Enteral Nutrition for CD
• Inclusion
– Adult patients in remission at the beginning of trial
(CDAI<150)
• Methods (prospective study)
– 50% of caloric needs from an elemental diet (Elental ®) by
overnight NG feed for 1 year (n=20)
VS
– Normal diet (n=20)
Yamamoto T et al. Inflamm Bowel Dis 2007;13:1493
Maintenance Therapy with
Enteral Nutrition for CD
• Primary endpoints at 12 months included:
– Clinical remission (CDAI)
– Endoscopic assessment
– Mucosal cytokine concentrations
• Il-1β
• Il-6
• TNF-α
Yamamoto T et al. Aliment Pharmacol Ther 2007;13:1493
Can remission be maintained with
Partial Enteral Therapy?
• Proportion in remission
was higher in the Enteral
Nutrition group (P=0.01)
Yamamoto T et al. Inflamm Bowel Dis 2007;13:1493
Maintenance Therapy with
Enteral Nutrition for CD
Severity of mucosal inflammation was graded 0-3
Regular
diet
p< 0.04*
Formula
diet
Conclusion: Endoscopic inflammation was significantly higher in
the normal diet group at 12 months*
Yamamoto T et al. Aliment Pharmacol Ther 2007;13:1493
Maintenance Therapy with
Enteral Nutrition for CD
EN Group
Normal Diet
IL-1β (pg/mg)
P=0.32
P=0.02*
At Entry
12 months
102
110
104
150
P=0.18
P=0.002*
At Entry
12 months
810
900
900
1300
TNF-α (pg/mg)
P=0.2
P=0.001*
At Entry
12 months
135
150
160
215
IL-6 (pg/mg)
Conclusion: Pro-inflammatory mucosal cytokines were
significantly higher in the normal diet group at 12 months*
Yamamoto T et al. Aliment Pharmacol Ther 2007;13:1493
Can a semi-vegetarian diet prevent relapse
of Crohn’s disease?
• Daily
– rice, miso soup
– egg, yogurt, milk
– vegetables, fruit, legumes, algae
• Fish once a week
• Meat once every 2 weeks
Chiba M, et al. World Journal of Gastroenterology 2010;16 (20):2484-95
Can a semi-vegetarian diet prevent relapse
of Crohn’s disease?
Chiba M, et al. World Journal of Gastroenterology 2010;16 (20):2484-95
Summary
• Maintenance of Remission for CD
– Evidence supports the use of partial enteral
nutrition
• 50% of calorie needs from formula (PO or NG)
– Limited evidence supports the use of a Crohn’s
Disease Exclusion Diet
Future Direction
• The challenge moving forward will be to
provide evidence for dietary influences on the
intestinal microbiome that have meaningful
effects on human physiology
– Changing the intestinal microbiome through
dietary modifications may ultimately provide a
powerful approach to disease prevention and
therapy
CHOP Enteral Nutrition Therapy (ENT)
Induction
• 8-12 weeks
• 80-100% of estimated
needs from ENT
• 10-20% food
• NGT/PO/combo
Maintenance
• Post induction to . . . ?
• Lower % EN by 10-15%
in 8-10 week intervals
– ↓ # of days
– ↓ volume
• Repeat as able (goal:
50% EN + 50% table
food)
Conceptual Model
Susceptible Host (Genetics)
Environmental Trigger #1 Influences Steady State Gut Microbiome
(Mode of Delivery, Early Diet, Long Term Diet)
Environmental Trigger #2 Initiates Pathologic Inflammation
(Infection, Antibiotic Exposure, Starting or Stopping Smoking)
Diet Contributes to Perpetuation / Recurrence of Pathologic Inflammation
(Lack of Key Nutrients, Influencing Metabolite Production, Direct Action)
The Perfect Dietary Storm- Rodent Models
High Animal Fat
Milk Fat
Sulfites?
Dysbiosis
Gluten
High Animal Fat
Emulsifiers
Maltodextrin
Low Plant Fiber
Intestinal
Permeability
Mucous
Layer or
Bacterial
Clearance
Defect
Adherence
and
Translocation
Bacteria
Courtesy of A. Levine
Nutritional therapy vs. 6-MP as
maintenance therapy in CD
• Prospective 24 month randomized controlled openlabel trial (n=95)
– Inclusion: CDAI ≤ 150
• Randomly assigned to:
– 6-MP (0.5-1.5 mg/kg/day n=30)
– ED (elemental diet ≥ 900 kcal/day n=32)
– Control (5-aminosalicylic acid n=33)
– Relapse : ≥ 200 CDAI
Hanai H, et al. Digestive and Liver disease 2012; 649-654
Nutritional therapy vs. 6-MP as
maintenance therapy in CD
Results:
At 24 months, patients who maintained
remission were 60%, 46.9% and 27% for 6MP, ED and Controls
No significant difference between 6-MP and
ED
Hanai H, et al. Digestive and Liver disease 2012; 649-654
Dietary component
Low diversity,
Dysbiosis
Presence of Bilophila wadsworthia
IL 10–/– mice
Devkota S, Nature, 2012
High Fat + Simple
sugars
1.
2.
Low diversity,
Dysbiosis AIEC Colonization
CEABAC 10 mice
Martinez M. Gut, 2014
Carrageenan (E407).
1.
2.
Lowered Transepithelial resistance
Discontinuous and irregular ZO-1 (zonula occludens)
expression
HCT-8 cells, HT-29
Cells, Caco-2 Cells
Choi H, Toxicol Lett 2012
Claudin 2 over expressed
CEABAC 10 mice
Martinez M. Gut, 2014
Dose dependent
mutant obese
Long-Evans rats
Suzuki T, Nutr Metab (Lond)
2010
Zonulin release, causes tight junction disassembly
Increase Inflammation Ileum TNF Δ ARE/WT mouse
Human intestinal
epithelial cell
Caco2 cells
IEC6 cells
Lamers, Gastroenterology
2008
Wagner et al Inflamm Bowel
Dis 2013
M cells
Caco2 Cells
Roberts C, Gut 2010
Adherence
IL 10–/– mice
Swidsinski A , Inflamm Bowel
Dis 2009
Biofilms
Human intestinal
epithelial cell
monolayers
Nickerson KP, PLoS One 2012
Bacterial overgrowth (30,000 folds ) especially between villi.
IL 10–/– mice
Swidsinski A , Inflamm Bowel
Dis 2009
Decreased expression MUC2, Depleted Goblet Cells
CEABAC 10 mice
Martinez M. Gut, 2014
High Fat + Simple
sugars
High Animal Fat
Polysorbate -80
(E433)
Plantain and Brocoli
fiber
CMC (E466)
Carboxymethyl
cellulose
Maltodextrin
CMC (E466)
Mucous Layer
Reference
1.
2.
3.
Gluten
Adherence
Translocation
Biofilms
Model
Milk Fats
Microbiome
Intestinal
Permeability (IP)
Effect
High Fat + Simple
sugars
AIEC translocated 15.8 folds higher
Lowered AIEC translocation
Courtesy of A. Levine