Elsevier

Peptides

Volume 43, May 2013, Pages 160-166
Peptides

Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection

https://doi.org/10.1016/j.peptides.2013.03.006Get rights and content

Highlights

  • Changes of ghrelin and GLP-2 after massive intestinal resection are clarified.

  • Acyl ghrelin and GLP-2 increased immediately and peaked on postoperative day 4.

  • Des-acyl ghrelin increased immediately and reached its peak on postoperative day 1.

  • Adaptations in the residual intestine were promoted after postoperative day 4.

Abstract

Children with short bowel syndrome face life-threatening complications. Therefore, there is an urgent need for a new therapy to induce effective adaptation of the remnant intestine. Adaptation occurs only during feeding. We focused on preprandial acyl ghrelin and des-acyl ghrelin, and postprandial glucagon-like peptide-2 (GLP-2), which are known to have active orexigenic and trophic actions. This study aims to clarify the secretion trends of these hormones after massive small bowel resection and to obtain basic data for developing a new treatment. Sixty-three growing male rats were used: 3 were designated as controls receiving no operation and 60 were randomized into the 80% small bowel resection (80% SBR) group and the transection and re-anastomosis group. Changes in body weight, food intake, and remnant intestine morphology were also assessed for 15 days after the operation. Acyl ghrelin and des-acyl ghrelin levels increased immediately, equivalently in both operation groups (P = 0.09 and 0.70). Interestingly, in 80% SBR animals, des-acyl ghrelin peaked on day 1 and acyl ghrelin peaked on day 4 (P = 0.0007 and P = 0.049 vs controls). GLP-2 secretion was obvious in 80% SBR animals (P = 2.25 × 10−6), which increased immediately and peaked on day 4 (P = 0.009 vs. controls). Body weight and food intake in 80% SBR animals recovered to preoperative levels on day 4. Morphological adaptations were evident after day 4. Our results may suggest a management strategy to reinforce these physiological hormone secretion patterns in developing a new therapy for short bowel syndrome.

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.

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