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Title: The role of dietary fat and adipose tissues in the aetiopathogenesis and treatment of Crohn's disease
Author: Ajabnoor, Sarah
ISNI:       0000 0004 7962 7307
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2018
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Treatment of Crohn's disease (CD) is challenging. The use of enteral nutrition (EN) as primary therapy in adult patients with CD is not yet supported by high quality evidence. The fat composition of EN has been suggested to be a key factor in controlling the inflammation in CD. Moreover, deep understanding of disease pathogenesis is lacking. In CD, the mesentery attached to the inflamed intestine is often focally thickened: the phenomenon known as "fat-wrapping", but the reasons for this are unknown. Additionally, the alteration in tissue remodelling of intestinal epithelium by high fat intake is a newly suggested cellular mechanism for intestinal diseases. It is predicted that improved patient outcomes will come from novel nutritional therapies resulting from an improved understanding of the disease pathogenesis. The aims of my PhD research were to investigate novel mechanisms of action of dietary fatty acids in CD patients' mesenteric pre-adipocytes and epithelial cells which could benefit the development of optimized lipid formulation of enteral feeds. Here, in a systematic review of previous clinical trials in CD, we demonstrated that high remission rate is significantly associated with the intake of exclusive enteral nutrition (EEN) feeds that have a high n-6:n-3 ratio. The amount of medium chain triglyceride (MCT) in the feeds was also positively correlated with the remission rate but without statistical significance. lower remission rates were non-significantly associated with higher intakes of feeds enriched with long chain triglycerides (LCTs) or monounsaturated fatty acids (MUFA). In CD mesenteric adipose tissue (MAT) I have identified several abnormalities in their gene expression profile. Unlike typical adipose tissue, MAT in CD was associated with defective adipogenesis via reduced expression of leptin and CEBPa, and was associated with a low anti-inflammatory profile via decreased expression of M2 macrophage markers. Moreover, in in-vitro study I showed that mesenteric preadipocytes have an increased adipogenic response to oleic acid, linoleic acid, and alinolenic acid, which was predominantly modulated via CEBPa. Finally, in cell culture study I have shown that low concentration of lipids can modulate the physiology of the gut epithelium by reducing colonic crypt proliferation. In conclusion, my data indicate that the fatty acid composition of EEN can play a key role in improving clinical outcomes in CD. According to my findings, the mechanism of this action can be mediated via MAT function and possibly through intestinal stem cell function. Overall, the findings of this PhD research provide important insights into a new mechanism of action which can be exploited to target future therapeutic approaches in CD and to help optimize the lipid formulation of enteral feeds used in its treatment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available