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Illustration of 60% jejunoileal resection plus cecectomy in the rat that mimics human short bowel syndrome. The resected area, designated by shading, consists of intestine from 40 cm distal to the ligament of Treitz to 1 cm distal to the cecum. Continuity of the remaining 40 cm of jejunum and colon is restored with an end-to-end jejunocolic anastomosis. Transection consists of 2 parallel cuts with restoration of bowel continuity.
Source publication
Bowel resection may lead to short bowel syndrome (SBS), which often requires parenteral nutrition (PN) due to inadequate intestinal adaptation. The objective of this study was to determine the time course of adaptation and proglucagon system responses after bowel resection in a PN-dependent rat model of SBS.
Rats underwent jugular catheter placemen...
Context in source publication
Context 1
... animals were acclimated to their new environment for 5-7 days while being fed semipurified elemental powdered diet ad libitum. 16 Rats were randomly assigned to undergo 60% bowel resection (Figure 1) and to be killed at one of the following 10 time points postsurgery: 4 hours (n = 4), 12 hours (n = 6), 1 day (n = 4), 2 days (n = 6), 3 days (n = 5), 4 days (n = 3), 5 days (n = 4), 7 days (n = 10), 10 days (n = 5), and 12 days (n = 6). A baseline group that received the same presurgery care as surgery animals was also included. ...
Similar publications
Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral protein component, casein, soy, or whey protein, potenti...
Citations
... While patients with SBS with jejunostomy are the most challenging subjects to manage because of the massive loss of the small and large intestine and associated functions, very few studies, using mostly pigs, have reported complete colonic resection with jejunostomy anastomosis (5,136,139). Clearly, animal models are useful for finding novel therapies that improve adaptation; the development of treatments with GLP-2 analogs is an example (16,42,69,70,75,90,121,123). ...
... The time course of the studies should also be taken into consideration. For example, many studies of resected rat models focus on adaptation between 1 and 2 weeks postsurgery (16,29,44,46,69,70,88,89) and, less often, 3 to 4 weeks postsurgery (54,110). In the case of rodents that have undergone intestinal resection, the first 4 days can be considered an acute phase of postoperative recovery with a gradual recovery of oral feeding. ...
Short bowel syndrome (SBS) is a rare disease that results from extensive resection of the intestine. When the remaining absorption surface of the intestine cannot absorb enough macronutrients, micronutrients, and water, SBS results in intestinal failure (IF). Patients with SBS who suffer from IF require parenteral nutrition for survival, but long-term parenteral nutrition may lead to complications such as catheter sepsis and metabolic diseases. Spontaneous intestinal adaptation occurs weeks to months after resection, resulting in hyperplasia of the remnant gut, modification of gut hormone levels, dysbiosis, and hyperphagia. Oral nutrition and presence of the colon are two major positive drivers for this adaptation. This review aims to summarize the current knowledge of the mechanisms underlying spontaneous intestinal adaptation, particularly in response to modifications of luminal content, including nutrients. In the future, dietary manipulations could be used to treat SBS.
Please see http://www.annualreviews.org/page/journal/pubdates for expected final online publication date for the Annual Review of Nutrition, Volume 40. 2020
... Enteral nutrients, specifically fat, stimulate intestinal adaptation via trophic gastrointestinal hormones, the most widely studied of which is glucagon-like peptide 2 (GLP-2). This intestinal growth factor is produced by L cells in the ileum and colon [29]. This has led to the production of teduglutide, a long-acting GLP-2 analogue that is given to adults with PN-dependent short bowel syndrome and has shown benefit in reducing PN needs [30,31]. ...
Purpose of review
Short gut syndrome is life-altering and life-threatening disease resulting most often from massive small bowel resection. Recent advances in understanding of the perturbed physiology in these patients have translated into improved care and outcomes. This paper seeks to review the advances of care in SBS patients.
Recent findings
Anatomic considerations still predominate the early care of SBS patients, including aggressive preservation of bowel and documentation of remnant bowel length and quality. Intestinal adaptation is the process by which remnant bowel changes to fit the physiologic needs of the patient. Grossly, the bowel dilates and elongates to increase intestinal weight and protein content. Architectural changes are noted, such as villus lengthening and deepening of crypts. In addition, gene expression changes occur that function to maximize nutrient uptake and fluid preservation. Management is aimed at understanding these physiologic changes and augmenting them whenever possible in an effort to gain enteral autonomy. Complication mitigation is key, including avoidance of catheter complications, bloodstream infections, cholestasis, and nutrient deficiencies.
Summary
Multidisciplinary teams working together towards intestinal rehabilitation have shown improved outcomes. Today’s practitioner needs a current understanding of the ever-evolving care of these patients in order to promote enteral autonomy, recognize complications, and counsel patients and families appropriately.
... 119,122 The nature of nutrients that pass through the different intestinal segments differs depending on the type of anastomosis, most likely resulting in specific localized adaptation. Nevertheless, some authors reported colonic adaptation in rats with ileo-caecal resection under exclusive parenteral nutrition, 123,124 suggesting that adaptation may be independent of the luminal presence of nutrients. In fact, in this study, despite the absence of nutrients, bilio-pancreatic secretions were still present in the lumen of the intestine, and the colon was perhaps still exposed to unusual jejunal or ileal luminal content. ...
... In fact, in this study, despite the absence of nutrients, bilio-pancreatic secretions were still present in the lumen of the intestine, and the colon was perhaps still exposed to unusual jejunal or ileal luminal content. 124 It has also been recognized that this adaptation is facilitated by circulating factors such as GLP-2 (whose secretion can be stimulated by nutrients or luminal content), as illustrated by parabiosis experiments between resected and nonresected animals (for a review, see O'Brien et al 125 ). ...
The plasticity of a material corresponds to its capacity to change its feature under the effect of an external action. Intestinal plasticity could be defined as the ability of the intestine to modify its size or thickness and intestinal cells to modulate their absorption and secretion functions in response to external or internal cues/signals. This review will focus on intestinal adaptation mechanisms in response to diet and nutritional status. These physiological mechanisms allow a fine and rapid adaptation of the gut to promote absorption of ingested food, but they can also lead to obesity in response to overnutrition. This plasticity could thus become a therapeutic target to treat not only undernutrition but also obesity. How the intestine adapts in response to 2 types of surgical remodeling of the digestive tract-extensive bowel resection leading to intestinal failure and surgical treatment of pathological obesity (ie, bariatric surgeries)-will also be reviewed.
... As jejunal CCPI remained unchanged, the trophic effects of exogenous GLP-2 infusion may have been due to reduced apoptosis [32]. Isolated bowel resection had fewer effects on small bowel morphology, consistent with reports describing inadequate native jejunal adaptation after massive ileocecal resection [33,34]. This was in contrast to what we and others have demonstrated previously, noting striking increases in jejunal villus height or width, mucosal weight, DNA and protein content, and maltase activity after massive distal resection [23,35]. ...
To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats.GLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear.Sprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2.5 nmol/kg/h, n = 9). SBS groups underwent a 60% jejunoileal resection with cecectomy and jejunocolic anastomosis. All rats were maintained on parenteral nutrition for 7 d. Parameters measured included gut morphometry, qPCR for hexose transporter (SGLT-1, GLUT-2, GLUT-5) and GLP-2 receptor mRNA, whole mount immunohistochemistry for neurons (HuC/D, VIP, nNOS), plasma glucose, gut hormones, and body composition.Resection increased the proportion of nNOS immunopositive myenteric neurons, intestinal muscularis propria thickness and crypt cell proliferation, which were not recapitulated by GLP-2 therapy. Exogenous GLP-2 increased jejunal mucosal surface area without affecting enteric VIP or nNOS neuronal immunopositivity, attenuated resection-induced reductions in jejunal hexose transporter abundance (SGLT-1, GLUT-2), increased plasma amylin and decreased peptide YY concentrations. Exogenous GLP-2 attenuated resection-induced increases in blood glucose and body fat loss.Exogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2 to modulate resection-induced changes in peripheral glucose and lipid reserves may be important in understanding the whole-body response following intestinal resection, and is worthy of further study.
... Le type et la nature des nutriments qui passent dans les différents segments intestinaux varient selon le type d'anastomose entraînant très probablement une adaptation localisée spécifique. Néanmoins, certains auteurs rapportent une adaptation du côlon chez des rats avec une résection iléo-caecale placés sous nutrition parentérale exclusive [57,58], suggérant une adaptation indépendante de la présence luminale des nutriments. En fait, même en absence de nutriments, des sécrétions bilio-pancréatiques sont présentes dans la lumière du tube, et le côlon pourrait donc se retrouver exposer à un contenu luminal de type « jéjunal » ou « iléal » non habituel [58]. ...
... Néanmoins, certains auteurs rapportent une adaptation du côlon chez des rats avec une résection iléo-caecale placés sous nutrition parentérale exclusive [57,58], suggérant une adaptation indépendante de la présence luminale des nutriments. En fait, même en absence de nutriments, des sécrétions bilio-pancréatiques sont présentes dans la lumière du tube, et le côlon pourrait donc se retrouver exposer à un contenu luminal de type « jéjunal » ou « iléal » non habituel [58]. Il est également reconnu que cette adaptation est permise par des facteurs circulants comme le GLP2 (dont la sécrétion peut être stimulée par les nutriments ou le contenu luminal), et les expériences de parabiose entre animaux réséqués [59]). ...
La plasticité d’un matériau est sa propriété à modifier sa forme sous l’effet d’une action et à la conserver à l’arrêt de cette action. Par analogie, la plasticité neuronale décrit comment des neurones s’étendent, se rétractent ou se réorganisent en fonction de l’activité des synapses et des neurones qu’ils rencontrent et comment au niveau des synapses les récepteurs ou les neuropeptides secrétés sont modifiés. De la même façon, on peut définir la plasticité intestinale comme la capacité qu’a l’intestin à modifier sa taille ou son épaisseur et qu’ont les cellules épithéliales intestinales à moduler leurs fonctions d’absorption et de sécrétion en réponse à des signaux nutritionnels et métaboliques. Ces mécanismes physiologiques permettent une adaptation fine et rapide de l’intestin contribuant à favoriser l’absorption des aliments ingérés, mais ils peuvent être dérégulés sous l’effet de la surnutrition. Cette plasticité pourrait devenir une cible thérapeutique non seulement pour soigner l’obésité mais également la dénutrition.
... Gut hormones are key factors in this spontaneous intestinal adaptation 10 . Increased secretions of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) have been reported in preclinical models 11,12 and in SBS patients with the colon in continuity 3 , but not in SBS patients with jejunostomy (i.e. with no colon and no ileum) 4,13 These hormones are secreted, together with Peptide YY (PYY), by the enteroendocrine L cells of the ileum and colon, in response to nutrient stimulation 14 . They play key roles in orchestrating gastrointestinal functions, such as intestinal trophicity 12 , expression of intestinal nutrient transporters 10,15,16 and gastro-intestinal motility 4,17 . ...
... Since morphological and hormonal secretion adaptations have been reported to be maximal in different rat models of resection between day 4 and day 12 after intestinal resection 11,27,28 , the experimental period for the rat model was set up at 7 days. The colonic morphological adaptation observed in our IR-JC model are in agreement with previous reports for patient with jejuno-colonic anastomosis, i.e increase of crypt depth and of proliferating cell number with a controlled hyperplasia 29 and increased GLP-2 secretions 3 . ...
... Previous studies have reported maximal intestinal morphological changes between day 4 and 12 after the surgery 11,27 .Thus, we set 7 days as the experimental period for this study. Body weight was monitored daily and food intake was determined from day 2 to 7 post-surgery. ...
Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations.
... Glucagon-like peptide-2 (GLP-2) is produced by the enteroendocrine L cells, predominantly found in the ileum and colon [81]. GLP-2 leads to villous hyperplasia, stimulation of crypt cell growth, reduced enterocyte apoptosis and increased intestinal absorption [82]. ...
The ultimate goal in the treatment of short bowel syndrome is to wean patients off parenteral nutrition, by promoting intestinal adaptation. Intestinal adaptation is the natural compensatory process that occurs after small bowel resection. Stimulating the remaining bowel with enteral nutrition can enhance this process. Additionally, medication can be used to either reduce factors that complicate the adaptation process or to stimulate intestinal adaptation, such as antisecretory drugs and several growth factors. The aim of this review was to provide an overview of the best nutritional strategies and medication that best promote intestinal adaptation.
... A functioning colon is believed to support intestinal adaptation (82), although its importance in pediatric SBS remains debated (55). Studies in rats suggest that the colonic secretion of endogenous growth factors (see later section) is not sufficient to induce significant intestinal adaptation (134). Since most studies in animal models have used a proximal or midjejunal resection with an intact colon, these studies generally report dramatic adaptation following resection (16,51,150,172,180,221). ...
... In the adult rat model of distal bowel resection with a jejunocolic anastomosis to restore intestinal continuity, EN is not sufficient to meet the nutritional needs and facilitate adequate adaptive growth of the remnant intestine, as observed with proximal small bowel resection. Rats develop prolonged malabsorption with weight loss and high mortality when fed orally after this resection (137,205), although significant increases in colonic mass, crypt depth, and proglucagon expression occur (77,79,134). Jejunum and colon show a differential time course of adaptation with increases in jejunal cellularity that peak at 3-4 days and decline to baseline by 12 days postresection, whereas colon crypt depth steadily increases, peaking at 7-12 days postresection (134). ...
... Rats develop prolonged malabsorption with weight loss and high mortality when fed orally after this resection (137,205), although significant increases in colonic mass, crypt depth, and proglucagon expression occur (77,79,134). Jejunum and colon show a differential time course of adaptation with increases in jejunal cellularity that peak at 3-4 days and decline to baseline by 12 days postresection, whereas colon crypt depth steadily increases, peaking at 7-12 days postresection (134). Thus PN in combination with massive gut resection is required to provide the appropriate nutritional support for this stringent distal bowel resection model, which better reflects the condition of SBS with IF seen in human neonates (77,145). ...
Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption, and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, nutritional interventions and growth factor therapies. Animal studies may help but careful evaluation of the cellular mechanisms, safety and translational relevance of new procedures are required. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically-relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rat and mice more easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g. glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g. PN, milk diets, long/short chain lipids, pre- and probiotics). Conversely, newborn pigs and weanling rats represent a translational advantage for infant SBS due to their immature intestine. A balance among practical, economical, experimental and ethical constraints determines the choice of SBS model for each clinical or basic research question.
... In contrast, increasing plasma GLP-2 levels by supplementing total parenteral nutrition (TPN) with short-chain fatty acids augmented mucosal growth after intestinal resection in neonatal pigs (1). An important aspect of all previously reported animal SBS studies is that they have employed a surgical model with resection of the majority of the small intestine (50 -80%), leaving the ileum and colon in continuity (26,27,29). This procedure elevates the endogenous GLP-2 release after resection (26,27,29), as shown also in adult patients with SBS (21,24). ...
... An important aspect of all previously reported animal SBS studies is that they have employed a surgical model with resection of the majority of the small intestine (50 -80%), leaving the ileum and colon in continuity (26,27,29). This procedure elevates the endogenous GLP-2 release after resection (26,27,29), as shown also in adult patients with SBS (21,24). In a recent study using neonatal pigs, an ileal resection model was described along with the well-established jejunal resection model, but both models still had a colon in continuity (44). ...
... In more mature rodents (27), pigs (29), and humans (24), jejunal resection with a reconnected colon leads to elevated plasma GLP-2 levels. Even if the ileum is resected and the colon remains in continuity with the remnant intestine, GLP-2 levels are still increased (21), and this endogenous colonic GLP-2 release may significantly improve intestinal adaptation (6,26,44). Our results suggest that, under the clinically relevant conditions of SBS with a jejunostomy, endogenous GLP-2 deficiency leads to limited adaptation of the remnant intestine in the premature neonatal intestine. ...
Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following intestinal resection in preterm pigs. Preterm pigs were fed enterally for 48 hours before undergoing resection of 50% of the small intestine and establishment of a jejunostomy. Following resection, pigs were maintained on total parenteral nutrition (TPN) without (SBS, n=8) or with GLP-2 treatment (3.5 μg/kg BW/h, SBS+GLP-2, n=7), and compared with a group of unresected preterm pigs (Control, n=5). After 5 days of TPN, all piglets were fed enterally for 24 h and a nutrient balance study was performed. Intestinal resection was associated with markedly reduced endogenous GLP-2 levels. GLP-2 increased the relative absorption of wet weight (46 vs 22%), energy (79 vs 64%) and all macronutrients (all parameters p<0.05). These findings were supported by a 200% increase in sucrase and maltase activities, a 50% increase in small intestinal epithelial volume (p<0.05), as well as increased DNA and protein contents and increased total protein synthesis rate in SBS+GLP-2 versus SBS pigs (+100%, p<0.05). Following intestinal resection in preterm pigs, GLP-2 induced structural and functional adaptation, resulting in a higher relative absorption of fluid and macronutrients. GLP-2 treatment may be a promising therapy to enhance intestinal adaptation and improve digestive function in preterm infants with jejunostomy following intestinal resection.
... Following resection, 5 ml of warm 0.9% sodium chloride was instilled in the peritoneal cavity for resuscitation before the peritoneum was closed with absorbable suture, and the skin incision was closed with wound clips. Next, rats underwent cannulation of the superior vena cava with placement of a 3-Fr catheter to allow infusion of PN as previously described (28,29,(37)(38)(39). Following surgery, all rats were recovered in individual wire-bottom cages and received 0.18 mg/kg intraperitoneal oxymorphone hydrochloride (SAGENT Pharmaceuticals) every 6 h ϫ 48 h for analgesia and 200 mg/kg of ampicillin every 12 h ϫ 48 h for perioperative prophylaxis. ...
... M formaldehyde gel electrophoresis staining for ribosomal bands using ethidium bromide. Expression of proglucagon, GLP-2 receptor (GLP-2R), and IGF-I mRNA in the residual jejunum and colon was measured in a two-step reverse transcriptase real-time PCR (RT-qPCR) using SYBR green detection method as previously described (29,47). -Actin mRNA expression was determined for both segments and acted as a reference gene based on evidence that mean -actin mRNA expression did not differ between treatment groups. ...
... However, as expected, a noticeable 63% decrease in plasma GLP-2 concentration was observed in the group treated with PN ϩ EN ϩ GLP-2 for 7 days compared with the group treated with PN ϩ EN ϩ GLP-2 for 18 days. In addition, the group provided PN ϩ EN ϩ GLP-2 for 7 days had a significant 28% elevation in plasma GLP-2 concentration compared with the group treated with TPN alone and was greater than the usual range of 25-30 pmol/l observed in the nonsurgical oral reference group from our studies (29,38,39) (Fig. 8A). All groups that underwent resection had decreased plasma IGF-I concentrations compared with a nonsurgical oral reference group with a trend toward higher plasma IGF-I concentrations in the group treated with PN ϩ EN ϩ GLP-2 for 7 days compared with the group treated with PN ϩ EN ϩ GLP-2 for 18 days (P ϭ 0.0575) (Fig. 8B). ...
Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that shows promise for the treatment of short bowel syndrome (SBS). Our objective was to investigate how combination GLP-2 + enteral nutrients (EN) affects intestinal adaption in a rat model that mimics severe human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg(-1)·day(-1)), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral reference group. Animals underwent massive distal bowel resection followed by jejunocolic anastomosis and placement of jugular catheters. Starting on postoperative day 4, rats in the EN groups were allowed ad libitum access to EN. Groups provided PN + EN + GLP-2 had their rate of PN reduced by 0.25 ml/day starting on postoperative day 6. Groups provided PN + EN + GLP-2 demonstrated significantly greater body weight gain with similar energy intake and a safe 80% reduction in PN compared with TPN ± GLP-2. Groups provided PN + EN + GLP-2 for 7 or 18 days showed similar body weight gain, residual jejunal length, and digestive capacity. Groups provided PN + EN + GLP-2 showed increased jejunal GLP-2 receptor (GLP-2R), insulin-like growth factor-I (IGF-I), and IGF-binding protein-5 (IGFBP-5) expression. Treatment with TPN + GLP-2 demonstrated increased jejunal expression of epidermal growth factor. Cessation of GLP-2 after 7 days with continued EN sustained the majority of intestinal adaption and significantly increased expression of colonic proglucagon compared with PN + EN + GLP-2 for 18 days, and increased plasma GLP-2 concentrations compared with TPN alone. In summary, EN potentiate the intestinotrophic actions of GLP-2 by improving body weight gain allowing for a safe 80% reduction in PN with increased jejunal expression of GLP-2R, IGF-I, and IGFBP-5 following distal bowel resection in the rat.
