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- PATIENTS AND METHODS
The relative merits of corticosteroids and enteral nutrition in the treatment of Crohn’s disease remains an area of controversy. Although meta-analysis of the clinical trials comparing enteral nutrition therapy with corticosteroids suggests that enteral nutrition may not be as effective in inducing clinical remission, enteral therapy has the significant advantage over corticosteroids in having fewer side-effects.1–3 In children in particular, the relative sparing of linear growth achieved with nutritional therapy, confirmed in several trials is a major consideration in deciding which treatment to use.4–6
A significant problem with enteral nutritional therapy, however, is compliance; feeds in the past have been unpalatable, requiring a naso–gastric tube for administration.7 Recently more palatable polymeric diets, which use whole protein as the nitrogen source have become available, and have been shown to be as effective as elemental feeds.1 We have previously demonstrated that a polymeric diet used in infant nutrition (AL110; Nestle, Vevey, Switzerland) is effective in inducing remission and mucosal healing, in some children with active small bowel Crohn’s disease.8 Based on these preliminary results, a new specific oral polymeric formula, CT3211, was developed. It is casein-based and rich in transforming growth factor β2 which may be contributing to its therapeutic action.
The possible mode of action of enteral nutrition has been the source of some debate. There is however, growing evidence that it can reduce mucosal inflammation. Beattie et al. reported histological evidence of mucosal healing with enteral nutrition, whilst Breese et al. demonstrated that enteral nutrition reduced the number of mucosal cells producing interleukin-2, interferon γ and tumour necrosis factor α.8–10 Further evidence of down-regulation of mucosal pro-inflammatory cytokines has been reported by Ferguson et al.11 By measuring cytokine levels in whole gut lavage fluid it was demonstrated that enteral nutrition reduced the loss of IgG and interleukin-1β into the intestinal lumen. These results emphasize the importance of focusing on the mucosa when assessing the response to treatment in Crohn’s disease.
This study documents the effect of an 8 week course of treatment with CT3211 as the sole source of nutrition in children with active Crohn’s disease. Children were assessed both clinically and endoscopically before and after treatment. The effect of enteral nutritional therapy on the mucosal inflammatory process was evaluated histologically and by more detailed studies of mucosal cytokine mRNA. These latter observations confirmed the anti-inflammatory properties of enteral nutritional therapy, and demonstrated that this effect involves both the colonic and ileal mucosa.
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- PATIENTS AND METHODS
This prospective cohort study into the therapeutic action of nutritional therapy with a polymeric diet CT3211, has shown that this oral treatment is effective in inducing a clinical remission in children with active Crohn’s disease. The clinical response was associated with a decrease in serum C-reactive protein and tumour necrosis factor α levels, whilst in the intestinal mucosa there was evidence of mucosal healing together with a down regulation of the pro-inflammatory cytokines interleukin-1β, interleukin-8 and interferon γ.
The remission rate of 75% after 8 weeks of CT3211 is an encouraging preliminary indicator as to the efficacy of the treatment. It is in keeping with the results of the large Canadian paediatric comparative trial of nutritional and corticosteroid treatment which despite excluding children with colonic disease, reported similar remission rates of 75% for enteral nutrition and 89% for corticosteroids.18 It also compares favourably with the remission rates of 58% and 79% for nutrition and corticosteroids calculated by meta-analysis of trials in adults.3 To fully evaluate the relative efficacy of CT3211 compared to other therapies will however, require formal randomized trials. These would also help answer the question of whether the transforming growth factor β2 in CT3211 is contributing to its therapeutic action. Such trials should ideally be performed separately in both children and adults since there appears to be a discrepancy between the results from studies performed on paediatric or adult subjects, the former tending to include more newly diagnosed cases. Although a separate meta-analysis has yet to be performed specifically on paediatric studies, the fact that all paediatric studies have found no difference in remission rates for steroid or nutrition treated groups contrasts with the more disappointing results from adult studies.3–5, 18, 19
Endoscopic and histological assessment of mucosal biopsies demonstrated significant improvement, and in some cases healing, of the mucosa in both the terminal ileum and colon. This colonic response, particularly in the light of the mucosal cytokine changes, demonstrates the therapeutic efficacy of enteral nutrition in colonic disease, a conclusion previously reached by Griffiths et al. following meta-analysis of the clinical trials.1
The improved palatability of CT3211 meant that the children could take the volumes required to meet their full daily nutritional requirements orally. This is a significant advance, particularly over elemental and semi-elemental feeds, since a naso–gastric tube is now no longer required for the 2 to 3 months of therapy. As well as this relatively short-term usage of enteral nutrition to achieve remission, there is now growing evidence for the beneficial effects of long-term nutritional therapy both in promoting linear growth and possibly also in maintaining remission.20–22 In fact with CT3211, the relapse rate within 10 months of completion of CT3211 treatment was relatively low at 39%. This compares favourably with relapse rates by 1 year of 65% and 67% for enteral nutrition and corticosteroids, respectively, derived by pooling the results of the two adult randomized trials with follow-up data.7, 23 Whether the CT3211 relapse rate could be further improved by long-term administration is, however, worth exploring. Traditionally such continuing therapy has required naso-gastric administration, which represents a significant imposition on the child. Long-term oral supplementation would obviously be preferable, and in view of this a prospective trial into the effect on relapse of chronic administration of CT3211 is currently being undertaken.
The clinical response to CT3211 was associated with a fall in inflammatory mediators documented both in the circulation and in the mucosa. Elevated levels of C-reactive protein and ESR in Crohn’s disease are believed to be caused by the release of intestinal inflammatory mediators into the circulation and their subsequent action on the liver.24 This was also demonstrated in this study, with a fall in both C-reactive protein and ESR in response to treatment being associated with a fall in circulating levels of one such inflammatory mediator, tumour necrosis factor α. The changes in tumour necrosis factor α levels are however, much less striking than the changes in C-reactive protein or ESR, once again emphasizing the need wherever possible to monitor cytokines in the mucosa in Crohn’s disease rather than peripheral blood.
The fall in mucosal interleukin-1β mRNA in response to treatment observed in both the colon and ileum is consistent with the concept that enteral nutrition influences the underlying mucosal inflammatory process of Crohn’s disease. Although mucosal mRNA estimation is by definition not a direct measure of cytokine release, this finding is consistent with the observations of Ferguson et al. who reported a fall in interleukin-1β in the intestinal lumen following nutritional therapy.11 It is also in line with our earlier observations which demonstrated that mucosal release of another macrophage-derived cytokine, tumour necrosis factor α, goes down in response to treatment.9
Whereas the changes in interleukin-1β were similar in the ileum and colon the results for interferon γ, transforming growth factor β1 and interleukin-8 differed in the two sites. The fall in interferon γ mRNA in the ileum was consistent with our previous report of falls in the number of mucosal interferon γ and interleukin-2 secreting cells in response to enteral nutrition, and is compatible with the model of Crohn’s disease as a chronic inflammatory condition driven by lymphocytes of a predominantly T helper-1 (Th-1) phenotype.25 The rise with treatment in transforming growth factor β1 mRNA in the ileum has not previously been reported in Crohn’s disease, although the suppressive effect of transforming growth factor β on the Th-1 inflammatory response is well recognized in animal models.26 Whether this increase in ileal transforming growth factor β occurs with other treatments, and other diets, or is an effect of this specific diet which is itself rich in transforming growth factor β, is a matter for speculation.
In the case of interleukin-8, the fall in mRNA levels were only significant in the colon. This site however, had higher pre-treatment levels, which may go some way to explaining the predominance of infiltrating neutrophils, for which interleukin-8 is a chemo-attractant, affecting the colon in Crohn’s disease.27 An underlying mechanism to explain the observed differences between colon and ileum is however, not obvious. The presence in the terminal ileum of organized lymphoid tissue in the form of Peyer’s patches does, however, mean that biopsies from the ileum are more likely to include these specialized structures than those taken from the colon.
The mechanism by which enteral nutrition exerts the therapeutic and immunological effects in Crohn’s disease remains unknown although several hypotheses have been proposed. The traditional hypothesis that enteral nutrition works by the exclusion of dietary antigens seems unlikely since specific disease-associated foods have only rarely been identified, and in our study, despite the systematic re-introduction of foods following therapy, in no case was a specific food identified which caused symptoms.28 Another possible explanation is that enteral nutrition has an effect on the bowel flora, although specific alterations in bowel flora have not yet been identified. An alternative mechanism for enteral nutrition to exert its therapeutic action, could be by the repletion of nutritional deficiencies, thus promoting mucosal healing. Unraveling the relative importance of these, and other putative mechanisms will however, require further investigation.