Abstract
The inflammatory bowel diseases (IBD) include Crohnâ s disease (CD) and ulcerative colitis. Although several therapeutic approaches are used to
modulate the inflammatory response in IBD, they do not cure the disease and few lead to histological healing. An alternative approach is to use
enteral formula given exclusively (EEN) to treat IBD. However, the mechanism(s) in which EEN alters intestinal inflammation is unknown. The aim
of this thesis was to begin investigating mechanisms by which EEN interacts with the epithelium, and to define how EEN exerts a clinical benefit. In
vitro and in vivo models were used to investigate effects of polymeric formula (PF), as used for EEN, upon epithelial inflammatory responses and
gut barrier function. These effects were evaluated by measuring inflammatory markers, indicators of mucosal integrity, histology, and bacterial
load. This thesis demonstrated: i) elevated osteoprotegerin (OPG) levels in serum, stool and mucosa of children at diagnosis of CD and that the
inflamed gut is a source of the elevated OPG. Furthermore, OPG levels decrease with EEN treatment and may be a result of direct suppression of
OPG expression by PF; ii) that OPG possesses pro-inflammatory properties, and similar to TNF-α, could enhance the mucosal inflammatory
response and gut barrier dysfunctions through nuclear factor (NF)-κB activation; iii) that PF acts directly on epithelial cells to maintain normal gut
barrier function/integrity in the presence of inflammatory stimuli. Furthermore, EEN is as effective as infliximab, and more effective than
hydrocortisone, in resolving pro-inflammatory-induced barrier dysfunction; iv) that administration of EEN to mice with infection induced-colitis,
reduce mucosal cytokine levels and lead to recovery of barrier function, resolved mucosal histological changes, and reduced intestinal bacterial
load. These findings begin to explain the important events involved in achieving mucosal healing, as is observed with EEN treatment in CD
patients, compared to corticosteroids treatment where mucosal healing is not achieved; v) that PF reduces inflammatory responses, primarily
through modulation of NF-κB. In summary, the results arising from this thesis have significantly advanced our understanding of how EEN interacts
directly with epithelium and how it can exert a clinical benefit, independent of modulating intestinal bacteria.