Table 1.

Summary of the nutritional therapy intervention studies in children with Crohn’s disease, as described in Section 4.

Ref	Study Design	Aim	Population (Activity)	Intervention (Duration), n	Comparator (Duration), n	Key Findings
Exclusive Enteral Nutrition
Belli et al. [85]	Prospective	To reestablish growth	Pediatric CD with growth failure (n.r.)	Intermittent EEN (1 year: 3 times 1 month EEN, with 3 month breaks) n = 8	No EEN, matched n = 4	-Intermittent EEN show sign. decrease in CDAI and prednisone intake -Intermittent EEN shows sign. height and weight gain -Similar rate of pubertal development in both groups
Ludvigsson et al. [78]	RCT	To compare efficacy and safety of elemental and polymeric diets	Pediatric CD (PCDAI > 12)	Elemental formula (6 weeks) n = 17	Polymeric formula (6 weeks) n = 18	-Similar remission rates in both groups at week 6 -Sign. higher weight gain in polymeric formula
Rubio et al. [79]	Retrospective	To analyze the efficiency of oral fractionated versus continuous enteral feeding	Pediatric CD (n.r.)	EEN oral (8 weeks) n = 45	EEN continuous enteral (8 weeks) n = 61	-Similar remission rates in both groups -Similar effects on PCDAI and inflammatory markers in both groups -Sign. more weight gain in enteral feeding group
Connors et al. [21]	Retrospective, propensity score-matched	To compare short- and long-term disease outcomes	Pediatric new-onset CD (PCDAI ≥ 10)	EEN (8–16 weeks) n = 82	CS (n.r.) n = 45	-EEN sign. more effective in inducing remission -EEN associated with long term steroid avoidance over 6 years -Similar outcomes on long term linear growth, hospitalization, need for biologic therapy and surgical intervention in both groups
Pigneur et al. [72]	RCT	To study anti-inflammatory effects and its modulatory effect on the microbiota	Pediatric new-onset CD (HBI > 5)	EEN (8 weeks) n = 13	CS (4 weeks, tapered) n = 6	-EEN induces sign. higher mucosal healing at week 8 -Similar drop in inflammatory markers at week 8 -Higher proportion of Ruminococcus bacteria and bacteria belonging to clostridium genus in EEN group
Logan et al. [76]	Observational	To study changes in FCP during EEN and at food reintroduction and explore associations with MEN	Pediatric CD (n.r.)	EEN (8 weeks) n = 68 optional MEN	-	-Sign. increase in FCP within 17 and 52 days after food reintroduction -Sign. lower FCP in MEN group compared to EEN at day 17 -MEN not associated with prolonged remission
Partial Enteral Nutrition
Wilschanski et al. [91]	Retrospective	To examine whether continuation of EN as nocturnal supplement lengthens remission	Pediatric CD successfully treated with EEN (n.r.)	PEN nocturnal (n.r.) n = 28	No PEN n = 19	-Additional PEN induces sign. prolongation of remission at 6 and 12 months -Additional PEN induces sign. increased linear growth
Johnson et al. [86]	RCT	To compare PEN with EEN for induction of remission	Pediatric CD PCDAI > 20	PEN (6 weeks) n = 26	EEN (6 weeks) n = 24	-EEN sign. superior to PEN in inducing clinical remission -EEN and PEN both induce sign. drop in PCDAI -PEN PCDAI drop due to/symptomatic/nutritional benefits -EEN suppresses inflammation
Kang et al. [94]	Prospective open-label study	To examine the effects of concomitant use of PEN as adjuvant therapy	Pediatric severe CD PCDAI > 45	PEN (4 weeks) n = 18	Normal diet n = 16	-PEN improved nutritional status sign. after 1 year
Lee et al. [88]	Prospective	To compare effectiveness between PEN, EEN, and anti-TNF therapy for induction of remission	Pediatric CD PCDAI > 10	EEN (8 weeks) n = 22 PEN (8 weeks) n = 16	Anti-TNF (n.r.) n = 52	-Clinical remission PEN 50%, EEN 76%, anti-TNF 73% -EEN sign. superior in inducing remission -FCP < 250 ug/g sign. higher in EEN and anti-TNF -Improvement QOL similar in all groups
Schulman et al. [92]	Retrospective	To evaluate efficacy of PEN for preventing clinical relapse	Pediatric CD successfully treated with EEN (n.r.)	PEN as supplementary diet (median 6 months) n = 42	No PEN n = 45	-Similar duration of maintenance of remission in both groups -Suppl. PEN sign. increases weight and BMI
Specific diet
Sigall et al. [99]	Retrospective	To report on experience with CDED and its efficiency in inducing remission	Pediatric and young adults with CD PCDAI ≥ 10 HBI > 3	CDED + PEN (12 weeks) n = 40 CDED alone (12 weeks) n = 7	-	-Remission achieved in 78.8% of participants at week 6 (24/34 children and 9/13 adults) -Remission maintained in 84% of participants at week 12 -Remission in 6/7 participants on CDED alone -Sign. reduction of PCDAI and inflammatory markers
Sigall et al. [98]	Retrospective	To report on experience of CDED for induction of remission in patients with loss of response to infliximab/adalimumab or combination therapy	Pediatric and young adults with CD with flare/active inflammation on biological (n.r.)	CDED + PEN (12 weeks) n = 12 CDED alone (12 weeks) n = 4 Modified EEN + CDED (2 + 12 weeks) n = 5	-	-Clinical remission 62% (13/21) -Among patients failing combination therapy 53% reach remission (9/17) -Sign. reduction of inflammatory markers overall
Levine et al. [3]	RCT	To study tolerability of the diet and efficacy in induction of remission	Pediatric mild to moderate CD 10 ≤ PCDAI ≤ 40	CDED + PEN (12 weeks) n = 40	EEN (6 weeks) n = 34	- CDED and EEN equally effective in inducing remission at week 6 - CDED superior in sustained remission at week 12 -CDED sustained changes in fecal microbiome at week 12 -CDED and EEN induce a rapid clinical response (by week 3) -Identification of patients with a rapid response to diet could identify those who will be in clinical remission by week 6 with good compliance [103]
Svolos et al. [44]	Open-label	To test efficacy of CD-TREAT to induce clinical remission and ameliorate inflammatory markers	Pediatric relapsing CD wPCDAI ≥ 12.5	CD-TREAT (8 weeks) n = 5	-	-CD-TREAT induced clinical response 80% (4/5) -CD-TREAT induced clinical remission 60% (3/5) -CD-TREAT induced decrease in fecal calprotectin 4/5
Urlep et al. [97]	RCT	To compare clinical and endoscopic remission rates and mucosal healing	Pediatric CD PCDAI > 10	AID-CD + PEN (6 weeks) n = 12	EEN (6 weeks) n = 13	-AID-CD and EEN equally effective in inducing clinical and endoscopic remission -EEN had superior mucosal healing, although not significant

RCT: randomized controlled trial. CD: Crohn’s disease. EEN: exclusive enteral nutrition. CS: corticosteroids. HBI: Harvey Bradshaw Index. PCDAI: Pediatric Crohn’s Disease Activity Index. FCP: fecal calprotectin. MEN: maintenance enteral nutrition. EN: enteral nutrition PEN: partial enteral nutrition. CDED: Crohn’s disease exclusion diet. CD-TREAT: CD treatment with diet. AID-CD: anti-inflammatory diet–CD; sign.: significant. n: sample size. n.r.: not reported.