Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection
Introduction
The loss of a large part of the small bowel in infants, owing to surgical removal or a congenital defect, leads to a condition called short bowel syndrome. The 3 most common causes of short bowel syndrome in children are necrotizing enterocolitis, intestinal atresia, and midgut volvulus [22]. When a large part of the small intestine is lost, the functional ability of the remaining intestine is often inadequate to support growth and hydration, and prolonged parenteral nutritional support is required. Children with a short bowel are at risk for many life-threatening complications such as sepsis due to catheter-related blood stream infection and parenteral nutrition-associated liver disease even when these children are under total parenteral nutrition. In the clinic, decisions about the optimal management of pediatric short bowel syndrome are often based on repeated trial-and-error treatments, depending on the condition of a specific patient. Therefore, there is an urgent need for a new therapy to compensate for the lost functionality of the small intestine.
Fundamentally, when a large section of the small intestine is lost, the reduction in nutritional absorption is compensated gradually by an increase in the mucosal surface area of the remaining bowel, accompanied by increases in the villus height and crypt cell proliferation rates. This process is known as adaptation [32]. The regulation and augmentation of the function of the remaining intestine is induced through a complex interaction of many different factors, including luminal nutrients and gastrointestinal hormones [22], [28]. Physiologically, bowel adaptation is supposed to occur only in response to oral feeding [32]. In this study, we investigated the levels of 3 gastrointestinal hormones, acyl ghrelin, des-acyl ghrelin, and glucagon-like peptide-2 (GLP-2).
Ghrelin is secreted by the X/A-like cells of the stomach and the proximal small intestine. Two major molecular forms of ghrelin exist, of which acyl ghrelin with n-octanoylated modification appears to serve multiple functions [7], [15], [27], including exerting positive effects on food intake, growth hormone secretory action, glucose and lipid metabolism, gastrointestinal motility, cell proliferation, and hemodynamics, all of which may contribute to intestinal adaptation after massive small bowel resection. On the other hand, non-acylated des-acyl ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying [2]. Furthermore, des-acyl ghrelin suppresses acyl ghrelin-induced food intake [10]; a continuous infusion of des-acyl ghrelin is reported to reduce weight gain [21].
GLP-2 is secreted by the intestinal L-cells of the distal ileum and proximal colon in response to both direct stimulation of luminal nutrients and vagally mediated pathways, which are activated by the presence of nutrients in the proximal bowel [12]. GLP-2 is best known for its beneficial role in intestinal adaptation and has become a focus of studies on short bowel syndrome [32]. A randomized placebo-controlled study of teduglutide, a GLP-2 analog, showed a potential reduction in the dependency on parenteral support of adult patients with short bowel syndrome [11]. However, this treatment has not been applied clinically in children.
The purpose of this study was to clarify the trends in the secretion of endogenous acyl ghrelin, des-acyl ghrelin, and GLP-2 following massive small bowel resection in order to obtain basic data for the future investigation of a new treatment that may induce efficient intestinal adaptation in patients with short bowel syndrome.
Section snippets
Animals
Sixty-three 7-week-old male Sprague-Dawley rats weighing 200–240 g (purchased from Kyudo Co., Ltd., Saga, Japan) were used in this experiment. The animals were individually housed in cages with free access to standard rat chow and water, and maintained under standardized temperature (23 °C ± 1 °C), humidity (50% ± 10%), and 12-h light-dark cycles (lights on at 7:00 a.m.).
All experimental procedures were approved by the Laboratory Animal Committees of Kagoshima University Graduate School and were
Changes in daily assessment data
The body weight of animals in the 80% SBR group returned to preoperative levels within 4 days, and continued to increase steadily (Fig. 1). Food intake in the 80% SBR animals recovered to preoperative levels on postoperative day 4. After day 4, roughly equivalent intake was maintained between the 2 operative groups, the 80% SBR animals and the sham-operated animals (Fig. 2). The sham-operated animals showed higher water intake, amount of stool, and amount of urine than the 80% SBR animals until
Discussion
Ideally, the progression of intestinal adaptation in infants with short bowel syndrome would occur gradually over 1 to 2 years [32]. In the first 1 to 2 weeks after resection, ileus occurs in the remaining bowel. The next 1 to 6 months are characterized by hypersecretion. Fluid and electrolytes are lost owing to a large amount of watery stool excretion. Subsequently, morphological and functional adaptations occur, such as an increase in the absorptive mucosal surface area. Adaptation is known
Conclusion
This is the first report to show the trends of endogenous preprandial plasma acyl ghrelin, des-acyl ghrelin and postprandial plasma GLP-2 in the context of massive small bowel loss. The expansion of the absorptive mucosal surface area became evident after postoperative day 4. All the 3 gastrointestinal hormones studied were elevated immediately after resection. The acyl ghrelin and GLP-2 levels were peaked at the same time as when body weight and food intake recovered to the preoperative levels
Conflicts of interest
The authors declare that they have no conflicts of interest.
Acknowledgments
This work was supported by the Institute of Laboratory Animal Sciences, Kagoshima University.
References (37)
- et al.
Glucagon-like peptide 2 inhibits ghrelin secretion in humans
Regul Pept
(2006) - et al.
Compensation by the residual intestine after intestinal resection in the rat. II. Influence of postoperative time interval
Gastroenterology
(1977) - et al.
Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats
Peptides
(2008) - et al.
The effects of variations in dose and method of administration on glucagon like peptide-2 activity in the rat
Eur J Pharmacol
(2008) - et al.
Temporal changes in the intestinal growth promoting effects of glucagon-like peptide 2 following intestinal resection
J Surg Res
(2009) - et al.
Glucagon receptor expression and glucagon stimulation of ghrelin secretion in rat stomach
Biochem Biophys Res Commun
(2007) - et al.
Ghrelin – a hormone with multiple functions
Front Neuroendocrinol
(2004) - et al.
Acute psychological stress raises plasma ghrelin in the rat
Regul Pept
(2006) - et al.
Growth factors: possible roles for clinical management of the short bowel syndrome
Semin Pediatr Surg
(2010) - et al.
Intestinal adaptation: structure, function, and regulation
Semin Pediatr Surg
(2001)
Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety
Regul Pept
Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications
Peptides
Gastrointestinal hormones and food intake
Gastroenterology
Intestinal function and metabolism in the early adaptive phase after massive small bowel resection in the rat
J Pediatr Surg
Glucagon inhibits ghrelin secretion in humans
Eur J Endocrinol
Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin
Gut
Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2
J Endocrinol
Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse
Gut
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