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Nutrients. 2016 June; 8(6): 334.
Published online 2016 June 1. doi:  10.3390/nu8060334
PMCID: PMC4924175

Nutrition in Pediatric Inflammatory Bowel Disease: From Etiology to Treatment. A Systematic Review

Abstract

Nutrition is involved in several aspects of pediatric inflammatory bowel disease (IBD), ranging from disease etiology to induction and maintenance of disease. With regards to etiology, there are pediatric data, mainly from case-control studies, which suggest that some dietary habits (for example consumption of animal protein, fatty foods, high sugar intake) may predispose patients to IBD onset. As for disease treatment, exclusive enteral nutrition (EEN) is an extensively studied, well established, and valid approach to the remission of pediatric Crohn’s disease (CD). Apart from EEN, several new nutritional approaches are emerging and have proved to be successful (specific carbohydrate diet and CD exclusion diet) but the available evidence is not strong enough to recommend this kind of intervention in clinical practice and new large experimental controlled studies are needed, especially in the pediatric population. Moreover, efforts are being made to identify foods with anti-inflammatory properties such as curcumin and long-chain polyunsaturated fatty acids n-3, which can possibly be effective in maintenance of disease. The present systematic review aims at reviewing the scientific literature on all aspects of nutrition in pediatric IBD, including the most recent advances on nutritional therapy.

Keywords: nutrition, inflammatory bowel disease, children, etiology, treatment

1. Introduction

Nutrition is involved in several aspects of pediatric inflammatory bowel disease (IBD), ranging from disease etiology to induction and maintenance of disease. The etiology of inflammatory bowel disease (IBD) is believed to be multifactorial, caused by an interplay of genetic, environmental, microbial, and immunological factors. Among the environmental risk factors, dietary elements have received considerable attention in recent years. Epidemiological studies have demonstrated a rising incidence of IBD in countries where the disease is more prevalent, such as Europe and North America, as well as in areas where IBD was previously thought to be uncommon [1]. This increase has occurred with the spread of the “Western” diet, which is high in fat and protein but low in fruit and vegetables [2,3]. Numerous studies, conducted mainly in adults, assessed whether there are associations between the development of IBD and diet and suggested that specific nutrients may play a role as risk factors or protective factors for the development of disease [3,4,5,6,7,8]. However, it must be noted that many of these studies rely on food frequency questionnaires, which have a poor accuracy due to recall bias. The hypothesis of dietary factors influencing gut inflammation may be explained through several biological mechanisms, including antigen presentation, change in prostaglandin balance, and alteration of the microflora [2,9]. Aside from etiology, nutrition plays a significant role in treatment of disease. Among the traditional nutritional approaches, exclusive enteral nutrition (EEN) is an extensively studied, well established, and valid approach to remission of pediatric Crohn’s disease (CD). The latter nutritional therapy presents several advantages including control of inflammatory changes, mucosal healing, positive benefits to growth and overall nutritional status, and avoidance of other medical therapies. Aside from EEN, recently several new nutritional approaches are emerging and have seemed to be successful. The present systematic review aims at reviewing the scientific literature on all aspects of nutrition in pediatric IBD, including the most recent advances in nutritional therapy.

2. Methods

A structured literature search was performed by two investigators (Francesca Penagini and Barbara Borsani) independently, in PubMed, EMBASE, and Medline starting from January 1982 up to April 2016 using the following keywords: “Pediatric Inflammatory Bowel Disease”, “Pediatric IBD”, “Inflammatory Bowel Disease in children”, “IBD in children” in any combination with “diet”, “dietary intakes”, “nutrition” and cross referenced with “etiology”, “induction of remission”, “relapse” and “treatment”. The search was limited to full-text papers in English and resulted in a total of 8229 articles. By screening titles and abstracts, studies performed in vitro, in animals, uncontrolled studies, case reports, and reviews were excluded. Duplicate studies were removed. Eligible papers were cross-checked for references, which resulted in two additional papers. Figure 1 shows the flow-chart of our systematic review. For randomized clinical trials the absolute risk change with exact 95% confidence intervals (CI) was calculated. For cohort studies, the incidence rates with exact 95% CI were calculated.

Figure 1
Flow-chart on the methods of the systematic review.

3. Nutrition in Etiology of Pediatric Inflammatory Bowel Disease

Data on diet as a risk factor for the onset of pediatric IBD are scarce. There are few studies in the literature apart from case-control studies, which have shown a potential role of some dietary elements as risk factors for disease onset in pediatric IBD. Nevertheless, these studies present methodological limitations such as the use of self-administered patient questionnaires, therefore recall bias. Table 1 summarizes the main studies on nutrition factors in etiology of pediatric IBD.

Table 1
Dietary factors and etiology in pediatric IBD. IBD = inflammatory bowel disease, UC = ulcerative colitis, CD = Crohn’s disease, LC = long chain.

The Japanese Epidemiology Group of the Research Committee of IBD conducted a multisite, hospital-based, case-control study to examine the environmental risk factors for UC in 101 patients who were 10–39 years old at the time of disease onset [10]. Information was obtained from self-administered patient questionnaires. Combined consumption of Western foods (bread for breakfast, butter, margarine, cheese, meats, and ham and sausage) was significantly related to an increased risk of UC Relative risk (RR) for low consumption of Western foods 1.0 (CI not available), for intermediate consumption RR = 1.9; 95% CI 1.0 to 3.7, for high consumption RR = 2.1; 95% CI 1.0 to 4.1, p = 0.04. Margarine (as an individual Western food item) was positively associated with UC (RR for low consumption: 1.0 (CI not available), for intermediate consumption RR = 1.2; 95% CI 0.6 to 2.4, for high consumption RR = 2.6; 95% CI 1.4 to 5.2; trend, p = 0.005. There was also a tendency towards positive association of bread for breakfast with UC. For low consumption RR = 1.0, for intermediate consumption RR = 0.7; 95% CI 0.4 to 1.4, for high consumption RR = 2.1; 95% CI 1.0 to 4.3, p = 0.07. The risk did not measurably vary with the consumption of typical Japanese foods, vegetables and fruits, confectioneries, or soft drinks (RR data not available) [10].

The group of Amre et al. [11] conducted a case-control study evaluating the pre-illness diet of new onset CD in Canadian children (age < 20 years, n = 103) using a validated food-frequency questionnaire (FFQ) in comparison to healthy controls matched for age and gender (n = 202). The FFQ was administered to the cases within one month of diagnosis and investigated dietary habits within the 12 months prior to disease diagnosis. Results showed negative associations with vegetables (OR = 0.69; 95% CI 0.33 to1.44, p = 0.03), fruits (OR = 0.49; 95% CI 0.25 to 0.96, p = 0.02), dietary fiber (OR = 0.12; 95%, CI 0.04 to 0.37, p < 0.001), and fish (OR 0,46, 95% CI 0.20–1.06, p = 0.02); consumption of long-chain ω-3 fatty acids was negatively associated with CD (OR = 0.44; 95%, CI 0.19 to 1.00, p < 0.001), whereas positive associations were evident for total fats (OR = 2.30; 95% CI 0.67 to 7.96, p = 0.15), monounsaturated (OR = 2.41; 95% CI 0.72 to 8.07, p = 0.08), and saturated (OR = 1.81; 95% CI 0.59 to 5.61, p = 0.40) fats, even though these associations were not statistically significant. The authors concluded that children who consumed higher amounts of fruits were at lower risk for CD (p = 0.02), as well as children who consumed higher amounts of fish and nuts, rich in long-chain ω-3 fatty acids such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) (OR = 0.44; 95% CI 0.19 to 1.0, p = 0.03). When the ratio of long chain ω-3/arachidonic acid was evaluated, a higher ratio was associated with a significantly reduced risk for CD (OR = 0.32; 95% CI 0.14 to 0.71, p = 0.02) [11]. In a similar case-control study, D’Souza et al. [12] investigated the role of specific dietary patterns in the risk for developing pediatric CD (n = 149, mean age at diagnosis 13.3 ± 2.6 years). They observed that dietary patterns characterized by meats, fatty foods, and desserts were positively associated with pediatric CD in both genders (OR = 4.7, 95% CI 1.6–14.2); on the contrary, dietary patterns characterized by vegetables, fruits, olive oil, fish, grains, and nuts were inversely associated with CD in both genders (girls OR = 0.3; 95% CI 0.1 to 0.9; boys OR = 0.2; 95% CI 0.1 to 0.5).

More recently, Jacobsen et al. [13] have investigated environmental risk factors for onset of IBD in children. The authors included 118 IBD patients aged < 15 years and 447 healthy controls. Risk factors were investigated by means of a questionnaire. Results showed that a high sugar intake was a risk factor for IBD (IBD OR = 2.5; 95% CI 1.0 to 6.2, CD OR = 2.9; 95% CI 1.0 to 8.5); while protective factors were daily vegetable consumption (CD OR = 0.3; 95% CI 0.1 to 1.0), UC OR = 0.3; 95% CI 0.1 to 0.8) and wholemeal bread consumption (IBD OR = 0.5; 95% CI 0.9 to 0.9), CD OR = 0.4; 95% 0.2 to 0.9) [13].

There are plausible biological mechanisms that can explain the abovementioned role of dietary factors in IBD pathogenesis. The n-3 polyunsaturated fatty acids (PUFAs) are present mainly in fish and can be synthesized in humans from alpha-linolenic acid, an essential fatty acid. EPA is a constituent of cell membranes and is metabolized to prostaglandin E3 and leukotriene B5, both of which are less pro-inflammatory than eicosanoids derived from n-6 PUFAs. A diet high in EPA may therefore protect the colonic mucosa against inflammation [7]. Plausible mechanisms exist to support the association between fiber intake and risk of CD. Anaerobic bacterial fermentation of undigested dietary carbohydrates and fiber polysaccharides produces short-chain fatty acids (SCAFs) like acetate, propionate, and butyrate, which are involved in the maintenance of colonic homeostasis. These molecules are utilized as fuel sources for colonocyte metabolism and seem to have an anti-inflammatory effect on epithelial cells, through inhibition of the production and release of inflammatory mediators. Consequently, a diet poor in fiber and lower in SCFAs may cause a disruption of the homeostasis between bacteria and colonocytes, leading to intestinal inflammation [16].

4. Nutrition in Induction of Remission in Pediatric Inflammatory Bowel Disease

The first reports on the successful use of enteral nutrition in induction of remission in pediatric CD date back to the 1980s [17,18]. Since then, exclusive enteral nutrition (EEN) with specific formulas has been thoroughly studied and has become a well-established nutritional approach shown to alleviate clinical symptoms, induce mucosal healing, improve nutritional status, and normalize laboratory parameters associated with active inflammation in pediatric CD. These data have been confirmed in two meta-analyses demonstrating that EEN is as effective as corticosteroids in inducing disease remission in pediatric CD [19,20], achieving normalization of inflammatory markers and clinical remission rates in >80% of subjects [21] irrespective of disease phenotype [22].

Studies on the efficacy of EEN in active CD are reported in Table 2, a comparison between two different nutritional regimens is given in Table 3, and studies comparing the efficacy of EEN on corticosteroids in active CD are reported in Table 4. As the included studies were significantly heterogeneous for study design, outcomes observed, and sample size, a meta-analysis was not performed.

Table 2
Clinical studies on efficacy of exclusive enteral nutrition in pediatric CD. CREN = constant rate enteral nutrition, PF = polymeric formula, ED = elemental diet, PCDAI = Pediatric Crohn Disease Activity Index, PEN = partial enteral nutrition, EEN = exclusive ...
Table 3
Clinical studies comparing efficacy between two enteral nutrition regimens. PCDAI = Pediatric Crohn’s Disease Activity Index, PF = polymeric formula, ED = elemental diet, PEN = partial enteral nutrition, EEN = exclusive enteral nutrition, IFX ...
Table 4
Clinical studies comparing exclusive enteral nutrition to corticosteroids. PCDAI = Pediatric Crohn’s Disease Activity Index, ED = elemental diet, PEN = partial enteral nutrition, CS = corticosteroids, EEN = exclusive enteral nutrition, IFX = infliximab, ...

More recently, novel nutritional approaches have been proposed and their efficacy has been proved in case series and dietary intervention studies [48,49,50,51]. Table 5 summarizes the main studies on the novel nutritional approaches for induction of remission in pediatric IBD. Among the novel approaches, the specific carbohydrate diet (SCD) has gained attention. It restricts complex carbohydrates and eliminates refined sugar from the diet, based on the rationale that the sugars and complex carbohydrates are malabsorbed and could cause alterations in microbiome composition, contributing to the intestinal inflammation of IBD. The clinical efficacy in inducing remission of symptoms and improvement of laboratory parameters has been demonstrated by reviewing medical records and in a prospective trial. Suskind et al. [49] reviewed medical records of children and adolescents with CD (n = 10) aged 7–16 years, treated with the SCD for a period of 5–30 months. Symptoms of all patients were resolved at a routine clinic visit three months after initiating the diet. Laboratory indices and fecal calprotectin either normalized or significantly improved at the follow-up clinic visits. It must be noted that the study was retrospective, hence the observed events (improvement of symptoms, laboratory parameters, and fecal calprotectin) could be due to chance. Cohen et al. conducted a trial evaluating clinical improvement and mucosal healing in children and adolescents with active CD, (mean age 13.6 years (n = 9)) after a 12–52 week trial of a SCD. The study showed at both the 12-week endpoint and the 52-week extension period clinical improvement assessed by PCDAI. In 6/10 patients (60%) remission was achieved by week 12. Mucosal healing (Lewis score < 135) was observed in 40% (4/10) of patients at week 12, 80% of patients showed significant mucosal improvement at week 12 when compared to baseline (p = 0.012) [50]. Aside from SCD, another novel dietary intervention has been proposed and studied in a prospective randomized trial by Sigall-Boneh et al. [51]. The new approach consists of 50% caloric intake with an exclusion diet specific for CD and 50% intake with a polymeric formula for a period of six weeks. The authors studied children and young adults (n = 47, 34 children) with active CD and with a mean age of 16.1 ± 5.6 years. The specific CD diet excludes many types of foods, including dairy products, margarine, gluten-containing cereals, smoked products (meat and fish), maize and potato flour, sauces, snacks, fruit juices, chocolate, coffee, and alcohol. Response and remission was obtained in 37 (78.7%) and 33 (70.2%), patients, respectively. Remission was obtained in 70% of children and 69% of adults.

Table 5
Novel nutritional approaches for induction of remission in pediatric IBD. SCD = Specific Carbohydrate Diet. CD = Crohn’s Disease, PEN = partial enteral nutrition, PCDAI = Pediatric Crohn’s Disease Activity Index, IR = incidence rate.

The effect of a cow’s milk protein (CMP) elimination diet on the induction and maintenance of remission in children with ulcerative colitis (UC) has been assessed in a randomized controlled trial by Strisciuglio et al. [52]. The authors randomized children to receive a CMP elimination diet or a free diet associated with concomitant steroid induction and mesalazine maintenance treatment. No significant differences were noted between the two groups in frequency of induction of remission and frequency of relapse.

5. Nutrition in Maintenance of Remission in Pediatric IBD

Exclusive Enteral Nutrition (EEN) is recommended as first line therapy to induce remission in pediatric CD [53], but only few studies analyzed the effect of dietary intervention for IBD maintenance of remission. New approaches recently proposed consider the elimination of foods thought to be noxious, through exclusion diets, or the supplementation of anti-inflammatory substances. Some data show that maintenance enteral nutrition (MEN) could reduce relapse rates. Table 6 summarizes the main studies focusing on enteral nutrition in maintenance of disease remission in pediatric IBD. In a study of Belli et al. [54], a small group of children continued intermittent EEN via nasogastric tube (NT) for one month out of four over the course of one year, showing improvement in CD clinical activity and growth [2]. Recently, in a retrospective study, Duncan et al. [55] analyzed 59 children with newly diagnosed CD, showing that the remission rate at one year was significantly higher in patients continuing MEN 60% (9/15), compared to 15% (2/13) in patients taking no treatment (p = 0.001) and with patients taking azathioprine (p = 0.14). Referring to Partial Enteral Nutrition (PEN), data about maintenance of remission in pediatric IBD are scarce. Evidences from adult population suggest that this kind of treatment could reduce the risk of relapse and improve the response to biological drugs [55,56,57,58,59,60]. A report of Wilschanski et al. [61] studied the effect of providing supplementary enteral nutrition, in addition to normal diet, in children and adolescents affected by CD after induction of remission with EEN. The study demonstrated fewer relapses and improvements of linear growth in children who continued supplementary feeding respect to control group [61]. Considering new nutritional interventions, a lacto-ovo vegetarian diet, also called a semi-vegetarian diet (SVD), has been evaluated in a prospective study on patients affected by CD, showing a significant effect on relapse prevention compared to an omnivorous diet (remission rate at two years 94% (15/16) for SVD vs. 33% (2/6), p = 0.0003) [62]. Another kind of exclusion diet has been attempted by Obih et al. [63] in a retrospective study including pediatric patients affected by CD or UC. A group of children followed the Specific Carbohydrate Diet (SCD) for a period between three and 48 months (mean of 9.6 ± 0.1 months); some of the patients were treated in conjunction with medical therapy, while the second group was treated only with standard medical therapy. The SCD group showed improvement of clinical and inflammatory markers, but the compliance to SCD was often poor and some of the patients who followed the SCD experienced weight loss [63].

Table 6
Nutrition in maintenance of disease remission. ED = elemental diet, MEN = maintenance enteral nutrition, EEN = exclusive enteral nutrition, SCD = specific carbohydrate diet, CRP = C-reactive protein, BMI = body mass index, 5-ASA = 5-aminosalycilates, ...

Beyond nutritional therapy for maintenance of remission through exclusion diets, efforts are being made to evaluate the possible efficacy of supplementation of anti-inflammatory substances. One of the most studied is diferuloymethane, also known as curcumin. It is the most important component of the plant Curcuma longa or turmeric, belonging to the family Zingiberaceae. This kind of plant is typical of India, China, and Sri Lanka [64]. It is used in Indian and Chinese traditional medicine and it appears to have many properties such as anti-inflammatory, antioxidant, anti-tumor, antiplatelet, antibacterial, and antifungal effects [65,66]. Pathogenic mechanisms that explain all the curcumin properties are complex and partially known, but evidences suggest that the modulation of the NF-kB pathway has a pivotal role [67].The therapeutic use of curcumin is limited by its unfavorable pharmacokinetics, but oral administration of the drug reaches active levels in the gastrointestinal tract, so this natural substance could be useful for treating gut diseases [68]. Recent studies demonstrate that curcumin may be used as an adjunctive therapy for maintenance of remission in IBD, in particular in UC. Hanai et al. [69] evaluated the efficacy of curcumin as additional therapy for maintenance of remission in patients between 13 and 65 years with quiescent UC and consuming mesalazine or sulfasalazine. In this randomized, multicenter, double-blind, placebo-controlled trial, a group of patients receiving 2 g curcumin per day for six months has been compared with a group treated with a placebo. During the study period, relapses were lower in patients taking curcumin than in the placebo group (2/43 (4.65%) in curcumin group vs. 8/39 (20.51%) in placebo group, p = 0.049). Moreover, the authors noted improvements in the Clinical Activity Index (CAI) and the Endoscopic Index (EI) (secondary pre-specified outcomes) in patients receiving curcumin (CAI, p = 0.038 and EI, p = 0.0001) [69]. Finally, this natural anti-inflammatory agent seems to have high tolerability, without severe adverse effects in the pediatric population. The average intake of curcumin in countries where it is traditionally used in the diet, such as in India, is approximately 60–100 mg of curcumin daily in an adult individual [70]. Suskind et al. [71] enrolled 11 patients between 11 and 18 years affected by CD or UC in a tolerability study. During the trial, the curcumin dose was gradually increased from 500 mg twice a day to 2 g twice a day and continued for three weeks, without significant side effects [71].

Great interest has also been shown in n-3 PUFAs and their pleiotropic effects. The longer chain n-3 PUFAs, represented by EPA, DHA, and DPA, are mainly contained in fish oil and have numerous properties such as anti-inflammatory, anti-thrombotic, anti-arrhythmic, hypolipidemic, and vasodilatory activity [72,73]. Their anti-inflammatory effect, especially, seems to be due to n-3’s role in the arachidonic acid pathway and the subsequent downregulation of proinflammatory cytokine synthesis, decreased leukocyte chemotaxis, and decreased T cell reactivity [74,75]. During the last decades, the idea that an n-3 rich diet could have positive effects in patients affected by IBD has been evaluated in numerous studies, particularly in the adult population, with conflicting results [76,77,78]. Meister et al. have studied in vitro the influence of a fish oil enriched enteral diet on intestinal tissues taken from CD, UC, and non-IBD control patients, showing that the anti-inflammatory effect of fish oil is significantly more marked in UC compared with CD [79]. Some evidence has shown clinical improvement after supplementation of n-3; however the most robust evidence is from two randomized double-blind, placebo-controlled studies on large adult populations affected by CD; these have not demonstrated any significant effects of n-3 supplementation in relapse prevention [80], and a recent Cochrane review has concluded that omega 3 fatty acids are probably ineffective for maintenance of remission in CD [81]. Concerning pediatric IBD, an Italian double-blind, randomized, placebo-controlled study showed a significant effect on reduction of relapse. The number of patients who relapsed at 12 months was significantly lower in the Omega-3 fatty acid group (group 1) compared to patients receiving a placebo (group 2) (relapse rate group 1 11/18 (61%), group 2 19/20 (95%); p < 0.001 [82]. In conclusion, although Omega-3 appears to be safe, except for mild gastrointestinal tract symptoms (diarrhea, unpleasant taste, bad breath, heartburn, and nausea), further studies are needed to confirm the real efficacy of n-3 for IBD treatment in pediatric population. Table 4 summarizes the main pediatric studies on nutrition in maintenance of disease remission.

6. Health Benefits of Nutritional Therapy in Pediatric IBD

With respect to adult forms, pediatric IBD have specific features, not only for severity and extension, but also because the disease involves growing individuals, with possible irreversible consequences in adult life. Weight loss and failure to thrive, delayed puberty, and low bone mineral density are frequent signs in children affected by IBD, in particular in CD, because of malabsorption and malnutrition. The etiology of poor nutritional status in children affected by IBD is complex and involves reduced dietary intake, increased gastrointestinal nutrient losses, increased energy requests due to inflammation, and altered metabolism [83,84]. Moreover, the linear growth and nutritional status of children affected by IBD are also compromised by immunosuppressant drugs, especially corticosteroids, used for the treatment of the disease [85]. All these reasons justify the particular importance of nutritional therapy in pediatric IBD. EEN is at least as efficacious as corticosteroids in inducing remission in pediatric CD, but it has minimal side effects and several advantages in terms of mucosal healing, restoration of nutritional status, bone health, and liner growth in children [53]. Multiple studies demonstrate that, with respect to conventional immunosuppressant drugs, nutritional therapy improves weight gain, height velocity, body composition, and insulin-like growth factor (IGF)-1 and IGF binding protein 3 (IGFBP-3) [18,54,61,86,87,88,89,90]. Table 5 illustrates the main studies on the health benefits of nutritional therapy in pediatric IBD. Berni Canani et al. [44], in a retrospective study on 47 children with active CD, compared the effect of EEN versus corticosteroid therapy. Children treated with EEN for eight weeks showed higher serum iron and albumin levels, and more pronounced linear growth than group treated with corticosteroids [44]. Moreover, bone health seems to benefit from nutritional therapy too. The pathogenesis of bone loss in pediatric IBD is complex: malnutrition, compromised linear growth, lean mass deficit, delayed puberty, menstrual irregularity, reduced physical activity, persistent inflammation, and prolonged use of corticoids are the major factors responsible [91,92,93]. Although the direct effect of EEN in increasing bone mineral density (BMD) has been poorly studied, Whitten et al. demonstrated that the normalization of bone turnover markers in children was affected by CD after eight weeks of treatment with EEN [6]. In addition, in the latest clinical guidelines about skeletal health issued by ESPGHAN and NASPGHAN, the authors affirm the benefits of enteral nutrition. In terms of linear growth and lean mass, EEN or supplemental enteral nutrition could induce improvement of bone health, and they recommend these tactics not only during the acute phase, but also during remission phases of IBD, particularly in children and adolescents with delayed linear growth [7]. Table 7 shows the main studies on the health benefits of nutritional therapy in pediatric IBD.

Table 7
Health benefits of nutritional therapy in pediatric IBD. ED = elemental diet, REE = resting energy expenditure, IGF-1 = insulin like growth factor 1, IGFBP-3 = insulin like growth factor binding protein, EEN = exclusive enteral nutrition, corticosteroids ...

7. Strengths and Limitations

The main strength of the present systematic review is the rigorous methodological assessment and analysis of the literature using pre-specified criteria. The methods we used helped to reduce the risk of bias (thorough literature research performed by two researchers independently and duplicate data abstraction). Nevertheless, some limitations should be pointed out. In the first instance, the methodological quality of included trials was not high and some trials had small sample sizes. Moreover, a significant limitation lies in the lack of standardization of outcome measures, clinical heterogeneity of subjects enrolled, variation in the length of follow-up and in the duration of interventions, and the use of concomitant medications.

8. Conclusions

Nutrition has a significant role in pediatric IBD. With regards to etiology, the available pediatric data suggest that dietary patterns characterized by consumption of meats, fatty foods, desserts, and a high sugar intake are associated with an increased risk of disease. Likely protective factors are represented by consumption of vegetables, fruits, fish, olive oil, and wholemeal bread. Large scale randomized controlled clinical trials are needed to confirm these data.

For treatment of disease, EEN is the only nutritional approach with robust evidence of effectiveness in induction of remission; PEN is known to be advantageous in reducing relapse rates. Besides the known elemental, semi-elemental, and polymeric formulas, the scientific community is currently looking into modifying dietary habits to maintain disease remission mainly through exclusion diets: the Specific Carbohydrate Diet and the Crohn’s Disease exclusion diet are now in the spotlight. Nevertheless, the poor compliance to nutritional intervention and the risk of nutritional deficits when exclusion diets are too strict are factors that have to be considered when these kinds of treatments are proposed. Despite the promising results of the novel nutritional approaches, the available data are not strong enough to recommend these interventions in clinical practice and new large controlled studies are needed, especially in pediatric population, to confirm these data.

Acknowledgments

This systematic review would not have been possible without the excellent collaboration of all the participants. We would like to thank Barbara Borsani, Lucia Cococcioni, Erica Galli for the effort in the literature research, selection of manuscripts, interpretation of results and writing of our systematic review. We would like to thank Giorgio Bedogni for his fundamental help for the statistical analyses. We would like to thank Dario Dilillo, Giovanna Zuin and Gian Vincenzo Zuccotti for their involvement in the study coordination and for mentoring us during the preparation of the manuscript.

Author Contributions

Author Contributions

All authors actively contributed to the conceptual development of this review paper. All authors have primary responsibility for the final content.

Conflicts of Interest

Conflicts of Interest

The authors have no conflicts of interest to declare.

References

1. Thia K.T., Loftus E.V., Jr., Sandborn W.J., Yang S.K. An update on the epidemiology of inflammatory bowel disease in Asia. Am. J. Gastroenterol. 2008;103:3167–3182. doi: 10.1111/j.1572-0241.2008.02158.x. [PubMed] [Cross Ref]
2. Hou J.K., Abraham B., El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: A systematic review of the literature. Am. J. Gastroenterol. 2011;106:563–573. doi: 10.1038/ajg.2011.44. [PubMed] [Cross Ref]
3. Ananthakrishnan A.N., Khalili H., Konijeti G.G., Higuchi L.M., de Silva P., Fuchs C.S., Willett W.C., Richter J.M., Chan A.T. Long term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut. 2014;63:776–784. doi: 10.1136/gutjnl-2013-305304. [PMC free article] [PubMed] [Cross Ref]
4. Jantchou P., Morois S., Clavel-Chapelon F., Boutron-Ruault M.C., Carbonnel F. Animal protein intake and risk of inflammatory bowel disease: The E3N prospective study. Am. J. Gastroenterol. 2010;105:2195–2201. doi: 10.1038/ajg.2010.192. [PubMed] [Cross Ref]
5. Tjonneland A., Overvad K., Bergmann M.M., Nagel G., Linseisen J., Hallmans G., Palmqvist R., Sjodin H., Hagglund G., Berglund G., et al. IBD in EPIC Study Investigators. Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: A nested case-control study within a European prospective cohort study. Gut. 2009;58:1606–1611. [PubMed]
6. De Silva P.S., Luben R., Shrestha S.S., Khaw K.T., Hart A.R. Dietary arachidonic and oleic acid intake in ulcerative colitis etiology: A prospective cohort study using 7-day food diaries. Eur. J. Gastroenterol. Hepatol. 2014;26:11–18. doi: 10.1097/MEG.0b013e328365c372. [PubMed] [Cross Ref]
7. John S., Luben R., Shrestha S.S., Welch A., Khaw K.T., Hart A.R. Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: A UK prospective cohort study. Eur. J. Gastroenterol. Hepatol. 2010;22:602–606. doi: 10.1097/MEG.0b013e3283352d05. [PubMed] [Cross Ref]
8. Ananthakrishnan A.N., Khalili H., Konijeti G.G., Higuchi L.M., de Silva P., Korzenik J.R., Fuchs C.S., Willett W.C., Richter J.M., Chan A.T. A prospective study of long term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology. 2013;145:970–977. doi: 10.1053/j.gastro.2013.07.050. [PMC free article] [PubMed] [Cross Ref]
9. Lee D., Albenberg L., Compher C., Baldassano R., Piccoli D., Lewis J.D., Wu G.D. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology. 2015;148:1087–1106. doi: 10.1053/j.gastro.2015.01.007. [PMC free article] [PubMed] [Cross Ref]
10. Epidemiology Group of the Research Committee of Inflammatory Bowel Disease in Japan Dietary and other risk factors of ulcerative colitis. A case-control study in Japan. J. Clin. Gastroenterol. 1994;19:166–171. [PubMed]
11. Amre D.K., D’Souza S., Morgan K., Seidman G., Lambrette P., Grimard G., Israel D., Mack D., Ghadirian P., Deslandres C., et al. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn’s disease in children. Am. J. Gastroenterol. 2007;102:2016–2025. doi: 10.1111/j.1572-0241.2007.01411.x. [PubMed] [Cross Ref]
12. D’Souza S., Levy E., Mack D., Israel D., Lambrette P., Ghadirian P., Deslandres C., Morgan K., Seidman E.G., Amre D.K. Dietary patterns and risk for Crohn’s disease in children. Inflamm. Bowel Dis. 2008;14:367–373. doi: 10.1002/ibd.20333. [PubMed] [Cross Ref]
13. Jakobsen C., Paerregaard A., Munkholm P., Wewer V. Environmental factors and risk of developing paediatric inflammatory bowel disease—A population based study 2007–2009. J. Crohn’s Colitis. 2013;7:79–88. doi: 10.1016/j.crohns.2012.05.024. [PubMed] [Cross Ref]
14. Gilat T., Hacohen D., Lilos P., Langman M.J. Childhood factors in ulcerative colitis and Crohn’s disease. An international cooperative study. Scand. J. Gastroenterol. 1987;22:1009–1024. doi: 10.3109/00365528708991950. [PubMed] [Cross Ref]
15. Baron S., Turck D., Leplat C., Merle V., Gower-Rousseau C., Marti R., Yzet T., Lerebours E., Dupas J.L., Debeugny S., et al. Environmental risk factors in paediatric inflammatory bowel diseases: A population based case control study. Gut. 2005;54:357–363. doi: 10.1136/gut.2004.054353. [PMC free article] [PubMed] [Cross Ref]
16. Galvez J., Rodríguez-Cabezas M.E., Zarzuelo A. Effects of dietary fiber on inflammatory bowel disease. Mol. Nutr. Food Res. 2005;49:601–608. doi: 10.1002/mnfr.200500013. [PubMed] [Cross Ref]
17. Navarro J., Vargas J., Cezard J.P., Charritat J.L., Polonovski C. Prolonged constant rate elemental enteral nutrition in Crohn’s disease. J. Pediatr. Gastroenterol. Nutr. 1982;1:541–546. doi: 10.1097/00005176-198212000-00015. [PubMed] [Cross Ref]
18. Sanderson I.R., Udeen S., Davies P.S., Savage M.O., Walker-Smith J.A. Remission induced by an elemental diet in small bowel Crohn’s disease. Arch. Dis. Child. 1987;62:123–127. doi: 10.1136/adc.62.2.123. [PMC free article] [PubMed] [Cross Ref]
19. Heuschkel R.B., Menache C.C., Megerian J.T., Baird A.E. Enteral nutrition and corticosteroids in the treatment of acute Crohn’s disease in children. J. Pediatr. Gastroenterol. Nutr. 2000;31:8–15. doi: 10.1097/00005176-200007000-00005. [PubMed] [Cross Ref]
20. Dziechciarz P., Horvath A., Shamir R., Szajewska H. Meta-analysis: enteral nutrition in active Crohn’s disease in children. Aliment. Pharmacol. Ther. 2007;26:795–806. doi: 10.1111/j.1365-2036.2007.03431.x. [PubMed] [Cross Ref]
21. Zachos M., Tondeur M., Griffiths A.M. Enteral nutritional therapy for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev. 2007;1:CD000542. doi: 10.1002/14651858.CD000542.pub2. [PubMed] [Cross Ref]
22. Buchanan E., Gaunt W.W., Cardigan T., Garrick V., McGrogan P., Russell R.K. The use of exclusive enteral nutrition for induction of remission in children with Crohn’s disease demonstrates that disease phenotype does not influence clinical remission. Aliment. Pharmacol. Ther. 2009;30:501–507. doi: 10.1111/j.1365-2036.2009.04067.x. [PubMed] [Cross Ref]
23. Fell J.M., Paintin M., Arnaud-Battandier F., Beattie R.M., Hollis A., Kitching P., Donnet-Hughes A., MacDonald T.T., Walker-Smith J.A. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn’s disease. Aliment. Pharmacol. Ther. 2000;14:281–289. doi: 10.1046/j.1365-2036.2000.00707.x. [PubMed] [Cross Ref]
24. Afzal N.A., Van Der Zaag-Loonen H.J., Arnaud-Battandier F., Davies S., Murch S., Derkx B., Heuschkel R., Fell J.M. Improvement in quality of life of children with acute Crohn’s disease does not parallel mucosal healing after treatment with exclusive enteral nutrition. Aliment. Pharmacol. Ther. 2004;20:167–172. doi: 10.1111/j.1365-2036.2004.02002.x. [PubMed] [Cross Ref]
25. Bannerjee K., Camacho-Hübner C., Babinska K., Dryhurst K.M., Edwards R., Savage M.O., Sanderson I.R., Croft N.M. Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease. J. Pediatr. Gastroenterol. Nutr. 2004;38:270–275. doi: 10.1097/00005176-200403000-00007. [PubMed] [Cross Ref]
26. Gavin J., Anderson C.E., Bremner A.R., Beattie R.M. Energy intakes of children with Crohn’s disease treated with enteral nutrition as primary therapy. J. Hum. Nutr. Diet. 2005;18:337–342. doi: 10.1111/j.1365-277X.2005.00631.x. [PubMed] [Cross Ref]
27. Afzal N.A., Davies S., Paintin M., Arnaud-Battandier F., Walker-Smith J.A., Murch S., Heuschkel R., Fell J. Colonic Crohn’s disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved. Dig. Dis. Sci. 2005;50:1471–1475. doi: 10.1007/s10620-005-2864-6. [PubMed] [Cross Ref]
28. Knight C., El-Matary W., Spray C., Sandhu B.K. Long-term outcome of nutritional therapy in paediatric Crohn’s disease. Clin. Nutr. 2005;24:775–779. doi: 10.1016/j.clnu.2005.03.005. [PubMed] [Cross Ref]
29. Day A.S., Whitten K.E., Lemberg D.A., Clarkson C., Vitug-Sales M., Jackson R., Bohane T.D. Exclusive enteral feeding as primary therapy for Crohn’s disease in Australian children and adolescents: A feasible and effective approach. J. Gastroenterol. Hepatol. 2006;21:1609–1614. doi: 10.1111/j.1440-1746.2006.04294.x. [PubMed] [Cross Ref]
30. De Bie C., Kindermann A., Escher J. Use of exclusive enteral nutrition in paediatric Crohn’s disease in The Netherlands. J. Crohns Colitis. 2013;7:263–270. doi: 10.1016/j.crohns.2012.07.001. [PubMed] [Cross Ref]
31. Grover Z., Burgess C., Muir R., Reilly C., Lewindon P.J. Early Mucosal Healing with Exclusive Enteral Nutrition is Associated with Improved Outcomes in Newly Diagnosed Children with Luminal Crohn’s disease. J. Crohn’s Colitis. 2016:1–6. doi: 10.1093/ecco-jcc/jjw075. [PubMed] [Cross Ref]
32. Akobeng A.K., Miller V., Stanton J., Elbadri A.M., Thomas A.G. Double-blind randomized controlled trial of glutamine-enriched polymeric diet in the treatment of active Crohn’s disease. J. Pediatr. Gastroenterol. Nutr. 2000;30:78–84. doi: 10.1097/00005176-200001000-00022. [PubMed] [Cross Ref]
33. Ludvigsson J.F., Krantz M., Bodin L., Stenhammar L., Lindquist B. Elemental versus polymeric enteral nutrition in paediatric Crohn’s disease: A multicentre randomized controlled trial. Acta Paediatr. 2004;93:327–335. doi: 10.1111/j.1651-2227.2004.tb02956.x. [PubMed] [Cross Ref]
34. Johnson T., Macdonald S., Hill S.M., Thomas A., Murphy M.S. Treatment of active Crohn’s disease in children using partial enteral nutrition with liquid formula: A randomised controlled trial. Gut. 2006;55:356–361. doi: 10.1136/gut.2004.062554. [PMC free article] [PubMed] [Cross Ref]
35. Rodrigues A.F., Johnson T., Davies P., Murphy M.S. Does polymeric formula improve adherence to liquid diet therapy in children with active Crohn’s disease? Arch. Dis. Child. 2007;92:767–770. doi: 10.1136/adc.2006.103416. [PMC free article] [PubMed] [Cross Ref]
36. Hartman C., Berkowitz D., Weiss B., Shaoul R., Levine A., Adiv O.E., Shapira R., Fradkin A., Wilschanski M., Tamir A., et al. Nutritional supplementation with polymeric diet enriched with transforming growth factor-beta 2 for children with Crohn’s disease. Isr. Med. Assoc. J. 2008;10:503–507. [PubMed]
37. Rubio A., Pigneur B., Garnier-Lengliné H., Talbotec C., Schmitz J., Canioni D., Goulet O., Ruemmele F.M. The efficacy of exclusive nutritional therapy in paediatric Crohn’s disease, comparing fractionated oral vs. continuous enteral feeding. Aliment. Pharmacol. Ther. 2011;33:1332–1339. doi: 10.1111/j.1365-2036.2011.04662.x. [PubMed] [Cross Ref]
38. Grogan J.L., Casson D.H., Terry A., Burdge G.C., El-Matary W., Dalzell A.M. Enteral feeding therapy for newly diagnosed pediatric Crohn’s disease: A double-blind randomized controlled trial with two years follow-up. Inflamm. Bowel Dis. 2012;18:246–253. doi: 10.1002/ibd.21690. [PubMed] [Cross Ref]
39. Lee D., Baldassano R.N., Otley A.R., Albenberg L., Griffiths A.M., Compher C., Chen E.Z., Li H., Gilroy E., Nessel L., et al. Comparative Effectiveness of Nutritional and Biological Therapy in North American Children with Active Crohn’s Disease. Inflamm. Bowel Dis. 2015;21:1786–1793. doi: 10.1097/MIB.0000000000000426. [PubMed] [Cross Ref]
40. Thomas A.G., Taylor F., Miller V. Dietary intake and nutritional treatment in childhood Crohn’s disease. J. Pediatr. Gastroenterol. Nutr. 1993;17:75–78. doi: 10.1097/00005176-199307000-00011. [PubMed] [Cross Ref]
41. Ruuska T., Savilahti E., Mäki M., Ormälä T., Visakorpi J.K. Exclusive whole protein enteral diet versus prednisolone in the treatment of acute Crohn’s disease in children. J. Pediatr. Gastroenterol. Nutr. 1994;19:175–180. doi: 10.1097/00005176-199408000-00006. [PubMed] [Cross Ref]
42. Terrin G., Canani R.B., Ambrosini A., Viola F., De Mesquita M.B., Di Nardo G., Dito L., Cucchiara S. A semielemental diet (Pregomin) as primary therapy for inducing remission in children with active Crohn’s disease. Ital. J. Pediatr. 2002;28:401–405.
43. Borrelli O., Cordischi L., Cirulli M., Paganelli M., Labalestra V., Uccini S., Russo P.M., Cucchiara S. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn’s disease: A randomized controlled open-label trial. Clin. Gastroenterol. Hepatol. 2006;4:744–753. doi: 10.1016/j.cgh.2006.03.010. [PubMed] [Cross Ref]
44. Berni Canani R., Terrin G., Borrelli O., Romano M.T., Manguso F., Coruzzo A., D’Armiento F., Romeo E.F., Cucchiara S. Short- and long-term therapeutic efficacy of nutritional therapy and corticosteroids in paediatric Crohn’s disease. Dig. Liver. Dis. 2006;38:381–387. doi: 10.1016/j.dld.2005.10.005. [PubMed] [Cross Ref]
45. Soo J., Malik B.A., Turner J.M., Persad R., Wine E., Siminoski K., Huynh H.Q. Use of exclusive enteral nutrition is just as effective as corticosteroids in newly diagnosed pediatric Crohn’s disease. Dig. Dis. Sci. 2013;58:3584–3591. doi: 10.1007/s10620-013-2855-y. [PubMed] [Cross Ref]
46. Luo Y., Yu J., Zhao H., Lou J., Chen F., Peng K., Chen J. Short-Term Efficacy of Exclusive Enteral Nutrition in Pediatric Crohn’s Disease: Practice in China. Gastroenterol. Res. Pract. 2015;2015:428354. doi: 10.1155/2015/428354. [PMC free article] [PubMed] [Cross Ref]
47. Grover Z., Muir R., Lewindon P. Exclusive enteral nutrition induces early clinical, mucosal and transmural remission in paediatric Crohn’s disease. J. Gastroenterol. 2014;49:638–645. doi: 10.1007/s00535-013-0815-0. [PubMed] [Cross Ref]
48. Gupta K., Noble A., Kachelries K.E., Albenberg L., Kelsen J.R., Grossman A.B., Baldassano R.N. A novel enteral nutrition protocol for the treatment of pediatric Crohn’s disease. Inflamm. Bowel Dis. 2013;19:1374–1378. doi: 10.1097/MIB.0b013e318281321b. [PubMed] [Cross Ref]
49. Suskind D.L., Wahbeh G., Gregory N., Vendettuoli H., Christie D. Nutritional therapy in pediatric Crohn disease: The specific carbohydrate diet. J. Pediatr. Gastroenterol. Nutr. 2014;58:87–91. doi: 10.1097/MPG.0000000000000103. [PubMed] [Cross Ref]
50. Cohen S.A., Gold B.D., Oliva S., Lewis J., Stallworth A., Koch B., Eshee L., Mason D. Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. J. Pediatr. Gastroenterol. Nutr. 2014;59:516–521. doi: 10.1097/MPG.0000000000000449. [PubMed] [Cross Ref]
51. Sigall-Boneh R., Pfeffer-Gik T., Segal L., Zangen T., Boaz M., Levine A. Partial enteral nutrition with a Crohn’s disease exclusion diet is effective for induction of remission in children and young adults with Crohn’s disease. Inflamm. Bowel Dis. 2014;20:1353–1360. doi: 10.1097/MIB.0000000000000110. [PubMed] [Cross Ref]
52. Strisciuglio C., Giannetti E., Martinelli M., Sciorio E., Staiano A., Miele E. Does cow’s milk protein elimination diet have a role on induction and maintenance of remission in children with ulcerative colitis? Acta Paediatr. 2013;102:e273–e278. doi: 10.1111/apa.12215. [PubMed] [Cross Ref]
53. Ruemmele F.M., Veres G., Kolho K.L., Griffiths A., Levine A., Escher J.C., Amil Dias J., Barabino A., Braegger C.P., Bronsky J., et al. Consensus guidelines of ecco/espghan on the medical management of pediatric Crohn’s disease. J. Crohn’s Colitis. 2014;8:1179–1207. doi: 10.1016/j.crohns.2014.04.005. [PubMed] [Cross Ref]
54. Belli D.C., Seidman E., Bouthillier L., Weber A.M., Roy C.C., Pletincx M., Beaulieu M., Morin C.L. Chronic intermittent elemental diet improves growth failure in children with Crohn’s disease. Gastroenterology. 1988;94:603–610. [PubMed]
55. Duncan H., Buchanan E., Cardigan T., Garrick V., Curtis L., McGrogan P., Barclay A., Russell R.K. A retrospective study showing maintenance treatment options for paediatric CD in the first year following diagnosis after induction of remission with EEN: Supplemental enteral nutrition is better than nothing! BMC Gastroenterol. 2014;14:334 doi: 10.1186/1471-230X-14-50. [PMC free article] [PubMed] [Cross Ref]
56. Takagi S., Utsunomiya K., Kuriyama S., Yokoyama H., Takahashi S., Iwabuchi M., Takahashi H., Takahashi S., Kinouchi Y., Hiwatashi N., et al. Effectiveness of an ‘half elemental diet’ as maintenance therapy for Crohn’s disease: A randomized-controlled trial. Aliment. Pharmacol. Ther. 2006;24:1333–1340. doi: 10.1111/j.1365-2036.2006.03120.x. [PubMed] [Cross Ref]
57. Yamamoto T., Nakahigashi M., Umegae S., Kitagawa T., Matsumoto K. Impact of long-term enteral nutrition on clinical and endoscopic recurrence after resection for Crohn’s disease: A prospective, non-randomized, parallel, controlled study. Aliment. Pharmacol. Ther. 2007;25:67–72. doi: 10.1111/j.1365-2036.2006.03158.x. [PubMed] [Cross Ref]
58. Yamamoto T., Shiraki M., Nakahigashi M., Umegae S., Matsumoto K. Enteral nutrition to suppress postoperative Crohn’s disease recurrence: A five-year prospective cohort study. Int. J. Colorectal Dis. 2013;28:335–340. doi: 10.1007/s00384-012-1587-3. [PubMed] [Cross Ref]
59. Hirai F., Ishihara H., Yada S., Esaki M., Ohwan T., Nozaki R., Ashizuka S., Inatsu H., Ohi H., Aoyagi K., et al. Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn’s disease in adults. Dig. Dis. Sci. 2013;58:1329–1334. doi: 10.1007/s10620-012-2374-2. [PMC free article] [PubMed] [Cross Ref]
60. Yamamoto T., Nakahigashi M., Umegae S., Matsumoto K. Prospective clinical trial: Enteral nutrition during maintenance infliximab in Crohn’s disease. J. Gastroenterol. 2010;45:24–29. doi: 10.1007/s00535-009-0136-5. [PubMed] [Cross Ref]
61. Wilschanski M., Sherman P., Pencharz P., Davis L., Corey M., Griffiths A. Supplementary enteral nutrition maintains remission in paediatric Crohn’s disease. Gut. 1996;38:543–548. doi: 10.1136/gut.38.4.543. [PMC free article] [PubMed] [Cross Ref]
62. Chiba M., Abe T., Tsuda H., Sugawara T., Tsuda S., Tozawa H., Fujiwara K., Imai H. Lifestyle-related disease in Crohn’s disease: Relapse prevention by a semi-vegetarian diet. World J. Gastroenterol. 2010;16:2484–2495. doi: 10.3748/wjg.v16.i20.2484. [PMC free article] [PubMed] [Cross Ref]
63. Obih C., Wahbeh G., Lee D., Braly K., Giefer M., Shaffer M.L., Nielson H., Suskind D.L. Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic ibd center. Nutrition. 2015;32:418–425. doi: 10.1016/j.nut.2015.08.025. [PubMed] [Cross Ref]
64. Goel A., Kunnumakkara A.B., Aggarwal B.B. Curcumin as “curcumin”: From kitchen to clinic. Biochem. Pharmacol. 2008;75:787–809. doi: 10.1016/j.bcp.2007.08.016. [PubMed] [Cross Ref]
65. Basile V., Ferrari E., Lazzari S., Belluti S., Pignedoli F., Imbriano C. Curcumin derivatives: Molecular basis of their anti-cancer activity. Biochem. Pharmacol. 2009;78:1305–1315. doi: 10.1016/j.bcp.2009.06.105. [PubMed] [Cross Ref]
66. O’Sullivan-Coyne G., O’Sullivan G.C., O’Donovan T.R., Piwocka K., McKenna S.L. Curcumin induces apoptosis-independent death in oesophageal cancer cells. Br. J. Cancer. 2009;101:1585–1595. doi: 10.1038/sj.bjc.6605308. [PMC free article] [PubMed] [Cross Ref]
67. Lawrence T., Fong C. The resolution of inflammation: Anti-inflammatory roles for nf-kappab. Int. J. Biochem. Cell Biol. 2010;42:519–523. doi: 10.1016/j.biocel.2009.12.016. [PubMed] [Cross Ref]
68. Hanai H., Sugimoto K. Curcumin has bright prospects for the treatment of inflammatory bowel disease. Curr. Pharm. Des. 2009;15:2087–2094. doi: 10.2174/138161209788489177. [PubMed] [Cross Ref]
69. Hanai H., Iida T., Takeuchi K., Watanabe F., Maruyama Y., Andoh A., Tsujikawa T., Fujiyama Y., Mitsuyama K., Sata M., et al. Curcumin maintenance therapy for ulcerative colitis: Randomized, multicenter, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 2006;4:1502–1506. doi: 10.1016/j.cgh.2006.08.008. [PubMed] [Cross Ref]
70. Shah B.H., Nawaz Z., Pertani S.A., Roomi A., Mahmood H., Saeed S.A., Gilani A.H. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem. Pharmacol. 1999;58:1167–1172. doi: 10.1016/S0006-2952(99)00206-3. [PubMed] [Cross Ref]
71. Suskind D.L., Wahbeh G., Burpee T., Cohen M., Christie D., Weber W. Tolerability of curcumin in pediatric inflammatory bowel disease: A forced-dose titration study. J. Pediatr. Gastroenterol. Nutr. 2013;56:277–279. doi: 10.1097/MPG.0b013e318276977d. [PMC free article] [PubMed] [Cross Ref]
72. Akabas S.R., Deckelbaum R.J. Summary of a workshop on n-3 fatty acids: Current status of recommendations and future directions. Am. J. Clin. Nutr. 2006;83:1536S–1538S. [PubMed]
73. Ergas D., Eilat E., Mendlovic S., Sthoeger Z.M. N-3 fatty acids and the immune system in autoimmunity. Isr. Med. Assoc. J. 2002;4:34–38. [PubMed]
74. Calder P.C. N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am. J. Clin. Nutr. 2006;83:1505S–1519S. [PubMed]
75. Calder P.C. Fatty acids and immune function: Relevance to inflammatory bowel diseases. Int. Rev. Immunol. 2009;28:506–534. doi: 10.3109/08830180903197480. [PubMed] [Cross Ref]
76. Belluzzi A., Brignola C., Campieri M., Pera A., Boschi S., Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. N. Engl. J. Med. 1996;334:1557–1560. doi: 10.1056/NEJM199606133342401. [PubMed] [Cross Ref]
77. Lorenz-Meyer H., Bauer P., Nicolay C., Schulz B., Purrmann J., Fleig W.E., Scheurlen C., Koop I., Pudel V., Carr L. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn’s disease. A randomized controlled multicenter trial. Study group members (german Crohn’s disease study group) Scand. J. Gastroenterol. 1996;31:778–785. doi: 10.3109/00365529609010352. [PubMed] [Cross Ref]
78. Seidner D.L., Lashner B.A., Brzezinski A., Banks P.L., Goldblum J., Fiocchi C., Katz J., Lichtenstein G.R., Anton P.A., Kam L.Y., et al. An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: A randomized, controlled trial. Clin. Gastroenterol. Hepatol. 2005;3:358–369. doi: 10.1016/S1542-3565(04)00672-X. [PubMed] [Cross Ref]
79. Meister D., Ghosh S. Effect of fish oil enriched enteral diet on inflammatory bowel disease tissues in organ culture: Differential effects on ulcerative colitis and Crohn’s disease. World J. Gastroenterol. 2005;11:7466–7472. doi: 10.3748/wjg.v11.i47.7466. [PMC free article] [PubMed] [Cross Ref]
80. Feagan B.G., Sandborn W.J., Mittmann U., Bar-Meir S., D’Haens G., Bradette M., Cohen A., Dallaire C., Ponich T.P., McDonald J.W., et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: The epic randomized controlled trials. J. Am. Med. Assoc. 2008;299:1690–1697. doi: 10.1001/jama.299.14.1690. [PubMed] [Cross Ref]
81. Lev-Tzion R., Griffiths A.M., Leder O., Turner D. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease. Cochrane Database Syst. Rev. 2014;2:CD006320. doi: 10.1002/14651858.CD006320.pub4. [PubMed] [Cross Ref]
82. Romano C., Cucchiara S., Barabino A., Annese V., Sferlazzas C. Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn’s disease: A double-blind, randomized, placebo-controlled study. World J. Gastroenterol. 2005;11:7118–7121. doi: 10.3748/wjg.v11.i45.7118. [PMC free article] [PubMed] [Cross Ref]
83. Azcue M., Rashid M., Griffiths A., Pencharz P.B. Energy expenditure and body composition in children with Crohn’s disease: Effect of enteral nutrition and treatment with prednisolone. Gut. 1997;41:203–208. doi: 10.1136/gut.41.2.203. [PMC free article] [PubMed] [Cross Ref]
84. Bannerman E., Davidson I., Conway C., Culley D., Aldhous M.C., Ghosh S. Altered subjective appetite parameters in Crohn’s disease patients. Clin. Nutr. 2001;20:399–405. doi: 10.1054/clnu.2001.0463. [PubMed] [Cross Ref]
85. Gerasimidis K., McGrogan P., Edwards C.A. The aetiology and impact of malnutrition in paediatric inflammatory bowel disease. J. Hum. Nutr. Diet. 2011;24:313–326. doi: 10.1111/j.1365-277X.2011.01171.x. [PubMed] [Cross Ref]
86. Beattie R.M., Camacho-Hubner C., Wacharasindhu S., Cotterill A.M., Walker-Smith J.A., Savage M.O. Responsiveness of IGF-1 and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn’s disease. Clin. Endocrinol. 1998;49:483–489. doi: 10.1046/j.1365-2265.1998.00562.x. [PubMed] [Cross Ref]
87. Motil K.J., Grand R.J., Maletskos C.J., Young V.R. The effect of disease, drug, and diet on whole body protein metabolism in adolescents with Crohn’s disease and growth failure. J. Pediatr. 1982;101:345–351. doi: 10.1016/S0022-3476(82)80056-5. [PubMed] [Cross Ref]
88. O’Morain C., Segal A.M., Levi A.J., Valman H.B. Elemental diet in acute Crohn’s disease. Arch. Dis. Child. 1983;58:44–47. doi: 10.1136/adc.58.1.44. [PMC free article] [PubMed] [Cross Ref]
89. Polk D.B., Hattner J.A., Kerner J.A., Jr. Improved growth and disease activity after intermittent administration of a defined formula diet in children with Crohn’s disease. J. Parenter. Enteral. Nutr. 1992;16:499–504. doi: 10.1177/0148607192016006499. [PubMed] [Cross Ref]
90. Cosgrove M., Jenkins H.R. Experience of percutaneous endoscopic gastrostomy in children with Crohn’s disease. Arch. Dis. Child. 1997;76:141–143. doi: 10.1136/adc.76.2.141. [PMC free article] [PubMed] [Cross Ref]
91. Sylvester F.A., Leopold S., Lincoln M., Hyams J.S., Griffiths A.M., Lerer T. A two-year longitudinal study of persistent lean tissue deficits in children with Crohn’s disease. Clin. Gastroenterol. Hepatol. 2009;7:452–455. doi: 10.1016/j.cgh.2008.12.017. [PubMed] [Cross Ref]
92. Finkelstein J.S., Klibanski A., Neer R.M. A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. J. Clin. Endocrinol. Metab. 1996;81:1152–1155. doi: 10.1210/jc.81.3.1152. [PubMed] [Cross Ref]
93. Lopes L.H., Sdepanian V.L., Szejnfeld V.L., de Morais M.B., Fagundes-Neto U. Risk factors for low bone mineral density in children and adolescents with inflammatory bowel disease. Dig. Dis. Sci. 2008;53:2746–2753. doi: 10.1007/s10620-008-0223-0. [PubMed] [Cross Ref]
94. Whitten K.E., Leach S.T., Bohane T.D., Woodhead H.J., Day A.S. Effect of exclusive enteral nutrition on bone turnover in children with Crohn’s disease. J. Gastroenterol. 2010;45:399–405. doi: 10.1007/s00535-009-0165-0. [PubMed] [Cross Ref]

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