Gut hormones, and short bowel syndrome: the enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation

Abstract

Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenteral nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenteral nutrition while enhancing the intestinal adaptive response would be valuable. Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2 is a trophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However, the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action, and utility of GLP-2 in the regulation of intestinal mucosal growth.

Figure 1

Potential pathways involved in the production, release, activity, and sites of action of GLP-2. GLP-2 produced by the L-cell is induced following the ingestion of a meal and can be induced either by direct stimulation of the L-cell, or potentially following the release of upstream neuronal /hormonal agonists. The GLP-2R has been localized to components of the enteric nervous system (ENS) and to regions of the brain, thus the growth-promoting effects associated with GLP-2 may involve interactions with the brain-gut axis. Potentially the ENS / vagal interface might be responsible for the early release of GLP-2.

Figure 2

An experimental rat model of SBS-induces changes in circulatory GLP-2 levels. The distal regions of the small bowel and/or the large intestine are necessary for GLP-2 production. In these experiments, the entire proximal small bowel was removed; therefore the distal ileum and/or the colon are likely the cells responsible for the production of GLP-2 as all other bowel tissue had been removed. Resected = 90% intestinal resection leaving a 10 cm ileal remnant. CEC = cecetomy + removal of all but 20 cm of jejunum. The remnant jejunum was anastomosed to the ascending colon. ^aP < 0.05 vs cecetomized animals; ^cP < 0.05 vs 90% proximal resected animals that were enterally-fed (10 cm remnant ileum).

Figure 3

A: GLP-2 stimulation of the G_s-Coupled Receptor induced cell proliferation. The proposed GLP-2 /GLP-2R signaling pathway as characterized in cells that were transfected with the GLP-2R. See section on GLP-2 receptor-activity for description (pages 11-12); B: GLP-2 stimulation of the Gα_i-Coupled Receptor induced cell proliferation. Possible trafficking pathways triggered by GLP-2 in cells that tested negative for the characterized GLP-2R. Potentially, GLP-2 induces divergent signaling pathways which results in an increase in the rate of cell proliferation. See section on GLP-2 receptor-activity for description (pages 11-12).

Figure 4

GLP-2 stimulation of the enteric nervous system. GLP-2 binds to 7-TM G protein-coupled receptors localized to components of the ENS. This results in a conformational change in the GLP-2R that eventually activates c-fos expression via the Gαs, AC, c-AMP pathway. This suggests that a rise in circulatory GLP-2 levelsmight stimulate the GLP-2R leading to an increased stimulation of the myenteric and/or submucosal neurons. Potentially the trophic effects on the gut mucosa associated with GLP-2 are the result of a second downstream mediator, either a neurotransmitter or direct innervation that is activated upon GLP-2’s initial stimulation of the ENS localized GLP-2R.

Figure 5

Neural or humoral mechanism involvement in the early release of GLP-2. The delivery of a meal significantly increases serum GLP-2 levels in rats with discontinuous small bowel (ANOVA, P < 0.007). The disruption of the continuity of the bowel (stoma creation) did not inhibit the initial nutrient-stimulated GLP-2 response. Thus, GLP-2 production is increased at least in part by neural and/or hormonal mechanisms. Serum GLP-2 levels reported as ng/mL.