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Can nutritional therapy be used on a practical basis for maintenance? Robert N. Baldassano, MD Colman Professor of Pediatrics University of Pennsylvania,

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Presentation on theme: "Can nutritional therapy be used on a practical basis for maintenance? Robert N. Baldassano, MD Colman Professor of Pediatrics University of Pennsylvania,"— Presentation transcript:

1 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

2 I have the following financial relationships to disclose Products or services produced by this company are relevant to my presentation Janssen Pharmaceuticals Takeda Pharmaceuticals AbbVie, Inc. Avaxia Biologics, Inc

3 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…….?????????

4 The Gut Microbiota in Health and Disease Adapted from Walker, A.W. et al. Pharmacological Research Health IBD Therapeutic disruption of dysbiosis Antibiotics, Probiotics, Prebiotics Fecal Transplantation Dietary Intervention Dysbiosis (altered microbiota composition associated with disease)

5 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

6 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

7 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

8 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

9 Greater Mucosal Healing with More Restrictive Diet Calprotectin Concentration at Week 8 (mcg/g) Percentage of Patients PLEASE (Induction)

10 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. Greater Mucosal Healing with More Restrictive Diet PLEASE

11 Partial Enteral Nutrition with a Crohn's Disease Exclusion Diet Is Effective for Induction of Remission Sigall-Boneh, et al. IBD. 20(8): , 2014 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

12 Sartor RB. Nat. Rev. Gastro. and Hep. 2012;9: Devkota et al. Nature 2012;487:104 Dietary-fat-induced taurocholic acid promotes colitis in Il10 -/- mice

13 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

14 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

15 The basis for enterotype clustering is unknown but appears to be independent of: Nationality Gender Age Body Mass Index (BMI). Arumugam et al. Nature 2011;473: Enterotypes Abundance of one of three genera Bacteroides Prevotella Ruminococcus Enterotypes of the Human Gut Microbiome Prevotella Ruminococcus Bacteroides Enterotype 1Enterotype 2 Enterotype 3

16 Are nutrients associated with specific bacterial taxa? Wu et al. Science 2011;334:105-8 Conclusions: Clustering by nutrient group Inverse correlation between carbohydrates and amino acids and fats and fiber Inverse correlation between Bacteroides and Prevotella Blue- Rarely Eats Red – Often Eats COMBO - Cross-Sectional Study of Diet and Stool Microbiota

17 Bacterial Enterotypes and Long Term Diet Animal Protein Animal Fat Blue- Rarely Eats Red – Often Eats Wu G, et al. Science Oct 7;334(6052):105-8 Associations seen with long term, but not with recent diet patterns The Bacteroides enterotype: Highly associated with animal protein and saturated fats, which suggests meat consumption as in a Western diet The Prevotella enterotype: Highly associated with carbohydrates and simple sugars, which suggests a carbohydrate-based diet more typical of agrarian societies

18 Dietary components regulate bacterial gene transcription Bacteroides thetaiotaomicron Highly abundant obligate anaerobe in the microbiota of most adults Known for its ability to metabolize polysaccharides Sonnenburg et al. Science Important function of the intestinal microbiome is metabolism of glycans (complex carbohydrates and polysaccharides)

19 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

20 Diet, the Gut Microbiome, Metabolome, and Disease Holmes et al. Cell Met. 2012;16:559 Diet serves as a substrate for the microbiota to produce certain metabolites We are not the only organism consuming what we eat

21 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)

22 Hypothesis: IBD arises from inappropriate handling of intestinal bacteria Should we be Immunosuppressing our Patients?

23 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

24 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

25 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

26 Maintenance Therapy with Enteral Nutrition for CD Formula diet Conclusion: Endoscopic inflammation was significantly higher in the normal diet group at 12 months* p< 0.04* Severity of mucosal inflammation was graded 0-3 Yamamoto T et al. Aliment Pharmacol Ther 2007;13:1493 Regular diet

27 Maintenance Therapy with Enteral Nutrition for CD P=0.002* P= IL-6 (pg/mg) At Entry 12 months P=0.001* P= TNF-α (pg/mg) At Entry 12 months P=0.02* P= IL-1β (pg/mg) At Entry 12 months Normal DietEN Group 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

28 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):

29 Can a semi-vegetarian diet prevent relapse of Crohn’s disease? Chiba M, et al. World Journal of Gastroenterology 2010;16 (20):

30 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

31 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

32 CHOP Enteral Nutrition Therapy (ENT) Induction 8-12 weeks % 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)

33

34 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)

35 The Perfect Dietary Storm- Rodent Models Dysbiosis Intestinal Permeability Intestinal Permeability Mucous Layer or Bacterial Clearance Defect Mucous Layer or Bacterial Clearance Defect Adherence and Translocation Bacteria Adherence and Translocation Bacteria Emulsifiers Maltodextrin Low Plant Fiber High Animal Fat Milk Fat Sulfites? Gluten High Animal Fat Courtesy of A. Levine

36 Nutritional therapy vs. 6-MP as maintenance therapy in CD Prospective 24 month randomized controlled open- label trial (n=95) – Inclusion: CDAI ≤ 150 Randomly assigned to: – 6-MP ( 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;

37 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 6- MP, ED and Controls No significant difference between 6-MP and ED Hanai H, et al. Digestive and Liver disease 2012;

38 Reference Model EffectDietary component Devkota S, Nature, 2012IL 10–/– mice 1.Low diversity, 2.Dysbiosis 3.Presence of Bilophila wadsworthia Milk Fats Microbiome Martinez M. Gut, 2014CEABAC 10 mice 1.Low diversity, 2.Dysbiosis AIEC Colonization High Fat + Simple sugars Choi H, Toxicol Lett 2012 HCT-8 cells, HT-29 Cells, Caco-2 Cells 1.Lowered Transepithelial resistance 2.Discontinuous and irregular ZO-1 (zonula occludens) expression Carrageenan (E407). Intestinal Permeability (IP) Martinez M. Gut, 2014CEABAC 10 miceClaudin 2 over expressed High Fat + Simple sugars Suzuki T, Nutr Metab (Lond) 2010 mutant obese Long-Evans rats Dose dependentHigh Animal Fat Lamers, Gastroenterology 2008 Wagner et al Inflamm Bowel Dis 2013 Human intestinal epithelial cell Caco2 cells IEC6 cells Zonulin release, causes tight junction disassembly Increase Inflammation Ileum TNF Δ ARE/WT mouse Gluten Roberts C, Gut 2010 M cells Caco2 Cells AIEC translocated 15.8 folds higher Polysorbate -80 (E433) Adherence Translocation Biofilms Lowered AIEC translocation Plantain and Brocoli fiber Swidsinski A, Inflamm Bowel Dis 2009 IL 10–/– miceAdherence CMC (E466) Carboxymethyl cellulose Nickerson KP, PLoS One 2012 Human intestinal epithelial cell monolayers BiofilmsMaltodextrin Swidsinski A, Inflamm Bowel Dis 2009 IL 10–/– miceBacterial overgrowth (30,000 folds ) especially between villi.CMC (E466) Mucous Layer Martinez M. Gut, 2014CEABAC 10 miceDecreased expression MUC2, Depleted Goblet Cells High Fat + Simple sugars Courtesy of A. Levine


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