Although a recent study showed that disease improvement precedes nutritional rehabilitation and may suggest that nutrition rehabilitation is not implicated as a mechanism of action of EEN, the authors of this study assessed only indices of energy-protein status (267). Whether disease improvement is a direct effect of improvement and replenishment of micronutrient status from EEN has not been investigated. Micronutrients play a vital role in metabolism, antioxidant status and the integrity of the colonic epithelium. Reactive oxygen species exhibit deleterious effects on epithelial cells in CD and studies have shown decreased levels of antioxidant enzymes and vitamins in the intestinal mucosa and in the plasma of patients with CD (Section 1.3.6). Replenishment of micronutrient status during EEN is one of the possible modes of action mediating the efficacy of EEN in CD where micronutrient deficiencies and malnutrition are common as opposed to its inefficacy in UC were deficiencies in minerals and vitamins are unusual.
Moreover, there are additional reasons why replenishment of micronutrient in EEN is important. Conventional EEN regimes, intended for use in active CD, provide age and gender specific energy requirements, as reflected by the increase in body weight and anabolic effects, but there is no evidence to ensure that the micronutrient content of these feeds is adequate to replenish deficiencies or supply the essential requirements of these patients. The dietary adequacy of micronutrients in these feeds has been ascribed to the provision of national reference daily intakes, originally established to cover the needs of the healthy population, but whether the same requirements apply to patients with CD is questionable. A study (335) 20 years ago failed to show improvement of vitamin status of IBD adults on EEN despite provision of higher amounts of micronutrients than the RDA.
Moreover EEN feeds are “artificial food” made of composite simple food ingredients and nutrients for which recommended allowances have been established and therefore may lack
‘non-nutrient compounds’ that occur naturally in food (e.g. polypenols), ave important role in the human health, but whose supplementation in artificial feeds is uncommon.
An extensive literature search was carried out by the researcher in 2004 and updated in 2008 to review all studies on the effect of EEN therapy on blood micronutrient status in IBD patients. Studies using total parenteral nutrition were excluded. Overall seven studies were retrieved. The studies were heterogeneous in design, subject characteristics, duration or type of feeds used, and the mode of nutritional support (Table 1.5.3). Four studies were conducted in CD adults, whereas two included UC patients. All but one study used EEN. One used partial supplementation of normal diet. The duration of nutritional therapy varied from 12 days to one year. Only one adult study including UC patients assessed a wide range of micronutrients. The rest assessed a limited number of micronutrients, focusing mainly on antioxidant trace elements and vitamins. Some studies assessed changes of the enzymatic antioxidant systems and one study measured changes in oxidative stress (Table 1.5.3).
The results were inconsistent and no overall conclusions could be drawn. Nutrients like Se increased in some studies but decreased in others (Table 1.5.3). Similar results were found for other nutrients like vitamin A. The use of different feed formulae and duration of administration among studies could explain some of these differences. No study in children as investigated changes in a wide range of vitamins. Thomas et al (183) assessed only changes in Se, whereas Akobeng et al (336) studied additionally vitamins A, E and C.
The as yet limited evidence does not support a mechanism for the therapeutic action of EEN that is mediated by micronutrient replenishment. Phylactos et al (148) showed that paediatric CD is characterized by reduced activity of enzymatic antioxidant systems in erythrocytes, but this did not improve with eight weeks treatment with EEN despite improvement in disease activity and systemic markers of inflammation (CRP and TNF-α). Although these results imply that the anti-inflammatory action of EEN in CD is caused by some mechanism other than restitution of specific antioxidants it still remains to be addressed whether disease improvement is associated with changes in other micronutrients. Akobeng et al (336) did not find significant changes in the antioxidant mechanisms or markers of oxidative stress of children with CD on four weeks of EEN. However the authors did not report changes of clinical activity or inflammatory markers and association.
There is limited evidence to suggest any micronutrient changes during therapy with EEN and how these correlate with the disease activity and inflammatory markers. Extrapolation of the results from adult studies to paediatric patients is inappropriate given the differences in the nutrient requirements between adults and children. The most comprehensive study in children included only four antioxidant nutrients and the duration of the EEN course was limited to one month. The recommended duration of EEN is now between six to eight weeks and different results might be expected. More evidence is needed
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as to whether EEN fully meets the nutritional needs of children with CD and whether or not it replenishes any deficiencies. Failure of EEN to cover the nutritional needs of children with CD will have implications for both the feed manufacturers and clinical practice.
Changes in micronutrient status with EEN and correlation with disease activity need to be further studied although the interpretation of the results is difficult as other factors beyond nutritional status and actual nutrient stores can affect serum circulating levels. As discussed in Section 1.3.6 the acute phase response during inflammation can affect serum nutrient circulating levels irrespective of body stores and therefore measurements in other tissues or cells might be more appropriate measures of body micronutrient status (179). The effect of EEN on micronutrient status in investigated in Chapter 5
Table 1.5.3: Studies on the effect of EN therapy on the systemic micronutrient status in adult and paediatric IBD.
Study Subjects Nutritional therapy Micronutrient Micronutrient change
ADULT STUDIES
Johtatsu et al 2007 (337) 8 CD Partial EN; 1y; Elental
low in Se and Zn
Se, Zn, Cu. Serum selenoprotein, GSHPx
Se and Zn depleted; Improved by supplementation with Se and Zn
Abad-Lacruz et al 1988 (335)
8 malnourished IBD EEN; 12-28 d Vit A, β-carotene, Vit E, Tocopherol:Cholesterol, B1, B2, B6, B12, Folate,
Biotin, Vit C
Folate, biotin, b-carotene, vit C, tocopherol/chol unchanged; B1, B2
decreased; vit A and E increased
Teahon et al 1995 (331) 19 CD EEN 5 wk; E028 &
Vivonex
Fe, Mg, Cu, Zn Fe increased, Cu decreased Fernandez-Banares et al
1990 (294)
7 malnourished IBD EEN; 20 d Zn, Se, Cu Zn, Cu did not improve, Cu:Zn ratio
decreased; Se increased PAEDIATRIC STUDIES
Akobeng et al 2007 (336) 15 CD EEN; 4 wk; 2 formulas
with different glutamine content
Vit A, Vit E, Vit C; Malondialdehyde, Se, urate, glutathione
Se improved; Vit E and Vit C reduced; No effect on Vit A, glutathione, urate, MHA
Phylactos et al 2001 (148) 14 CD EEN; 8 wk; Nestle
(CT3211)
Antioxidants enzymatic system (Se-GPx, Cu/Zn- SOD)
No change
Thomas et al 1994 (183) 11 CD EEN E028 Se, GSHPx Se decreased; Se increased on the steroid
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