Nutritional aspects and gut microbiota in paediatric inflammatory bowel disease.
PhD thesis, University of Glasgow.
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As Crohn’s disease (CD) is a disease of the gastrointestinal tract, nutrition is very important and is implicated in several aspects of the disease, from aetiology, management, and the long-term health of the patient. Nutritional therapy with EEN is the mainstream approach in the management of active paediatric CD and has a dual effect, inducing clinical remission and providing nutritional support and rehabilitation. Although its efficacy is well established by human trials and clinical experience, the mode of action remains unknown. Initial speculations for a mechanism of action mediated through gut rest, and protein/energy reconstitution have not been established. On the other hand the strong evidence for the role of the indigenous microbiota and micronutrients in disease aetiology and mucosal injury, challenged the researcher to explore whether the action of EEN is mediated through changes in these parameters.
This study aimed to assess aspects of the nutritional status of paediatric patients with inflammatory bowel disease (IBD), to appraise the use of nutritional remedies in the same population, and to explore putative mechanisms of action of EEN, the nutritional therapy, with the most robust evidence of clinically efficacy.
The first of these studies was a questionnaire survey which assessed the use of special diets, nutritional supplements, herbals, and alternative medicine in a representative sample of paediatric patients with IBD. Use of these treatments was declared by two thirds of the patients with probiotic use and dairy free diet being the commonest forms used.
Prevalence of anaemia and predictors of its progress at six and 12 months were assessed in a large retrospective case review study. Anaemia was as high as 73% of patients at diagnosis and haemoglobin concentration improvement at six and 12 post diagnosis was associated with the use of oral iron supplementation, improvement of nutritional status markers, growth, and systemic markers of disease activity.
In a mechanistic study the validity of a bedside method, used to assess the body composition of children with CD, was compared against a reference method. The agreement of the two methods was low and the inter-individual bias between them was substantial.
The aim of this thesis was to study the effect of EEN on gut microbiota diversity, bacterial metabolic activity, inflammatory response and nutritional status in paediatric patients with active CD.
Newly diagnosed children with active CD, and patients with longstanding disease, on clinical relapse, who started treatment with EEN as part of their standard clinical management, were recruited. Four stool samples were collected while on treatment with EEN and one when the patient returned to their normal diet. Bacterial diversity was assessed with molecular microbiology techniques, and bacterial metabolites were measured in serial stool samples and correlated with faecal calprotectin levels, systemic inflammatory markers and clinical activity. A single stool sample was collected from their first-degree relatives and two serial samples from healthy children with no family history of IBD.
Significant changes were observed for the metabolic activity of the commensal microbiota during the course of treatment. In particular, faecal butyrate significantly decreased by more than 100%, faecal pH moved into the alkaline range, and a five-fold increase was observed in total sulphide but only in those patients who achieved clinical remission, or in whom faecal calprotectin levels decreased at the end of treatment. No such changes were observed in children who did not achieve complete clinical remission or when the treatment failed. Gut bacterial diversity did not change significantly during treatment, but was significantly lower than in healthy children, who also presented a higher degree of similarity between the two serial samples. Interestingly the gut microbiota of the healthy first degree relatives of CD children had significantly lower bacterial diversity compared with the healthy children but no such difference was observed compared with their CD relatives. The majority of the healthy relatives had also significantly high levels of calprotectin suggesting intestinal inflammation but no clinical presentation of gastrointestinal disease.
A secondary outcome of this study was to measure changes in the systemic and gut specific markers of disease activity during treatment. Although systemic markers of disease activity improved to normal levels in the majority of the patients, intestinal inflammation was still ongoing and only one of the 16 children had normal calprotectin levels at the end of EEN. Moreover, only in those patients who achieved clinically complete remission, did calprotectin levels decrease significantly at the end of treatment.
From the same cohort of patients three blood samples were also collected before, at the end of treatment and on normal diet. Changes in the concentration of 19 different micronutrients were measured in the serum and some in erythrocytes and correlated with systemic markers of disease activity. Serial changes in anthropometry and body composition were assessed during EEN and correlated with disease activity markers.
Body weight increased in all patients at the end of treatment but fat free mass significantly increased only in those patients who entered in clinical remission. Several micronutrients and mainly antioxidants were below the reference range for the majority of patients at the time of treatment initiation. Most of them improved by the end of treatment but the serum concentration of carotenoids further deteriorated with more than 90% of the patients presenting concentration lower than the lower sensitivity level of the assay. A strong association was found between systemic markers of disease activity and antioxidant vitamins, but not with intestinal inflammation.
In conclusion, paediatric patients with IBD, and mainly those with CD present with suboptimal protein/energy status, anaemia, and low circulating levels for many antioxidants. Treatment with EEN corrected the majority of these markers of nutritional status but the carotenoid levels deteriorated. Although the improvement in the serum levels of some micronutrients can be an epiphenomenon of the acute phase response, it does not explain the depleted levels of carotenoids at the end of EEN. This may be attributed to the lack of carotenoids in the feeds used in conjunction with excessive utilisation during the active course of the disease.
On the other hand, the unhealthy intestinal microenvironment observed, in only those patients who clinically improved at the end of treatment; do not support a prebiotic mode of EEN action, as was proposed by a recent Italian study. These changes may be a secondary phenomenon, associated with changes in gut motility, better absorption of butyrate with disease improvement, or changes in the availability of colonic bacterial substrates. Alternatively these changes may be associated with changes in the microbiota composition and production of so far unknown bacterial bioproducts which may have a causative association with the onset and propagation of intestinal inflammation in CD.
These results may have significant implications in manufacturers of clinical nutrition products. Addition of carotenoids may improve the provision of antioxidant micronutrients and a dual nutritional therapy combining EEN with prebiotics, butyrate supplementation, or probiotics may increase the efficacy of the existing formulae. This should be addressed in future studies.
||Inflammatory bowel disease, enteral nutrition, body composition, gastroenterology, anaemia, alternative medicine, micronutrients, microbiota, calprotectin.
||R Medicine > RJ Pediatrics
||College of Medical Veterinary and Life Sciences
||Edwards, Professor Christine Ann and McGrogan, Dr. Paraic
|Date of Award:
Mr Konstantinos Gerasimidis
||Copyright of this thesis is held by the author.
||25 Jun 2009
||10 Dec 2012 13:26
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