Assessment for under- (or over-)nutrition is an essential component of medical care of children with IBD. At a minimum, screening should include measurement of body weight and height for age, with calculation of BMI. Nutritional status can be expressed in terms of the degree of height deficit (shortness), weight deficit (underweight or lightness), or relative weight for height or BMI for age (thinness). Each component captures a different aspect of growth, and interpretation is further complicated during puberty when differences in measures for thinness can be driven by changes in lean muscle and/or fat [26]. Growth parameters should be routinely collected and graphically recorded on standardized charts. It is important to obtain information on familial growth patterns, particularly parental heights, as well as pre-illness measurements to assess growth potential and the impact of disease on growth, respectively.

Ongoing assessment of nutritional status includes history, physical examination, and laboratory testing. History should attempt to obtain information on appetite, weight changes, and dietary intake (often with the assistance of a registered dietician), as well as identification of medications and nutritional or herbal supplements, including vitamins and minerals. Review of psychosocial factors such as economic and cultural or environmental influences may be useful.

Physical examination, in addition to growth parameters and BMI, should include anthropometric assessment of body habitus along with recordings of sexual maturation by Tanner staging. Examination may reveal signs of generalized malnutrition or specific nutrient deficiencies.

Laboratory tests are valuable in assessment of specific nutrient deficiencies; however some measures of nutritional status can also be affected by inflammation (e.g., serum albumin and ferritin). Serum pre-albumin has a much shorter half-life (2 days) than albumin (18–20 days) and may be more useful in the assessment of nutritional status changes with nutritional support [54].

Other potential tests of nutritional status are urinary creatinine/height ratio or 3-methylhistidine determinations which reflect somatic (muscle) protein status and 24 h urine urea nitrogen which reflects protein catabolism. However due to the difficulty obtaining accurate specimens and assumptions required for interpretation, these lab tests are not used in routine clinical practice. Additional research techniques for assessment of nutritional status are dual-energy X-ray absorptiometry [24], bioelectric impedance analysis, and total body electrical conductance to determine total body water and fat mass and isotopic labeling of various molecules to determine energy expenditure and metabolic turnover rates [19].

Serum leptin may also have a role in nutritional assessment as a marker of fat stores [55–57] and has been found to be lower in children with severe protein energy malnutrition [58]. Controversy exists in the literature regarding the correlation of leptin levels with inflammation or whether it simply reflects nutritional status regardless of underlying disease. Hoppin et al. found no difference in serum leptin levels between children with IBD and controls and concluded that serum leptin levels depend on BMI and sex and not on disease activity or severity [59].

Aurangzeb et al. explored the relationship between leptin and BMI in newly diagnosed children with IBD in comparison to controls. Significantly lower mean serum levels were found in 28 newly diagnosed IBD patients compared to 56 controls (2.32 pg/ml +/−1.88 vs 5.09 pg/ml +/−4.86, p+0.009). In this group of children with IBD, leptin levels did not correlate with the degree of inflammation, as defined by serum markers of inflammation [10]. Further studies are required to elucidate the role of leptin in nutritional assessment of IBD patients.

Following diagnosis of IBD, there are numerous ongoing aspects of nutritional management to address. Nutritional issues relating to therapy may arise. The use of steroids often leads to increased appetite and commonly alters fluid balance with initial fluid retention and weight gain that only partially reflects improvements in underlying nutritional status. Steroids are clearly linked with impaired bone mineralization, with enhanced resorption, and with decreased new bone formation [60, 61]. Adequacy of calcium and vitamin D intake must be reviewed regularly. Inhibition of linear growth and altered final height, due to suppression of insulin-like growth factor-1 (IGF-1), is also a feature of daily corticosteroid therapy [62].

Other medications may interfere with the absorption of specific micronutrients. Sulfasalazine may interfere with folate metabolism by reducing absorption; however, daily supplementation does not appear necessary [63]. In contrast, folate supplementation is required when the immunosuppressive drug methotrexate is used, as this drug acts to inhibit the conversion of folate to the active moiety tetrahydrofolate [64].

Questions related to nutrition and which foods to avoid are among the commonest raised by families both at diagnosis and in routine follow-up. The current consensus from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) is that diets of children with CD should be well balanced, based on the Food Guide Pyramid, and follow dietary reference intakes [19]. Brown et al. recently created a “global practice guideline,” which attempted to consolidate the existing information regarding diet and IBD proposed by medical societies or dietary guidelines from patient-centered, IBD-related organizations. The dietary suggestions included nutritional deficiency screening, avoiding foods that worsen symptoms, eating smaller meals at more frequent intervals, eliminating dairy if lactose intolerant, limiting excess fat, reducing carbohydrates, and reducing high-fiber foods during flares. Enteral nutrition was recognized as being recommended for CD in some parts of the world more often than others (e.g., more in Japan than in the USA) [65].

Overall, CD, in contrast to UC, can have a tremendous and long-lasting impact upon nutritional status but can also be successfully treated with nutritional therapy. Minimal evidence exists for the treatment of UC with enteral nutrition. Wedrychowicz et al. recently evaluated the effect of EEN on endothelial growth factor (VEGF) and transforming growth factor beta 1 (TGF-β1) in both UC and CD [66]. However, due to the concomitant use of antibiotics and 5ASA in this study, the role of EEN in UC is impossible to determine from this study. Therefore, the remainder of this chapter will focus on the nutritional impact and management of CD.

The intestinal microbiota plays a central role in the pathogenesis of IBD, although current data does not indicate any one species as being causative on its own. The impact of EEN upon the intestinal microbiota has been examined in human settings and in an animal model of IBD.

Two early studies used molecular techniques to examine the impact of EEN upon the flora in the context of IBD [70, 71]. These reports illustrated changes in the flora consequent to the introduction of the enteral formula. A more recent study employed a more comprehensive molecular approach (denaturing gel gradient electrophoresis or DGGE) with a wider selection of probes, enabling a broader profile of the changes [72]. This study showed a reduction in the diversity of the bacterial species and changes within all the main bacterial groupings. These changes were sustained, with effects well beyond the period of EEN alone.

A subsequent study utilized 16S rRNA and whole genome high-throughput sequencing to ascertain additional understanding of the impact of EEN upon the microbiota [73]. All five children included in this study had dysbiosis at diagnosis of CD. EEN resulted in a prompt reduction of the number of operational taxonomic units (OTU), which correlated with induction of disease remission. Subsequent exacerbation of disease leads to an increase in the number of OTU. Furthermore, six specific Firmicutes families were shown to correlate closely with disease activity during and after exposure to EEN [73].

More recently, further studies from the UK [74] and the USA [75] have utilized advanced molecular tools to further define changes in the intestinal microbiota consequent to EEN. Although each of these reports indicates the impact of EEN, they do not yet illustrate whether these changes result solely from the difference in the nutrients supplied in the formulae or how these changes then influence mucosal inflammation.

Data from an animal model of CD complements these data. Using an IL-10 knockout model of gut inflammation, a Japanese group assessed changes after the administration of elemental formula [76]. The bacterial diversity and bacterial number were both reduced in those animals given the formula compared to a control group with normal mouse diet.

Two recent studies have also assessed patterns of the intestinal flora consequent to enteral feeding in non-IBD contexts. Smith et al. [77] assessed changes in bacterial composition in the stomach and duodenum of adults receiving enteral formulae via a gastrostomy for various noninflammatory indications. Higher levels of bacterial DNA were found in the upper gut after enteral feeding. The fecal flora was not examined in this patient group. A second study examined the fecal microflora in a small group of adults requiring exclusive nasogastric feeding for a variety of medical indications [78]. Individuals with IBD were excluded from the study. The subjects provided stools at the start of, during, and at the end of a 14-day period of enteral feeds. Molecular methodology was employed to assess the flora (fluorescence in situ hybridization). Overall the investigators did not observe consistent changes in the microflora during this short period. However, they did note changes in particular groups of organisms in the individuals who developed diarrhea secondary to the enteral feeds. However, these effects differed to those seen consistently in individuals with IBD.

Meister et al. [79] demonstrated in vitro anti-inflammatory activities of formulae in a series of experiments using explants (short-term culture of colonic tissue samples obtained endoscopically). These samples were incubated directly with an elemental formula or maintained in a control situation. The production of interleukin (IL)-1-β, IL-1-receptor antagonist (RA), and IL-10 was used as an indicator of cell responses. The cells incubated with formula lead to an increase in the ratio between IL-1RA and IL-1-β, compared to the control cells (P < 0.05). These changes were also evident when full protein-based formulae were employed. Further, these changes were not observed in biopsies taken from individuals with UC or with noninflamed IBD tissue.

More recently, an in vitro model of intestinal cells has been used to elucidate the anti-inflammatory effects of formulae [80]. These experiments utilized established colonic epithelial cells lines, which were stimulated with one or more pro-inflammatory cytokines to replicate intestinal inflammatory events. Polymeric formulae were then used to rescue or to prevent the cellular response to this inflammatory insult, with interleukin (IL)-8 utilized as an indicator of epithelial response. The effect of adding polymeric formula (PF) to this model was assessed in a series of different ways, with particular use of a two-compartment model, whereby the PF was separated from the inflammatory cytokine. Experiments using this model demonstrated that PF leads to alteration of the inflammatory effects of TNF-α (reduced levels of IL-8) and suggested alteration of cellular signal transduction pathways as a mechanism for this finding [80].

A similar model was utilized to show that the application of PF resulted in modulation of nuclear factor (NF)-κB activity, thereby modulating the production of pro-inflammatory cytokines [81].

Subsequent studies showed that vitamin D and two specific amino acids (arginine and glutamine) mediated the effects of PF in this setting [82]. These findings suggest that active components within the nutritional products used for EEN may explain the anti-inflammatory effects seen in vivo.

Disruptions to barrier function, measured as altered intestinal permeability, are demonstrated in individuals with CD [83]. It is unclear whether these are primary events or are consequent to inflammation. Data showing similar alterations in permeability in asymptomatic first-degree relatives of people with IBD suggests that these could be primary changes, which could thereby predispose to the development of inflammatory changes in some individuals [84]. Intestinal permeability improves with resolution of inflammation [85] including following EEN [86].

Recent in vitro studies have explored these mechanisms further [87]. These studies employed an in vitro model of inflammation similar to that described above, whereby intestinal epithelial cell monolayers were stimulated with pro-inflammatory stimuli and then rescued with PF. Using an Ussing chamber, these experiments demonstrated that EEN lead to complete reversal of cytokine-induced changes in transepithelial resistance, short-circuit current, and horseradish peroxidase flux. In addition, PF was shown to correct cytokine-induced changes in tight junction proteins and key mediators of tight junction function. A subsequent series of confirmatory experiments were conducted using an animal model of colitis. Colitis induced in interleukin-10 knockout mice resulted in altered barrier function. These changes were reversed by the administration of a PF to the affected animals. PF in this setting also had reversal of mucosal inflammatory changes [88].

Although the molecular mechanisms of these observations are not yet defined, these findings provide significant clues to the activity of EEN in vivo. More work is required to clearly define the molecular events behind these important observations and also to translate these findings to the in vivo situation.

Multiple pediatric studies have indicated that approximately 60–90% of children fed an exclusive liquid diet will enter clinical remission. As shown in several studies and a meta-analysis [89] updated with the most recent randomized study [90], high remission rates with EEN are achieved irrespective of the type of enteral feed (14/15 93% achieved remission with elemental diet vs 15/19 73% on polymeric diet, n.s.).

In addition, there have been numerous open and comparative studies evaluating the use of EEN versus corticosteroids in adults [91–94] and children [69, 95, 96] with CD. Recently, patients enrolled at diagnosis into the growth relapse and outcomes with therapy in Crohn’s disease (GROWTH CD) study were evaluated for disease activity, CRP, and fecal calprotectin for 1 year. Clinical remission at 12 weeks with EEN was superior to corticosteroids both when considering remission by PCDAI (OR, 2.07; 95% CI, 1.8–18.3) or combined normal PCDAI and CRP (OR 3.4; 95% CI, 1.3–9) [97].

In three meta-analyses investigating the use of EEN in CD, steroids were found to be more effective in the induction of remission [98–100]. The most recent Cochrane meta-analysis comparing induction of remission by corticosteroids (160 patients) versus EEN (192 patients) yielded a pooled odds ratio (OR) of 0.33 (95% CI: 0.21–0.53) favoring corticosteroid therapy [75]. However, these analyses involved predominantly adult studies of varying quality. A well-conducted pediatric randomized controlled study [101], added to the latest meta-analysis, allowed for a sensitivity analysis of high-quality studies based on the Jadad scale [102]. The two high-quality studies had conflicting results, one favoring steroid therapy [103] and one favoring EEN [101] though neither study demonstrated statistically significant differences. However, the more recent study demonstrated mucosal healing after 10 weeks of EEN in 14/19 (74%) of participants versus only 6/18 (33%) of those treated with steroid therapy. The question of equivalent or superior efficacy of steroids to EEN in children is also raised by Heuschkel et al. who combined in meta-analysis the data accrued in controlled trials conducted exclusively in children and adolescents [104]. They concluded that nutritional treatment and conventional corticosteroids are equally effective in a pediatric population, even if not in adults. However, to reach this conclusion, their NNT was 182 patients to detect a 20% difference in treatment effects. The actual number they had from five randomized controlled trials was only 147 children, and hence, they included two nonrandomized trials to reach the desired sample size.

Day et al. have identified poor compliance resulting in inadequate volume of EEN received as a major reason why some patients did not achieve remission [105]. The effect of compliance was explored in a recently updated Cochrane meta-analysis by performing a sub-analysis of the data on a per-protocol basis, excluding patients who withdrew due to lack of acceptability of nasogastric tube feeding or palatability of the enteral feed. When comparing those who completed EEN therapy to the corticosteroid group, efficacy was equivalent for induction of clinical remission [ 89 ].

In addition, a number of pediatric retrospective studies have found that EEN is more effective than corticosteroids in improving disease severity and growth deficiency. Among these is a large retrospective study from Canada including 229 patients where EEN has been commonly used as induction therapy [106]. In addition, a recent retrospective study from China where the incidence of CD is much lower, EEN was also found to more effective than corticosteroids (90% vs 50% P < 0.05) [107]. Another large Canadian cohort found equal efficacy to corticosteroids [108].

In summary, existing studies and meta-analyses demonstrate high remission rates with EEN therapy depending on adherence. With efficacy to corticosteroids being similar, the advantages in mucosal healing, lack of corticosteroid side effects, and improvements in nutritional status strongly support the use of exclusive enteral nutrition over corticosteroid therapy for induction of remission. Current guidelines support EEN as the first-line therapy to induce remission in children with active CD [4]. Efforts to develop innovative palatable formulations to improve acceptance of this therapy among patients and strategies to improve geographic variability in utilization are required.

In a recent prospective study of 90 children with CD, clinical outcomes of disease activity, quality of life, and mucosal healing estimated by fecal calprotectin were compared between partial enteral nutrition (PEN) (n = 16), EEN (n = 22), and anti-TNF therapy (n = 52). Clinical response (PCDAI reduction ≥15 or final PCDAI ≤10) was achieved by 64% on PEN, 88% EEN, and 84% anti-TNF (test for trend P = 0.08). FCP ≤250 μg/g was achieved with PEN in 14%, EEN 45%, and anti-TNF 62% (test for trend P = 0.001). Improvement in overall quality of life was not statistically significantly different between the three groups [109]. Further clinical and cost-effective studies are required to aid in the therapeutic decision pathway of pediatric CD.

Following the induction of remission, the use of EN as maintenance therapy may have additional benefits to prolonging remission, including delaying the requirement for further therapy (i.e., corticosteroids) and optimizing growth and nutrition. Most often maintenance EN is practiced in combination with maintenance medical therapy, but limitations of adherence may similarly impact enteral therapy as it does medical therapy.

To date the majority of the literature on maintenance of remission of CD with EN therapy has been in adult patients, mostly arising from multiple centers in Japan. There is a smaller and older body of work in pediatrics.

Akobeng and Thomas [110] conducted a Cochrane review of enteral nutrition for maintenance of remission in Crohn’s disease. They identified only two maintenance studies in adult patients which were randomized controlled studies, one where the comparison groups were two types of formula (elemental vs polymeric) [111] and another where a maintenance EN regimen was compared with regular diet [112]. Verma and colleagues studied 33 adult steroid-dependent CD patients in remission, who were randomized to elemental (n = 19) versus polymeric (n = 14) formula, and followed for maximum of 12 months. Fourteen or 43% of the total population remained in remission and off corticosteroid at 12 months, with no significant difference in relapse rates noted between the two formula groups [111]. They did not identify any disease- or patient-related factors that predicted response to enteral nutrition; however, their sample size was small limiting their ability to make meaningful comparisons. Although no “toxicity” was encountered per se, 6 (18%) of patients withdrew within 2 weeks of study start due to intolerance to feeds related to smell or taste problems.

Takagi [112] studied 51 adult patients in remission who were randomized to receive a half-elemental diet (n = 26) or a free diet group (n = 25). The half-elemental diet group was required to take half the daily caloric allowance as an elemental formula (either orally or via a nasogastric tube). While there were some restrictions placed on the caloric intake of the other “half” of their diet (aided through use of semi-weighed food diaries), there were no specifications for its composition. This was one of many Japanese studies which has looked at the question of maintenance EN however, and as such, the unrestricted free diet is likely different from the equivalent Western diet. The authors in the Takagi study chose a primary outcome of relapse over a 2-year period [112]. The study was stopped before achieving the 2-year follow-up for all participants because the relapse rate in the half-elemental diet group was significantly lower than that in the free diet group (34.6% vs 64%) after a mean follow-up of 11.9 months.

Yamamoto [113] carried out a systematic review examining EN for the maintenance of remission in Crohn’s disease. They included studies where EN was compared with another therapy; thus the study by Takagi [112] was included, but not the study by Verma and colleagues [111]. They did not limit their review to RCTs, so three prospective nonrandomized trials [114–116] and six retrospective studies [117–121] were included. The number of patients included in most of these studies was small. One of the ten studies included pediatric patients alone [118]. Eight of ten studies were conducted in Japan. Knowledge of the country of origin for a study is important when interpreting the results and assessing generalizability. In Japan, EN has a central role in the management of CD. In all but one of the eight Japanese studies included in the systematic review, an elemental formula was used, and also in a majority of studies, the oral component of the diet was a low-fat diet. The impact of this dietary approach, compared with a maintenance polymeric formula and/or traditional Western diet, has not been directly studied. The contribution of the low-fat diet, and elemental formula with a relative low-fat component, may be a relevant factor in light of the work by Bamba et al. who suggested that a lower-fat diet may be an important factor related to the efficacy of EN in CD [122]. Another factor, when reviewing EN studies from Japan, is that virtually all participants with CD are on a 5ASA preparation, as this is viewed as a standard of care for maintenance [113]. Because all participants are exposed to this intervention, it would not be expected to bias the findings relative to the EN outcomes. Additionally azathioprine was used by a number of study participants, but as is the case with 5ASA, overall its use seemed to be balanced between the treatment and comparison groups in the studies, thereby limiting the bias this concomitant therapy might have introduced.

In the systematic review by Yamamoto [113], the authors broke down the studies by whether the patients had achieved a medically or surgically induced remission. Interestingly, different from what would be seen in studies conducted in North America, for those studies with patients who entered from a medically induced remission, the majority of patients went into remission with total parenteral nutrition or EEN. Regardless of the method of induction of remission (medical or surgical), the outcomes for the ten included studies showed benefit of EN for maintenance of remission (48–95%) over the non-EN comparison groups (21–65%) [113]. In four studies the impact of dose of EN on remission rates was evaluated [117, 119, 121]. They found that higher amounts of enteral formula were associated with higher clinical remission rates. Another interpretation of these findings could be that patients with less active disease tolerated the enteral feeding better and, therefore, reached greater intakes than those with more active disease. Thus patients with milder disease may tolerate the nutrition better, rather than the higher intake being a predictor of maintenance of remission. As well, because there was no standard approach to “dosing” used in these studies, at this time no clear recommendations can be made regarding the minimum dose of EN required to optimally maintain remission.

Maintenance EN programs have been provided in various forms: overnight NG feeds in conjunction with normal daytime eating, short intervals of exclusive NG feeds every few months interspersed with regular diet, or as oral supplements in addition to oral eating through the day. Two Canadian groups have considered the first two approaches [118, 123]. Researchers at the Hospital for Sick Children in Toronto, Canada, reported on 28 children who after entering remission with EEN had subsequently continued overnight supplementary NG feeds in addition to normal diet in the daytime [118]. They were compared with 19 children in whom EEN successfully induced remission but who opted to discontinue nocturnal elemental feeding. At 12 months, 43% (12/28) of those receiving nocturnal EN had relapsed compared with 79% (15/19) who had discontinued supplemental elemental feedings (P < 0.02). A second group, from Montreal, Quebec, published a report utilizing a different approach to EN feeds, with intermittent intensive periods of nutritional therapy (EEN) [123]. This small study included eight children with CD and associated growth failure who were given intensive exclusive periods of formula for 1 month out of every 4 months. Disease activity markers fell in this group over time and in comparison to a control group who did not receive this intensive therapy. These eight children managed with intensive nutritional therapy also had significant catch-up growth [123].

Thus far, the majority of studies investigating the role of EN with medical therapy have focused on concomitant use with infliximab. A meta-analysis of four adult studies, which were all from Japan, showed that specialized enteral nutrition therapy with infliximab resulted in 109 of 157 (69.4%) patients reaching clinical remission compared with 84 of 185 (45.4% with infliximab monotherapy [OR 2.73; 95% confidence interval 1.73–4.31, P < 0.01]. Maintenance of remission was also achieved in the combination treatment group [124].

In children, there have been minimal studies conducted to examine the use of immunomodulators and EEN in children with newly diagnosed CD, but Buchanan et al. reported that patients found it difficult to continue supplemental nutrition as maintenance or remission and therefore used a strategy of early introduction of azathioprine for maintenance of EEN-induced remission [125]. The relative importance of choice of initial induction therapy on 2-year outcomes in the setting of early thiopurine use was recently evaluated. In the setting of early thiopurine commencement, choice of EEN over corticosteroid induction was associated with reduced linear growth failure (7 vs 26%, P = 0/02), steroid dependency (7 vs 43%, P = 0.002), and improved primary sustained response to infliximab (86 vs 68%, P = 0.02) [126].

The effect of supportive short-term partial enteral nutrition (SPEN) on the treatment of children with severe CD along with unspecified conventional therapy was recently explored in a Korean cohort [127]. Patients with active CD were divided into mild, moderate, and severe categories according to PCDAI. The severe group was given the option of receiving SPEN, and 17 of 34 patients opted in. The remaining 17 patients were considered to be the non-SPEN group. Changes in nutritional status and PCDAI were significantly higher in the SPEN group (P < 0.05).

Further long-term study of the combination and synergistic effects of enteral nutrition and medical therapy particularly for maintenance of remission and mucosal healing is needed.

Despite the convincing results regarding immediate benefits of nutritional treatment, the efficacy of EEN for disease exacerbation and duration of remission is poorly studied.

The efficacy of repeated EEN therapy as a treatment for flares of disease tends to decrease with the second course. In a recent retrospective study, 26/52 patients received a second EEN course. The first compared to the second EEN tended to a higher remission rate (92% remission for the first course vs 77% n.s.). Duration of the second EEN therapy was shorter compared to the first (mean days 50 vs 43, P < 0.05). It was possible that nonadherence increased with the second course of EEN and contributed to the lower effectiveness. Disease activity measured by the mathematically weighted PCDAI (wPCDAI) was higher for the first course of EEN therapy (59 vs 40, P < 0.0001) [128]. Remission rates ranging from 57 to 80% have been reported by other retrospective studies evaluating a consecutive course of EEN [105, 129, 130].

In terms of 1–2-year outcomes, approximately half to two thirds of patients will relapse [128, 130, 131]. Predictors of higher relapse rates include the type of induction therapy (corticosteroids have higher relapse rates than EEN induction) [130, 131] and the type of NOD2 genotypes (92% R702W or G908R vs 50% 1007 fs vs 60% wild type, P < 0.01) [128].

For some time the treatment goals for the management of active CD have focused on the induction of remission, judged clinically (resolution of symptoms) and biochemically (normalization of altered inflammatory markers). More recently it has become clear that the goal of treatment should be the achievement of mucosal healing. Mucosal healing in both CD and UC is clearly associated with improved long-term outcomes [132]. Persisting inflammatory changes are likely to contribute to poor growth in children and are also associated with an increased risk of subsequent disease relapse [133]. Mucosal healing may also influence disease progression and extraintestinal disease patterns.

Both EEN and infliximab lead to high rates of mucosal healing in CD: more so than other therapies used to induce remission (such as corticosteroids) [134].

At the turn of the century, Fell and colleagues [135] undertook a prospective assessment of mucosal healing in a group of children treated with EEN. These 29 children with active CD were treated with a polymeric formula. In addition to baseline endoscopic assessment, repeat colonoscopy was completed after 6–8 weeks time in order to judge endoscopic and histologic changes. EEN lead to clinical remission in 79% of these children. Overall there was significant endoscopic improvement in these children. A one-point improvement in the colonoscopy grading score was seen in the ileum and colon (P < 0.0001 and P < 0.001, respectively). Eight of the children achieved mucosal healing in the ileal region, while eight also had colonic mucosal healing.

More recently the results of two prospective Italian studies and an Australian study show the enhanced rates of mucosal healing following EEN comparing to corticosteroids [101, 136, 137]. Berni-Canani and colleagues [101] evaluated the responses in children managed with EEN or corticosteroids. Thirty-seven children were treated nutritionally for 8 weeks with various different formulae (polymeric, semi-elemental, and elemental), while ten received corticosteroids. Clinical remission rates were similar in the two groups (86.5% vs 90%, respectively), but mucosal healing rates were quite different. Twenty-six of the 37 children treated nutritionally had mucosal improvements, and seven of them had complete mucosal healing. In contrast, just four of the steroid group had improvement noted, and none had mucosal healing.

In a second Italian study, children with active CD were allocated to receive either EEN (polymeric formula) or corticosteroids. Baseline colonoscopic assessment was followed by repeat colonoscopy at 10 weeks. Fourteen (74%) of the 19 children treated with EEN had mucosal healing. In contrast, mucosal healing was achieved in just six (33%) of the 18 children treated with corticosteroids (P < 0.05). Grover et al. evaluated the effects of 6 weeks of EEN in a cohort of 26 children. Paired endoscopic assessments showed that 58% of the group had complete or near-complete MH following EEN [137]. Subsequent work by this group in a larger group of children demonstrated that complete MH (seen in 18 of 54 children) after EEN resulted in sustained remission for up to 3 years [138].

Data from adult patients also clearly demonstrates high rates of mucosal healing consequent to EEN. Yamamoto et al. [139] assessed the mucosal changes following an elemental formula in 28 adults with active CD. In this series of patients treated with EEN, clinical remission was seen in 71%. Furthermore, endoscopic healing or improvements were documented in 44% and 78% of patients, respectively.

Mucosal healing with EEN does not appear to be dependent on the type of formula utilized. Benefits have been documented with elemental [101, 139, 140] or polymeric formulae [135, 136].

Coincident with promoting healing of the inflamed mucosa, EEN is also shown to lead to changes in levels of inflammatory mediators. Several reports published in the final decade of the last century demonstrated that EEN lead to reduced mucosal production of pro-inflammatory cytokines (especially TNF-α and interleukin-2) [140, 141] and prompted downregulation of pro-inflammatory genes measured within the intestinal mucosa [135, 142]. In addition, Fell et al. [135] also demonstrated increased levels of TGF-β mRNA, consistent with increased production of this anti-inflammatory cytokine. Yamamoto and colleagues [139] also showed that the mucosal levels of multiple pro-inflammatory cytokines fell to control levels consequent to treatment with an elemental formula. The ratio between IL-1β and IL-1ra within the mucosa was also normalized.

Overall these data clearly show alterations in levels of inflammatory mediators within the mucosa following treatment with EEN. The full implications of achieving mucosal healing with EEN in children are not yet well defined. Maintenance EN may have a role in maintaining the levels of mucosal healing. It is also not clear if mucosal healing with one therapy (such as EEN) is different to that achieved by another agent (e.g., steroids). Furthermore, treatment protocols have not yet evolved to stratify maintenance therapy upon the level of mucosal healing.

Various proteins measured in the stool are valid markers of the level and extent of gut inflammation [143]. The most well-known markers are calprotectin and lactoferrin, but others include S100A12 and osteoprotegerin.

In a study by Gerasimidis et al., fecal calprotectin (FC) levels were measured on multiple occasions during and following a course of EEN in 15 children [144]. The children received a polymeric formula, and clinical disease activity was defined by determination of PCDAI scores, with a score of 10 or less being judged as clinical remission. FC levels fell only in the children who were in clinical remission by the end of the period of EEN, but FC levels were normalized in only one child. Interestingly, the FC level after 1 month of EEN was associated with clinical response at the end of EEN, suggesting a predictive value at this time. In a study comparing partial EN (PEN), EEN, and anti-TNF therapy, FC ≤250 μg/g was achieved with PEN in 14%, EEN in 45%, and anti-TNF in 62% (test for trend P = 0.001).

The levels of S100A12 (a protein related to calprotectin) were evaluated in a small group of Australian children managed with EEN for active CD [145]. Levels fell in the subset of children who achieved clinical remission and normal CRP.

Recent work showed that EEN treatment also led to reductions in levels of another fecal inflammatory marker, osteoprotegerin (OPG) [146]. Levels of OPG fell to around 25% in response to 6–8 weeks of EEN (1994 ± 2289 pg/g at baseline to 406 ± 551 pg/g after EEN: P = 0.002). The value of this marker in predicting response to EEN or in correlating with mucosal healing has not yet been determined.

Along with improvements in disease activity, weight and growth improvements are also commonly seen with EEN. Numerous studies show improved weight gains, while some have illustrated changes in specific nutritional markers. Several studies have suggested that nutritional improvements occur at different times to changes in specific inflammatory markers. These studies demonstrate that improvements in nutrition do not correlate with the timing of normalizing inflammatory markers [54, 147]. It is not clear whether the nutritional changes are essential to achieve anti-inflammatory improvements. However, satisfactory weight gains are associated with response to EEN, illustrating the importance of these events [105].

Insulin-like growth factor (IGF)-1 is a key mediator of growth hormone signaling. Alterations in this protein occur due to the effects of cytokines (reduced hepatic production secondary to interleukin-6) and are commonly observed in active CD. A number of studies illustrate early increases in IGF-1 and its related binding protein (IGF-BP3) after commencement of EEN [148]; unpublished data, Day et al. [105]. IGF-1 levels rose after just 7 days of EEN in a small group of 12 children [147].

Detailed nutritional assessments, including body composition analysis, have been conducted in individuals receiving EEN. One key study evaluated body composition using multiple direct methods to define fat, water, total body protein, and potassium [149]. A group of 30 individuals with CD were assessed before and after 3 weeks of EEN. Within this short time, increased weight was linked with proportionate increases in body fat, protein, and water. Another study documented changes in body compartments in a group of Canadian children [25]. Body water, lean body mass, and height increases were observed in the children who had received EEN, but not in a comparison group treated with corticosteroids. EEN has been shown by other authors to promote anabolism consequent to suppression of proteolysis and enhanced protein synthesis [18, 37].

These changes in nutrition manifest in weight gains during EEN. The average weight gain in a group of Australian children treated with 6–8 weeks of EEN was 4.7 ± 3.5 kg [105]. In addition, weight Z scores increased over the duration of EEN from −0.2767 ± 0.9707 to 0.1866 ± 0.8024 (P = 0.0016). Weight standard deviation scores increased after 8 and 16 weeks (P < 0.05) in a small cohort of 14 UK children with a mean age of 12.5 years [148]. However, studies do report variable weight gains [136, 150].

EEN is also noted to have a positive benefit upon linear growth, with improved height velocity even within a short period of time [17, 69]. In a meta-analysis, Newby and colleagues [151] illustrated a significant improvement in height velocity Z scores with EEN compared to outcomes after treatment with corticosteroids. In the aforementioned Australian study, children receiving EEN gained up to 3 cm during the 8-week course of EEN; however there was no change in height Z scores across the whole group [105].

CD is associated with reductions in bone mineral density, which can lead to osteopenia and increased fracture risk. EEN appears to have benefits upon bone health. Whitten et al. [152] evaluated serum markers of bone turnover in a group of children with active newly diagnosed CD who were treated with polymeric formula as sole therapy to induce remission. Serum levels of bone resorption and bone production were measured at baseline and then again after 6–8 weeks of EEN. Control data was obtained from a group of children without IBD with normal growth patterns. Serum levels of C-terminal telopeptides of type-1 collagen (CTX), a marker of bone resorption, were elevated at baseline and fell during therapy (P = 0.002). In addition, levels of bone-specific alkaline phosphatase (BAP), a marker of new bone formation, were low at baseline but rose significantly during therapy (P = 0.02). This study did not include evaluation of other aspects of bone health or bone densitometry.

A more recent study has evaluated the impact of EEN upon vitamin D, an important factor involved in bone health [39]. This study retrospectively evaluated levels of vitamin D in 78 children with CD. A subgroup (n = 38) had been treated with EEN at diagnosis. These children treated with EEN had higher levels of vitamin D than a comparison group of 17 children treated with corticosteroids after diagnosis (P = 0.04), suggesting that EEN provided a protective effect for this aspect of bone health.