Gastroenterology

Gastroenterology

Volume 157, Issue 2, August 2019, Pages 440-450.e8
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial

https://doi.org/10.1053/j.gastro.2019.04.021Get rights and content

Background & Aims

Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn’s disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier.

Methods

We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12.

Results

Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68–115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria.

Conclusion

CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.

Keywords

Crohn’s Disease
Microbiome
Treatment
Inflammatory Bowel Disease

Abbreviations used in this paper

ATE
additive treatment effect
CD
Crohn’s disease
CDED
CD exclusion diet
CI
confidence interval
CRP
C-reactive protein
EEN
exclusive enteral nutrition
ITT
intention to treat
L/M
lactulose/mannitol
PCDAI
pediatric CD activity index
OR
odds ratio
PEN
partial enteral nutrition
TMLE
Targeted Maximum Likelihood Estimation

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Conflicts of interest These authors disclose the following: AL reports grants, from Nestlé Health Science, and grants from Janssen unrelated to this field; advisory boards, travel, speaker fees or DSMBs from Celgene, Takeda and AbbVie, and a licensing and consulting agreement with IP with Nestlé health to develop new products based on diet. EW reports personal fees from Janssen, personal fees from AbbVie, outside the submitted work. RSB reports personal fees from Consulting to Nestlé Health Science, during the conduct of the study; personal fees from Invited speaker by Nestlé Health Science, personal fees from Invited speaker by Takeda, outside the submitted work. RS reports personal fees from Janssen, AbbVie, Mead Johnson, Lapidot and Abbott, outside the submitted work. JVL reports consulting, travel and/or speaker fees and research support from AbbVie, Janssen, Nestlé Health Science, Merck, P&G, GSK, Illumina, Otsuka. The remaining authors disclose no conflicts.

Funding Initial funding for the study in Israel was provided by unrestricted grants from the Azrieli Foundation and Nestlé Health Science to AL. Nestlé Health Science also kindly provided Modulen to all participating sites to ensure uniformity of the formula used among participants and provide the formula to enrolled patients for the duration of the study. The conduct of the study in Canada (Halifax, Edmonton) was supported by local divisional funds, a Women and Children's Health Research Institute (WCHRI) Research Capacity Building Award (EW) and a Canadian Institutes of Health Research (CIHR) New Investigator award (JVL). The funders of the study had no role in the design of the study, data collection or analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. None of the funders or participating physicians had access to the data. All data were held confidentially by a single research coordinator and data manager who validated the data and performed an extensive query process (RSB).

Author names in bold designate shared co-first authorship.

§

Authors share co-senior authorship.

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