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Therapeutic Diets for IBD: What is the Evidence?
Lindsey Albenberg, DOChildren’s Hospital of PhiladelphiaCenter for Pediatric Inflammatory Bowel DiseaseAssistant Professor of PediatricsDivision of Gastroenterology, Hepatology, and Nutrition
Presented March 10, 2020
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Financial Support for this presentation was provided by Nestlé Health Science.The views expressed herein are those of the presenter and do not necessarilyrepresent Nestlé’s views. The material herein is accurate as of the date it waspresented, and is for educational purposes only and is not intended as asubstitute for medical advice.
Reproduction or distribution of these materials is prohibited.
© 2020 Nestlé. All rights reserved.
Learning Objectives:
Identify why we need therapeutic diets for IBD in the biologic era
Explain the evidence regarding diet and its effects on the gut microbiome, metabolome and relevance to inflammatory bowel disease
Describe dietary management approaches for IBD – past, present, and future
3
The IBD epidemic
Kaplan G, Ng S. Gastroenterology 2017
• Incidence of IBD rose steadily in the 20th
century in the Western world
• IBD was relatively rare in developing nations
• Over the past few decades, newly industrialized countries have documented the emergence of IBD
4
Global Burden of IBD: Prediction in 2025
• IBD is a global disease
• ~5 million affected worldwide
•Prevalence in the Western World 0.5%
• Rate in the rise of incidence is steep in
newly industrialized countries and in adolescents in industrialized countries
• The number of patients with IBD in newly industrialized countries might
approximate that in the Western world by 2025 owing to rising prevalence and
rapidly growing populations
Kaplan G. Nat Rev Gastroenterol Hepatol 20155
Targets in IBD Pathogenesis
Diet
Immunesystem
GutMicrobiome
‐Antibiotics‐Fecal transplant
Immunosuppressivemedications
??? Hypothesis: diet triggered changes in the intestinal microbiome might cause a proinflammatory state preceding the
development of IBD
6
1 2
3 4
5 6
2
Why Do We Need Dietary Therapies for IBD?
• Science tells us that something in the lumen of the gut is driving inflammation
• Our patients want to know what they should eat and the information on the internet is not consistent and not evidence based
– Our patients are already changing their diets
• Even our best therapies are not effective in all patients and they are associated with risks
7
Crohn’s Disease Surgery: An Experimental Model
• We have known for 20 years that diversion of the fecal stream is a treatment for some patients with CD
D’Haens GR, et al. Gastroenterology. 1998;114(2):262‐267.
8
Fecal Diversion Heals Ileal MucosaExposure to Ileal Contents Lead to Inflammation
Prior to infusion of ileal contents
Following infusion of ileal contents
Infusion of loop ileostomy effluent into distal ileum
0
1
2
3
4
5
6
7
8
Patient 1 Patient 2 Patient 3
0 0 0
5
6
8
Histologic Inflammation IndexDistal Ileum
Pre Post
D’Haens GR. Gastroenterology 1998;114:262–267 9
Breastfeeding OR (95% CI)
Strictures of penetrating complications 0.65 (0.44 – 0.96)
Lindoso L. Am J Gastroenterol 2018https://doi.org/10.1038/s41395‐018‐0239‐9
10
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.
11
High School Diet and Risk of Crohn’s disease
Ananthakrishnan AN. Inflamm Bowel Dis. 2015 Oct;21(10):2311‐9.
Food group Adjusted HR Q5 vs. Q1 Adjusted p(trend)
Fiber 0.48 (0.22 – 1.05) 0.047
Animal Fat 1.38 (0.58 – 3.32) 0.08
Heme‐Iron 1.81 (0.87 – 3.77) 0.058
Fish 0.45 (0.20 – 0.98) 0.027
Vegetables 0.44 (0.20 – 0.96) 0.097
Risk of IBD may also be modified by intake in early childhood and adolescence
12
7 8
9 10
11 12
3
• What and when you eat potentially influences your risk of developing IBD
• Earlier exposure may be more important than dietary changes later in life for purpose of prevention of disease
What Can We Learn From Epidemiologic Data?
13
Is There a Relationship Between Diet, the Gut Microbiota, and IBD?
Albenberg et al. Current Opinion Gastro. 2012. 14
Food Items CD (n=1121)
(B, W)
UC (n=597)
(B, W)
CD‐O (n=405)
(B, W)
UC‐P (n=206)
(B, W)
Improved Symptoms
Yogurt 108, 7* 54, 3* 26, 0* 19, 0*
Rice 59, 3* 30, 3* 20, 3† 16, 0*
Bananas NR NR NR 14, 0*
Worsened Symptoms
Non‐Leafy Vegetables 28, 221* 29, 81* 7, 90* 3, 36*
Spicy Foods 1, 145* 3, 79* 0, 46* 0, 33*
Fruit 50, 136* 40, 63 22, 51† 15, 24
Nuts 3, 120* 1, 33* 0, 52* 0, 21*
Leafy Vegetables 6, 115* 2, 50* 2, 29* 1, 14†
Fried Foods 0, 105* 0, 53* 0, 22* 0, 11†
Milk 6, 105* 0, 49* 5, 28* 2, 14†
Red Meat 6, 103* 7, 47* 2, 24* NR
Soda 11, 99* 0, 46* 0, 33* 0, 28*
Popcorn 2, 97* NR 0, 27* 0, 18*
Dairy 3, 94* 1, 56* NR 0, 12†
Alcohol 0, 90* 0, 54* NR 0, 23*
High Fiber 19, 87* 19, 35† 7, 46* NR
Corn 0, 77* 0, 31* 0, 29* NR
Fatty Foods 0, 62* NR NR NR
Seeds NR NR 0, 22* NR
Coffee NR 4, 37* NR NR
Beans NR 5, 30* NR NR
Patient-reported foods that improve / worsen symptoms
P values from the sign test. Bonferroni method p<0.00039 (i.e., 0.05/127) identified with an asterisk (*). Cohen AB Dig. Dis. Sci. 2012.15
Biologic and small molecule therapies in the last 2 decades
SONICColombel et al, NEJM 2010
CALMColombel et al, Lancet 2018
GEMINIFeagan et al, NEJM 2013
GEMINISandborn et al, NEJM 2013
UNITIFeagan et al, NEJM 2016
OCTAVESandborn et al, NEJM 2017
Targan et al, NEJM 1997
Infliximab
Vedolizumab
Ustekinumab
Tofacitinib
Adalimumab
PURSUITSandborn et al, Gastro 2014
Golimumab
16
Biologic and small molecule therapies in the last 2 decades
SONICColombel et al, NEJM 2010
CALMColombel et al, Lancet 2018
GEMINIFeagan et al, NEJM 2013
GEMINISandborn et al, NEJM 2013
UNITIFeagan et al, NEJM 2016
OCTAVESandborn et al, NEJM 2017
Targan et al, NEJM 1997
Infliximab
Vedolizumab
Ustekinumab
Tofacitinib
Adalimumab
PURSUITSandborn et al, Gastro 2014
Golimumab
~50‐60% clinical responders to induction tx
15% endoscopic & histologic remission
Loss of response 15% per year
100% recurrence of disease sometime after tx stop
17
Reduction in surgical rates in Crohn’s disease in the biologic era
Olivera P, et al. Curr Opin Gastroenterol 2017;33:246‐53.
Surgical trends in CD population‐based studies
Year
PRE‐BIOLOGIC ERA BIOLOGIC ERA
Danish National Patient Register
Size of circle represents number of patients in cohort
5‐year surgery rate
0
Can treating to target further decrease the number of surgeries?
20
40
60
80
100
1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
Manitoba
Copenhagen County
Olmstead County
Cardiff
Stockholm County
IBSEN
18
13 14
15 16
17 18
4
Beaugerie L, Kisrchgener J. Clin Gastroenterol Hepatol 2019
Safety concerns…
19 Beaugerie L, Kisrchgener J. Clin Gastroenterol Hepatol 2019
Safety concerns…
• Patients with IBD exposed to thiopurines exhibit an increased risk of cancers. • Young patients, particularly males, are at risk of postmononucleosis lymphomas and hepatosplenic T‐cell lymphomas.
• Patients with IBD exposed to thiopurines exhibit an increased risk of nonmelanocytic skin cancers
• Patients exposed to anti‐TNF agents are at increased risk of melanoma.
• Whether patients treated with anti‐TNF agents alone exhibit an excess risk of lymphoma remains controversial.
20
• Because it makes sense !
• Medications have limited efficacy
• Medications are not a cure !
• Safety concerns
• Children with IBD have a lifetime of treatment ahead of them
Why do we need nutrition therapy in IBD?
21
Diet and Crohn Disease: What’s out there?
22
Something “Bad” in Diet and the Microbiome?
Courtesy of Arie Levine
23
Challenges of Dietary Trials
• Lifestyle change
– Difficulty with adherence
• Broad variability in food
• Interactions
• Substitution effect
• Blinding
Lewis, JD. Inflamm Bowel Dis 2017. Willett, W. Nutr Epidemiology. Oxford Univ Press 1998.
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19 20
21 22
23 24
5
Dietary Approaches for Treating IBD
• Exclusive Enteral Nutrition (EEN)
• Exclusion diets:
– Specific carbohydrate diet (SCD)
–Crohn’s disease exclusion diet
– Semi‐vegetarian diet
–CD‐TREAT
– “Anti‐inflammatory” diet
25
Defined Formula Diets for CD: Background
• Enteral nutrition (EN) is a term used to describe the use of a liquid nutrition formula administered orally or through nasogastric tube for the treatment of CD
– Replacing all or the majority of daily calories with formula and excluding or limiting food
• Dates back to the 1970’s when the use of TPN and elemental formula diets were reported as potential treatments for CD
26
Meta‐analysis: EEN vs Steroids
Induction of remission: equivalent; OR 1.26 (0.77, 2.05) favoring EEN
Mucosal Healing: EEN is superior: OR 4.5 (1.46, 12.23)
Swamimanth et al., Aliment Pharmacol Ther 2017;46:546‐56. 27
Defined Formula Diets for CD
PCDAI CRP CDEISHistol ‐Ileum
Histol ‐Colon
Polymeric diet ‐ Pre 38.1 10.4 12.9 10.4 10.7
Polymeric diet ‐ Post 6.53 2 5.9 3.8 4.6
Corticosteroids ‐ Pre 35.5 11.9 12.7 11 11.1
Corticosteroids ‐ Post 7.5 2.2 9.8 9.6 8.8
0
5
10
15
20
25
30
35
40
45
Group M
ean
*
*
* * * *
*
10 Week open label RCT in newly diagnosed children with Crohn’sPolymeric diet (n=19) vs. Steroids (n=18)
* P<0.05 for Pre vs Post
Borrelli O. Clin Gastroenterol Hepatol 2006;4:744‐53 28
Elemental vs. Nonelemental
Response to Dietary Therapy
0
20
40
60
80
100
Elemental Nonelemental
Adapted from Zachos M. Cochrane Review 2007
No difference
29
EN for Induction of Remission in CD: Duration of Therapy
• 6‐8 weeks most common in the literature (range 4‐12 weeks)• Clinical response seen at 4 weeks (Rubio et al. 2011, PCDAI and Guo at al. 2013., CDAI)
• PLEASE Study: 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
Lewis JD, et al. Cell Host & Microbe 2015; 18: 489 30
25 26
27 28
29 30
6
EN for Induction of Remission in CD: Duration of Therapy: PLEASE study
• The microbiota composition among the EEN‐treated group changed within 1 week of therapy
• Significant reduction in FCP by week 4
Lewis JD, et al. Cell Host & Microbe 2015; 18: 489 31
0
10
20
30
40
50
60
70
FCP<50 FCP<250
0
14
5
45
30
62
Percentage of Patients
Calprotectin Concentration at Week 8 (mcg/g)
Partial EnteralNutrition (n=16)
Exclusive EnteralNutrition (n=22)
Anti‐TNF (n=52)
**
*p< 0.05 EEN vs anti‐TNF** p<0.05 PEN vs EEN and PEN vs. anti‐TNF
Lee, et al. Inflamm Bowel Dis 2015;21:1786‐92
For Induction of Remission, How Exclusive is Exclusive?
Similar amounts of formula intake for the Partial EN and Exclusive EN groups
*
**
32
How?
Induction of Remission – CHOP protocol
33
Exclusive versus Partial EN
• CHOP protocol
• 8‐12 weeks
• 80‐90% of estimated needs from formula
• 10‐20% food – Pediatric anti‐inflammatory diet pyramid
• NG tube/oral/comboREE
MalesFemales
0‐3 60.9W ‐ 54 61.0W ‐ 51
3‐10 22.7W + 495 22.5W + 499
10‐18 17.5W + 651 12.2W + 746
18‐30 15.3W + 679 14.7W + 496
• WHO’s REE multiplied by activity factor
• REE x 1.5 for no malnutrition • REE x 1.7‐1.8 if moderately
malnourished or more than 2 hours/day high intensity physical activity
34
10‐20% Estimated Needs from Solid Foods
80% of calories from formula
1600 calories
~4‐5 cans of concentrated (1.5 kcal/mL) formula
20 % of calories from food
400 calories
3‐4 snacks or mini meals
Example: 2000 calorie diet
35
10‐20% Estimated Needs from Solid Foods
80% of calories from formula
1600 calories
~4‐5 cans of concentrated (1.5 kcal/mL) formula
20 % of calories from food
400 calories
3‐4 snacks or mini meals
Example: 2000 calorie dietFruits/Vegetables Protein Mini Meals
• 1/2 cup blueberries + 2 Tbsp. whipped cream
• 1/2 sliced apple dipped into 1/2 Tbsp. natural peanut butter
• Grilled veggie kabobs
• 1 cup broccoli or 3 stalks celery with 3 Tbsp. yogurt dip or hummus
• 1 hardboiled egg + mustard
• 2 light laughing cow cheese wedge + 1 cracker + 1/4 cup cucumber slices
• 1 slice of whole wheat bread with 2 egg whites
36
31 32
33 34
35 36
7
EN for Maintenance of Remission
• Literature very heterogenous, difficult to assess systematically
• Systematic review of 12 studies (3 RCTs, only 1 evaluated to be low risk of bias) of EN for inactive CD (children and adults) concluded EN more effective than regular diet and as effective as some medications in maintaining remission (El‐Matary et al. Journal of Parenteral and Enteral Nutrition. 2017.)
– Could not perform metaanalysis
37
Where should we place EEN?
• Most common placement of EEN observed in the literature: alternative to corticosteroid as a bridge to thiopurine
• Scarce data evaluating combination of EEN with other therapies (1 study with anti‐TNF)
• Bridge to PEN for maintenance?
• Bridge to exclusion diets?
• Bridge to anti‐TNF (delayed insurance approval, allow immunization catch‐up in unimmunized, patients with intra‐abdominal abscess)
38
Exclusive Enteral Nutrition: Pros and Cons
+ At least as effective as steroids
+ Associated mucosal healing
+ Works quickly
+ Improves nutritional status
+ Improves bone health
+ No side effects
‐ Demands resources, education, & dedication
‐ Limited long‐term benefit
‐ Exit strategy?
39
CD‐TREAT: Emulating EEN with food
• Hypothesis: Ordinary food diet based on composition of Modulen formula can achieve similar efficacy as EEN for treatment of Crohn’s
• Diet: – Avoid gluten, lactose– Match macronutrients, vitamins, minerals, and fiber– Food delivered by catering company
• Results:– 28 Healthy adults: similar effects on microbiome and metabolome
– 5 children with Crohn’s: 4 improved, 1 discontinued because of symptom exacerbation
Svolos V. Gastroenterology. 2018.40
The Specific Carbohydrate Diet (SCD)• Restricted foods on the SCD:
– All grains
– Refined sugars
– Cow’s milk products (fully fermented yogurt ok)
– “Processed foods”
• Popular following in the community for variety of GI illnesses
– Anecdotal evidence plentiful
• Concerns: Elimination of whole food groups from the diet, inadequate calories, emotional well‐being
41
Author Study design n Summary
Two ongoing multicenter trials: 1) n‐of‐1 study of SCD and modified SCD (120 participants)2) SCD vs. Mediterranean diet (194 participants)
Suskind DL, J ClinGastro (2018)
Prospective case series
13 Clinical + laboratory improvements; significant microbiome shifts
Braly K, J Ped Gastro Nut (2017)
Prospective diet eval
9 Nutrient intake comparable to 2012 NHANES reference group for protein, vitamins, minerals
Obih C, Nutrition (2016)
Retrospectivecase series
26 Improved clinical and laboratory parameters for Crohn’s disease and UC
Suskind DL, Dig Dis Sci (2016)
Patient survey 417 Majority of respondents perceive clinical benefit to SCD
Burgis JC, World J Gastro (2016)
Retrospectivecase series
11 Improved labs, growth parameters
Kakodkar S, J AcadNut Diet (2015)
Retrospectivecase series
50 SCD is effective for some adults with IBD; High quality of life reported
Suskind DL, J Ped Gastro Nut (2014)
Retrospectivecase series
7 Improvement in clinical + lab parameters (Hct, CRP)
Cohen SA, , J Ped Gastro Nut (2014)
Prospective case series
16 Clinical and mucosal improvements seen
42
37 38
39 40
41 42
8
Crohn’s Disease Exclusion Diet is Equally Effective but Better Tolerated than Exclusive Enteral Nutrition for Induction of Remission in Mild to Moderate Active Paediatric
Crohn’s Disease: A Prospective Randomized Controlled Trial
43
CDED Trial ‐ RCT comparing CDED+PEN to EEN followed by PEN
78 patients mild to moderate CD , mean age 14.2±2.7 years
*Primary outcome = tolerance
44
CDED Phase I (weeks 0‐6)
Inclusions:Soluble fiberApple pectinResistant starch
Exclusions:High fat, animal fatTaurineRed meatDairyWheatAlcoholYeastCarrageenanMaltodextrinSulfitesTitanium dioxide
Levine A, Gastro. 2019. 45
Week 6: Comparison EEN vs CDED + PEN (50% calories from formula)
Levine A. Gastro. 2019. 46
Week 6 PCDAI and CRP
Levine A, Gastro. 2019. 47
Median FCP weeks 6 and 12
Levine A, Gastro. 2019.
Rebound at week 12 in EEN group with transition to 25% formula, 75% free diet
48
43 44
45 46
47 48
9
CDED RCT Conclusions
• Large (relatively)! And randomized, controlled!
• Not powered to be an efficacy trial but as good (? better) than EEN for induction of remission
• Mild disease cohort with short disease duration (<36 mos)
• No mucosal healing endpoint, but significant reduction in FCP
• Long term outcomes unknown
– Will patients achieve mucosal healing with diet alone by 6 months?
– Is the diet sustainable long term?
49
Conclusion• Exclusive enteral nutrition (EEN) is effective therapy for Crohn’s
• Restriction diets involving regular food have shown promise
• There are limitations to the clinical data for dietary therapy in IBD. This should not be a deterrent. – Shared decision making and following objective outcomes closely are critical– Consider dietary therapy ”a drug”
• I expect the same compliance with therapy and with monitoring and willingness to move on if therapy not working
• Further studies on dietary therapy needed, particularly those that address mechanism
50
Questions
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www.nestlenutrition‐institute.org
Visit the MyCE site at www.MyCEeducation.comOffering CE to dietitians and nurses
©2020 Nestlé 51
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