Fecal Microbial Transformation Diet as Therapy in IBD

David Suskind M.D.Professor of Pediatrics

Division of Gastroenterology

University of Washington

Seattle Children’s Hospital

Objectives

• Inflammatory Bowel Disease

• Fecal microbiome

• Immune homeostasis

• Determine the Fecal microbiome

• Diet modulates of the fecal microbiome

• Clinical experience with diet in IBD

IBD Paradigm: Immune dysregulation

Immune response Microbiome

Environment

Antibiotics

Food

Genetics

Incidence of

Inflammatory Bowel Disease

Bach, New England J Med 2002;347:911-20

Global Prevalence

Fecal microbiome

6

Who’s there?

What are they doing?

Who’s they are varies:

microbiota is plastic and personalized.

What they’re doing is adapting:

you, your body, and your environment.

Savage, DC. Annu Rev Microbiol 1977; 31:107-133

Backhed, F ,et al Science. 2005; 307: 1915-1920.

Valm et al, PNAS 2011

Keeping things in Check

• Buffer zone

• Physiochemical barrier

composed of a thick

mucus layer

• antimicrobial proteins

• secretory IgA antibodies

• Secondary defense

• tight junctions

• Bactericidal proteins:

defensins, cathelicidins

and C-type lectins

• Toll-like receptors

• Intestinal macrophages, LP

dendritic cells, B-cells and T-

cells

Shaping our Microbiome

Nutrition

Age

Other

• Antibiotic exposure

Genes

Diet vs Genotype on fecal microbiome

composition

• Diet effect on the fecal

microbiota of five inbred

mice strains

• mice deficient for genes

relevant to host-microbial

interactions

• MyD88-/-, NOD2-/-, Ob/ob

and Rag1-/- and >200

outbred mice

• High fat, high sugar diet

vs Low fat high fiber

Carmody, R, et al Cell Host & Microbe 2015, (17), 72-84

Diet Rapidly and reproducibly alters human

gut microbiome

David, L, et al Nature 2014; 505 (7484): 559-563

Diet Rapidly and reproducibly alters human

gut microbiome

David, L, et al Nature 2014; 505 (7484): 559-563

Microbiome in Specific

Carbohydrate Diet

Walters S, et al SOJ Microbiology and Infectious Disease 2014

Western Diet and IBD

• High total fat, omega-

6 fatty acids and

animal proteins

• Increased risk of CD

and UC

• High fruits and fiber

intake

• decreased risk of CD

• High in vegetables

intake• Decreased risk of UC

Hou JK et al. Am J Gastroenterol. 2011

Asakura H et al. J. Gastro Hepatol. 2008

Western diet induces Dysbiosis

• … with increased E. coli in CEABAC10

mice…

Martinez-Medina M, et al Gut 2014;63:116-124

Maltodextrin: Intestinal defense

• Chemical and enzymatic processed starch

• Generally recognized as safe (GRAS)

• 60% of all packaged items

Nickerson, K. et al Gut Microbes 6:1, 78-83.Nickerson, K, et al PLoS One 2012/2014

Dietary emulsifiers alter microbiota

localization, composition, and pro-inflammatory potential

Chassaing B, et al. Nature 519,92-96(2015)

Dietary emulsifiers promote colitis in

susceptible mice

Chassaing B, et al. Nature 519,92-96(2015)

Flipping the Paradigm

Exclusive Enteral Nutrition (EEN)

• Mainstay of nutritional therapy in Crohn’s disease

• 8-12 weeks of exclusive formula

• No other foods or drinks

• Oral or via nasogastric tube

Alimentary Pharmacology & Therapeutics 26(6): 795-806, 2007

Meta‐analysis: enteral nutrition in active Crohn’s disease in children

• Prospective open label randomized

controlled trial

• Steroids vs Polymeric formula

• Protocol

• Pediatric Crohn’s disease Activity Index

(PCDAI) at 2,4,6,8,10 weeks

• Laboratory studies

• Ileocolonoscopy at 0,10 weeks

Exclusive Enteral Nutrition (EEN)

Borelli O. , et al Clinical Gastro Hep. 2006; 4: 744-753

Results

PCDAI, laboratory results, and endoscopic score

Nutritional Therapy Group (NT):

Elemental, Semi-elemental feeds delivered by NGT

Polymeric formula taken orally

Exclusive enteral nutrition for 8 weeks then foods

gradually re-introduced

Corticosteroid Group (Cs):

1-2mg/kg/day for 4 weeks then taper

Maintenance therapy

Mesalamine 50-75mg/kg/day

Canani, RB. Et al Digestive and Liver Disease 38 (2006) 381-387

Type of EEN in Nutritional therapy

Induction Therapy

Clinical remission

32/37 in nutritional therapy

9/10 in steroid group

No significant differences between groups

8 wks

Follow-up: 1 year

Kaplan Meyer curve

Clinical relapse rate: 30% for EEN versus 70% for Cs

No significant differences between EEN groups

2

Partial EN and Exclusion Diet

Sigall-Boneh, Rotem, et al. Inflammatory Bowel Diseases. 20(8):1353-1360, August 2014.

4

Partial EN and Exclusion Diet

Sigall-Boneh, Rotem, et al. Inflammatory Bowel Diseases. 20(8):1353-1360, August 2014.

Specific Carbohydrate Diet(SCD)

Removes All grains

Milk products except for yogurt fermented greater than 24 hours

Sugars except honey

Sidney Haas MD Early 1930s used to treat celiac disease

Popularized by Elaine Gottschall Breaking the Vicious Cycle

Haas, S, Haas M, Am J Gastroenterol 1955 Apr;23(4):344-60

SCD Studies Study Type of study Pediatric/Adult Number of subjects Findings

Suskind DL, et al J Pediatr

Gastroenterol Nutr. (2014) *

Retrospective case series Pediatric Crohn’s disease 7 Normalized labs and

induced clinical remission

Cohen et al. JPGN (2014) Prospective case series Pediatric Crohn’s disease 10 Clinical and mucosal

improvements were seen in

children with CD

Kakodkar S et al. J Acad

Nutr Diet. (2015)

Retrospective case series Adult Crohn’s disease and

Ulcerative colitis

50 Effective for some patients

with IBD

Obih, C. al Nutrition (2016) * Retrospective case series Pediatric Crohn’s and

ulcerative colitis

26 improve clinical and

laboratory parameters for

pediatric CD as well as UC

Burgis JC, et al World J

Gastro (2016)

Retrospective case series Pediatric Crohn’s 11 Disease control may be

attainable with the SCD in

pediatric CD

Suskind DL, et al J Clin

Gastroenterol. (2016) *

Prospective case series Pediatric Crohn’s and

ulcerative colitis

13 Clinical improvement,

laboratory improvement and

microbiome shifts

Suskind DL, et al Dig Dis Sci.

(2016) *

Patient Survey Pediatric/Adult Crohn’s and

Ulcerative colitis

417 Most patients perceive

clinical benefit to use of the

SCD

Nakayuenyongsuk W, et al

Dig Dis Sci. 2017

Retrospective Case Pediatric Crohn’s disease 1 Effective after weaning from

EEN

Braly, K, et al. JPGN (2017) * Prospective diet evaluation Pediatric Crohn’s disease

and ulcerative colitis

9 Evaluated dietary intake of

patients on the SCD

Miller TL, et al, Dig Dis Sci.

(2017)*

Retrospective case series Pediatric VEO-IBD 2 Clinical, laboratory and

mucosal healing for 1 patient

• Retrospective study

• Children with Crohn’s disease

• Trialed dietary therapies as sole medical

treatment for their Crohn’s disease

• Seattle Children’s Hospital

•January 2005 to December 2012

SCD at SCH

Suskind DL, et al, JPGN. 2014 Jan;58(1):87-91.

Pediatric Crohn’s Disease Activity Index

Study IDPrior to Diet Intervention

3 Months

After

6 Months

After

12 Months

After

15 Months

After

18 Months

After

One 20 0 0

Two 30 0 0

Three 30 0 0 0 0

Four 10 0 0 0 0 0

Five 15 0 0 0

Nine 25 0 0

Ten 10 0 0 0

Suskind DL, et al, JPGN. 2014 Jan;58(1):87-91.

Suskind DL, et al, JPGN. 2014 Jan;58(1):87-91.

Prospective SCD study• Active Crohn’s Disease/Ulcerative Colitis

• Pediatric patients

• No change in medication

• Followed

• Baseline

• 2, 4, 8, 12 weeks

• Clinically, laboratory response,

microbiome

Suskind, et al, JCG 2016 Dec 27(Epub ahead of print)

Effect of SCD in IBD

Suskind, et al, JCG 2016

Microbiome Analysis

Species Baseline Week 2 Week 6 Week 12

Escherichia coli 12.3 0.3 1.8 0.2

Ruminococcus gnavus 15.0 4.7 4.4 1.9

Bacteroides fragilis 8.2 1.3 12.1 1.1

Bacteroides ovatus 8.4 3.0 1.1 1.6

Veillonella unclassified 4.3 0.1 0.0 0.0

Bacteroides stercoris 6.7 4.6 1.0 2.9

Species Baseline Week 2 Week 6 Week 12

Escherichia coli 12.3 0.3 1.8 0.2

Ruminococcus gnavus 15.0 4.7 4.4 1.9

Bacteroides fragilis 8.2 1.3 12.1 1.1

Bacteroides ovatus 8.4 3.0 1.1 1.6

Veillonella unclassified 4.3 0.1 0.0 0.0

Bacteroides stercoris 6.7 4.6 1.0 2.9

Suskind, et al, JCG 2016 Dec 27(Epub ahead of print)

Crohn’s disease: Blind Diet Controlled Study

Active Crohn’s Disease

SCD

SCD + Oats + Rice

Modified Whole Food Diet

Follow-up 2, 4, 8, 12 wks

Clinical Activity – PCDAI

Laboratory Study-

CBC, ESR, CRP,

calprotectin

Fecal Microbiome

- 8 – 21 years

- Mild to moderate

disease

- No change in

medications

- No stricture/fistula- Chef provided

foods

- Free food list

ClinicalTrials.gov Identifier: NCT02610101

Response specific carbohydrate diet in

pediatric Crohn’s disease

Burgis JC, et al World J Gastro 22(6):2111-7 2016

Further Evidence for SCD

• 9 pediatric patients with active CD

• No changes or addition of medications

• 6-mercaptopurine(4), 5-ASA(1), Budesonide(1)

• Symptoms/Labs over initial 12 weeks

• Improvement sustained in 7 children for 52 weeks

Cohen et al. JPGN 59(4):516-21 2014

SCD Clinical Protocol: CD

Measured Parameters for CD Patients (Mean)

Before diet 2 weeks – 6

weeks

4-6 months 12 months

PCDAI - diet initiated during

active disease

32.8 ± 13.2 20.8 ± 16.6 8.8 ± 8.5 0 ± 0

CRP 1.8 ± 1.0 1.3 ± 1.1 0.9 ± 0.2 0.9 ± 0.3

HEMATOCRIT 35.6 ± 2.9 37.3 ± 3.5 39.3 ± 2.4 39.3 ± 3.3

BMI 17.3 ± 2.3 17.9 ± 2.3 16.7 ± 2.9 18.3 ± 4.0

Obih, et al Nutrition Apri;32(4):418-25

SCD Clinical Protocol: UC

Measured Parameters for UC Patients (Mean)

Parameter

Before diet 2 weeks – 3

months

6 months 12 months

PUCAIdiet initiated during

active disease

28 ± 11.4 20.0 ± 17.3 18.3 ± 31.7 0 ± 0

CRP 1.0 ± 0.5 0.7 ± 0.3 0.9 ± 0.3 0.8 ± 0.1

HEMATOCRIT 35.1 ± 2.6 38.9 ± 3.2 37.5 ± 3.0 38.5 ± 3.3

BMI 17.2 ± 2.1 17.6 ± 1.6 18.0 ± 1.9 20.1 ± 1.7

Obih, et al Nutrition Apri;32(4):418-25

Ongoing Studies

•

• Double blind diet control study in Crohn’s

disease

• Low animal protein SCD in Ulcerative Colitis

• Reversed Engineered EEN in Crohn’s disease

• DIET Study - Low Residual vs SCD in Adult CD

• CD-Dine study – SCD vs Mediterranean diet

Additional Dietary Studies

• GAPs, Makers and Paleo

• IgG4 Targeted Exclusion

• Rajendran, Colorectal Dis 2011

• FODMAPs

• Gearry, J Crohns Colitis 2009

• Lacto-ovo-vegetarian fiber rich diet

• Chiba, World Journal of Gastro. 2010

Conclusion

• Fecal Microbiome is complex and

biologically important in

Inflammatory Bowel Disease

• Fecal Microbiome modulates us

• We modulate our Fecal Microbiome

“Let food be thy medicine”

- Hippocrates

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