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| Steroid Receptor Biology |
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Intestinal Adaptation The small intestine has a remarkable ability to adapt after injury, inflammation or resection. When an individual loses a large proportion of their small bowel through disease or surgery, the recovery and survival of the individual depends on the ability of the small bowel to grow and reproduce itself. This is particularly so in children with so-called 'short bowel syndrome’. During the process of intestinal adaptation a number of morphological and functional changes occur. Following resection, the residual bowel undergoes dilation, muscle wall hypertrophy and mucosal hyperplasia. There is also an increase in the size of the villi. Functionally, the absorptive capacity of the small bowel is increased, whilst there is a decrease in motility of the bowel, allowing a longer time for contact between the food and mucosa. This response is prompt and designed to maintain an adequate absorptive area. A well characterised model of studying intestinal adaptation is that of massive small bowel resection (MSBR). In this model 70-80% of the small bowel is surgically removed and the remaining bowel rejoined. The residual bowel undergoes a marked hypertrophic and hyperplastic response. A number of factors are known to be involved in the adaptation process at the cellular level, yet the relative importance and interplay between these factors is unknown. Our group has characterised the response of a number of genes thought to be involved in mediating the adaptive response. Of particular interest is the proglucagon gene and its products. Proglucagon is synthesized in L-cells of the intestinal mucosa and is thought to be an important humoral factor in adaptation. We have demonstrated a marked and early increase in glucagon mRNA levels in response to MSBR which is partly dependent on luminal nutrition. We have also demonstrated a marked increase in glucagon and PYY production in L-cells. PYY has also been postulated to play a role in intestinal adaptation. GLP-2, another product of the proglucagon gene, is currently of great interest for its potent trophic effects on the bowel following resection. GLP-2 is known to be inactivated by a serine protease dipeptidyl peptidase (DPP IV) and we postulated that DPP IV may limit the enterotrophic activity of GLP-2 in rats and humans. We have shown that DPP IV mRNA levels decrease following MSBR possibly allowing GLP-2 activity to be amplified during the adaptive response. It is possible that these and other factors regulating intestinal adaptation could be used a therapeutic agents for the treatment of short bowel syndromes. Currently, we are seeking to identify novel genes and further characterize known genes whose expression is regulated during the early phase of the adaptive response. We are also seeking to translate these findings into clinical practice through a series of collaborative studies with colleagues in the Departments of Gastroenterology (Dr. Julie Bines) and Surgery (Mr. Russell Taylor) at the Royal Children’s Hospital. These studies should provide further insight into the fundamental mechanisms of the adaptive response.
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