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1.  Exogenous Glucagon-Like Peptide-2 (GLP-2) Augments GLP-2 Receptor mRNA and Maintains Proglucagon mRNA Levels in Resected Rats 
Background
Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon-derived hormone that stimulates intestinal adaptive growth. Our aim was to determine whether exogenous GLP-2 increases resection-induced adaptation without diminishing endogenous proglucagon and GLP-2 receptor expression.
Methods
Rats underwent transection or 70% jejunoileal resection ± GLP-2 infusion (100 μg/kg body weight/d) and were fed a semipurified diet with continuous infusion of GLP-2 or saline by means of jugular catheter. After 7 days, body weight, mucosal cellularity (dry mass, protein and DNA), crypt–villus height, and crypt cell proliferation (by bromodeoxyuridine staining) were determined. Plasma bioactive GLP-2 (by radioimmunoassay), proglucagon and GLP-2 receptor mRNA expression (by Northern blot and real-time reverse transcriptase quantitative polymerase chain reaction) were measured. GLP-2 receptor was colocalized to neuroendocrine markers by immunohistochemistry.
Results
Low-dose exogenous GLP-2 increased mucosal cellularity and crypt–villus height in the duodenum, jejunum, and ileum; enterocyte proliferation in the jejunal crypt; and duodenal and jejunal sucrase segmental activity. Plasma bioactive GLP-2 concentration increased 70% upon resection, with an additional 54% increase upon GLP-2 infusion in resected rats (P < .05). Ileal proglucagon mRNA expression increased with resection, and exogenous ileum GLP-2 failed to blunt this response. Exogenous GLP-2 increased ileum GLP-2 receptor expression 3-fold in resected animals and was colocalized to vasoactive intestinal peptide-positive and endothelial nitric oxide synthase-expressing enteric neurons and serotonin-containing enteroendocrine cells in the jejunum and ileum of resected rats.
Conclusions
Exogenous GLP-2 augments adaptive growth and digestive capacity of the residual small intestine in a rat model of mid–small bowel resection by increasing plasma GLP-2 concentrations and GLP-2 receptor expression without diminishing endogenous proglucagon expression.
doi:10.1177/0148607108316198
PMCID: PMC3631545  PMID: 18443137
intestinal failure; intestinal adaptation; GI hormones; short bowel syndrome; bowel resection
2.  Colonic GLP-2 is not Sufficient to Promote Jejunal Adaptation in a PN-Dependent Rat Model of Human Short Bowel Syndrome 
Background
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.
Methods
Rats underwent jugular catheter placement and a 60% jejunoileal resection + cecectomy with jejunoileal anastomosis or transection control surgery. Rats were maintained exclusively with PN and killed at 4 hours to 12 days. A nonsurgical group served as baseline. Bowel growth and digestive capacity were assessed by mucosal mass, protein, DNA, histology, and sucrase activity. Plasma insulin-like growth factor I (IGF-I) and bioactive glucagon-like peptide 2 (GLP-2) were measured by radioimmunoassay.
Results
Jejunum cellularity changed significantly over time with resection but not transection, peaking at days 3–4 and declining by day 12. Jejunum sucrase-specific activity decreased significantly with time after resection and transection. Colon crypt depth increased over time with resection but not transection, peaking at days 7–12. Plasma bioactive GLP-2 and colon proglucagon levels peaked from days 4–7 after resection and then approached baseline. Plasma IGF-I increased with resection through day 12. Jejunum and colon GLP-2 receptor RNAs peaked by day 1 and then declined below baseline.
Conclusions
After bowel resection resulting in SBS in the rat, peak proglucagon, plasma GLP-2, and GLP-2 receptor levels are insufficient to promote jejunal adaptation. The colon adapts with resection, expresses proglucagon, and should be preserved when possible in massive intestinal resection.
doi:10.1177/0148607109336597
PMCID: PMC3631543  PMID: 19644131
intestinal failure; intestinal adaptation; GI hormones; short bowel syndrome; bowel resection
3.  Proximal enterectomy provides a stronger systemic stimulus to intestinal adaptation than distal enterectomy. 
Gut  1987;28(Suppl):165-168.
Enteroglucagon has been implicated as a tropic hormone in the control of intestinal adaptation. Because cells producing enteroglucagon are located mainly in the distal small bowel (and colon), ileal resection might be expected to produce less adaptive change than a jejunal resection of equivalent length. This hypothesis was tested in male Sprague-Dawley rats (n = 40) weighing 184.0 +/- 7.3 g and receiving a Thiry-Vella fistula (TVF) of the mid-60% of the small intestine. One group had concomitant resection of the jejunum proximal to the TVF (n = 12), another had resection of the ileum distal to the TVF (n = 13), while controls had a TVF alone (n = 15). When killed 10 days postoperatively rats with ileal resection weighed only 81% of controls (p less than 0.001) and 85% of those with jejunal resection (p less than 0.01). Jejunal resection produced an 81% increase in crypt cell production rate (measured by a stathmokinetic technique) over control values (28.5 +/- 4.2 v 15.8 +/- 2.3 cells/crypt/h: p = 0.025), whereas ileal resection had no demonstrable effect (17.5 +/- 2.3 cells/crypt/h). Adaptive hyperplasia in isolated small bowel is modulated by factors localised to the distal small intestine, enteroglucagon being a plausible candidate.
PMCID: PMC1434573  PMID: 3692304
4.  Effect of intestinal resection on human small bowel motility. 
Gut  1996;38(6):859-863.
BACKGROUND: Few data are available on adaptive changes of human small bowel motility after intestinal resection. AIM: To characterise jejunal motility after extensive and limited distal intestinal resection. METHODS: Seven patients with a short bowel syndrome after total ileal and partial jejunal resection (residual jejunal segments between 60 and 100 cm) and six patients with limited distal ileal resection (resected segment between 30 and 70 cm) underwent ambulatory 24 hour jejunal manometry 15 (6-24) months after the operation. Normal values were obtained from 50 healthy subjects. Fasting motility and the motor response to a 600 kcal solid meal were analysed visually and by a computer program. RESULTS: Limited ileal resection did not result in changed jejunal motility. After extensive distal resection, patients had a significantly shorter migrating motor complex (MMC) cycle and a significantly shorter duration of the postprandial motor response compared with controls (p < 0.005). Intestinal resection had no influence on jejunal contraction frequency and amplitude and did not lead to any abnormal motor pattern. CONCLUSION: Extensive distal resection of the small intestine produces distinct abnormalities of fasting and postprandial motility in the intestinal remnant. The shortening of digestive motility and the increased frequency of MMC cycling could contribute to malabsorption and diarrhoea in the short bowel syndrome.
PMCID: PMC1383193  PMID: 8984024
5.  Effect of Tangweian Jianji on upper gastrointestinal remodeling in streptozotocin-induced diabetic rats 
AIM: To investigate the effect of Tangweian Jianji (TWAJJ) on the biomechanical and morphometrical remodeling of the upper gastrointestinal tract in diabetic rats.
METHODS: Diabetes was induced in 27 rats by injecting streptozotocin (40 mg/kg body weight), the animals were then divided into three groups (n = 9 in each group), i.e., diabetic control (DM); high dose (10 g/kg, T1) and low dose (5 g/kg, T2). Another 10 rats acted as normal controls (Control). TWAJJ was administered by gavage once daily. Blood glucose and serum insulin levels were measured. Circumferential length, wall thickness and opening angle were measured from esophageal, duodenal, jejunal and ileal ring segments. The residual strain was calculated from the morphometric data. Step-wise distension was carried out on esophageal and jejunal segments. The obtained data on the length, diameter and pressure changes were then used to calculate the circumferential and longitudinal stresses and strains. Real-time reverse transcription polymerase chain reaction was used to detect the receptor of advanced glycation end-products (RAGE) mRNA level in jejunal tissues.
RESULTS: At the end of the experiment, the blood glucose level was significantly higher and the serum insulin level was significantly lower in DM, T1 and T2 groups than in the control group (Glucose: 30.23 ± 0.41 mmol/L, 27.48 ± 0.27 mmol/L and 27.84 ± 0.29 mmol/L vs 5.05 ± 0.04 mmol/L, P = 1.65 × 10-16, P = 5.89 × 10-19 and P = 1.63 × 10-18, respectively; Insulin: 1.47 ± 0.32 μg/L, 2.66 ± 0.44 μg/L, 2.03 ± 0.29 μg/L and 4.17 ± 0.54 μg/L, P = 0.0001, P = 0.029 and P = 0.025, respectively). However, these levels did not differ among the DM, T1 and T2 groups. The wet weight per unit length, wall thickness and opening angle of esophageal and intestinal segments in the DM group were significantly higher than those in the control group (from P = 0.009 to P = 0.004). These parameters in the T1 group were significantly lower than those in the DM group (wet weight, duodenum: 0.147 ± 0.003 g/cm vs 0.158 ± 0.001 g/cm, P = 0.047; jejunum, 0.127 ± 0.003 g/cm vs 0.151 ± 0.002 g/cm, P = 0.017; ileum, 0.127 ± 0.004 g/cm vs 0.139 ± 0.003 g/cm, P = 0.046; wall thickness, esophagus: 0.84 ± 0.03 mm vs 0.94 ± 0.02 mm, P = 0.014; duodenum: 1.27 ± 0.06 mm vs 1.39 ± 0.05 mm, P = 0.031; jejunum: 1.19 ± 0.07 mm vs 1.34 ± 0.04 mm, P = 0.047; ileum: 1.09 ± 0.04 mm vs 1.15 ± 0.03 mm, P = 0.049; opening angle, esophagus: 112.2 ± 13.2˚ vs 134.7 ± 14.7˚, P = 0.027; duodenum: 105.9 ± 12.3˚ vs 123.1 ± 13.1˚, P = 0.046; jejunum: 90.1 ± 15.4˚ vs 115.5 ± 13.3˚, P = 0.044; ileum: 112.9 ± 13.4˚ vs 136.1 ± 17.1˚, P = 0.035). In the esophageal and jejunal segments, the inner residual stain was significantly smaller and the outer residual strain was larger in the DM group than in the control group (P = 0.022 and P = 0.035). T1 treatment significantly restored this biomechanical alteration (P = 0.011 and P = 0.019), but T2 treatment did not. Furthermore, the circumferential and longitudinal stiffness of the esophageal and jejunal wall increased in the DM group compared with those in the control group. T1, but not T2 treatment, significantly decreased the circumferential wall stiffness in the jejunal segment (P = 0.012) and longitudinal wall stiffness in the esophageal segment (P = 0.023). The mRNA level of RAGE was significantly decreased in the T1 group compared to that in the DM group (P = 0.0069).
CONCLUSION: TWAJJ (high dose) treatment partly restored the morphometric and biomechanical remodeling of the upper gastrointestinal tract in diabetic rats.
doi:10.3748/wjg.v18.i35.4875
PMCID: PMC3447269  PMID: 23002359
Biomechanics and morphometric remodeling; Diabetes rats; Gastrointestinal tract; Mechanism; Tangweian Jianji
6.  Comparative evaluation of two reconstructive methods following laparoscopic assisted subtotal gastrectomy in dogs 
BMC Research Notes  2012;5:679.
Background
Laparoscopic gastrectomy is a new and technically challenging surgical procedure with potential benefit. The objective of this study was to investigate clinical and para-clinical consequences following Roux-en-Y and Jejunal Loop interposition reconstructive techniques for subtotal gastrectomy using laparoscopic assisted surgery.
Results
Following resection of the stomach attachments through a laparoscopic approach, stomach was removed and reconstruction was performed with either standard Roux-en-Y (n = 5) or Jejunal Loop interposition (n = 5) methods. Weight changes were monitored on a daily basis and blood samples were collected on Days 0, 7 and 21 post surgery. A fecal sample was collected on Day 28 after surgery to evaluate fat content. One month post surgery, positive contrast radiography was conducted at 5, 10, 20, 40, 60 and 90 minutes after oral administration of barium sulfate, to evaluate the postoperative complications. There was a gradual decline in body weight in both experimental groups after surgery (P < 0.05). There was no difference in blood parameters at any time after surgery between the two methods (P > 0.05). Fecal fat content increased in the Roux-en-Y compared to the Jejunal loop interposition technique (P < 0.05). No major complications were found in radiographs and gastric emptying time was similar between the two groups (P > 0.05).
Conclusion
Roux-en-Y and Jejunal loop interposition techniques might be considered as suitable approaches for reconstructing gastro-intestinal tract following gastrectomy in dogs. The results of this study warrant further investigation with a larger number of animals.
doi:10.1186/1756-0500-5-679
PMCID: PMC3549722  PMID: 23232040
Gastrectomy; Laparoscopy; Reconstruction; Dog
7.  Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors 
Purpose of review
To summarize recent evidence that IGF1 mediates growth effects of multiple trophic factors and discuss clinical relevance.
Recent findings
Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogues in short bowel syndrome and Crohn’s disease. This review highlights evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn’s disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that SOCS protein induction by GH or GLP2 in normal or inflamed intestine, may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed.
Summary
IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.
doi:10.1097/MOG.0b013e32835004c6
PMCID: PMC3685151  PMID: 22241077
intestinal growth; enterotrophic therapy; short bowel syndrome; Crohn’s disease
8.  Effect of cholera toxin on ileal water and solute transport after resection of the proximal small intestine in the rat. 
Gut  1981;22(11):953-957.
Intestinal adaptation after extensive small bowel resection results in mucosal hypertrophy and an increased capacity of the remaining small intestine to absorb solutes and water. We tested the ability of the adapted rat ileum to respond to a secretory stimulus, cholera toxin. Six weeks after 50% jejunal resection (short gut) or sham operation water and solute transport were measured in a 16 cm segment of ileum before and after exposure to cholera toxin in a single pass in vivo perfusion system. During the control periods absorption of glucose, acetate and water per unit length of intestine was significantly greater in short gut animals (P less than 0.05 to 0.001). After exposure to cholera toxin absorption of glucose and acetate was significantly reduced in both groups (P less than 0.05 to 0.01). Sodium and chloride secretion and net change in water movement in response to cholera toxin were significantly greater (P less than 0.05 to 0.01) in short gut animals. Generally the differences between short gut and sham operation animals disappeared when the data were normalised for mucosal weight. Chloride secretion per gram mucosa was less in short gut animals (P less than 0.001). The data indicate that the adapted small bowel is not only capable of enhanced absorption but also of enhanced net secretion in response to cholera toxin. The changes reflect the increased number of enterocytes per unit length of intestine after intestinal adaptation.
PMCID: PMC1419464  PMID: 7308849
9.  Complicated Jejunal Diverticulitis: A Challenging Diagnosis and Difficult Therapy 
Background/Aim:
In contrast to diverticulosis of the colon, jejunal diverticulosis is a rare entity that often becomes clinically relevant only after exacerbations occur. The variety of symptoms and low incidence make this disease a difficult differential diagnosis.
Patients and Methods:
Data from all patients who were treated in our surgical department for complicated jejunal diverticulitis, that is, gastrointestinal hemorrhage or a diverticula perforation were collected prospectively over a 6-year period (January 2004 to January 2010) and analyzed retrospectively.
Results:
The median age among the 9 patients was 82 years (range: 54–87). Except for 2 cases (elective operation for a status postjejunal peridiverticulitis and a re-perforation of a diverticula in a patient s/p segment resection with free perforation), the diagnosis could only be confirmed with an exploratory laparotomy. Perforation was observed in 5 patients, one of which was a retroperitoneal perforation. The retroperitoneal perforation was associated with transanal hemorrhage. Hemodynamically relevant transanal hemorrhage requiring transfusion were the reason for an exploratory laparotomy in 2 further cases. In one patient, the hemorrhage was the result of a systemic vasculitis with resultant gastrointestinal involvement. A singular jejunal diverticulum caused an adhesive ileus in one patient. The extent of jejunal diverticulosis varied between a singular diverticulum to complete jejunal involvement. A tangential, transverse excision of the diverticulum was carried out in 3 patients. The indication for segment resection was made in the case of a perforation with associated peritonitis (n=4) as well as the presence of 5 or more diverticula (n=2). Histological analysis revealed chronic pandiverticulitis in all patients. Median operating time amounted to 142 minutes (range: 65–210) and the median in-hospital stay was 12 days (range: 5–45). Lethality was 0%. Major complications included secondary wound closure after s/p repeated lavage and bilateral pleural effusions in one case. Signs of malabsorption as the result of a short bowel syndrome were not observed. Minor complications included protracted intestinal atony in 2 cases and pneumonia in one case. Median follow-up was 6 months (range: 1–18).
Conclusion:
Complicated jejunal diverticulitis often remains elusive preoperatively due to its unspecific clinical presentation. A definitive diagnosis can often only be made intraoperatively. The resection of all diverticula and/or the complete diverticula-laden segment is the goal in chronic cases. The operative approach chosen (tangential, transverse excision vs segment resection) should be based on the extent of the jejunal diverticulosis as well as the intraoperative findings.
doi:10.4103/1319-3767.93816
PMCID: PMC3326973  PMID: 22421718
Diverticulosis; jejunum; surgery
10.  Effect of growth hormone, hyperbaric oxygen and combined therapy on the gastric serosa 
AIM: To investigate the role of growth hormone (GH), hyperbaric oxygen therapy (HBOT) and combined therapy on the intestinal neomucosa formation of the gastric serosa.
METHODS: Forty-eight male Wistar-albino rats, weighing 250-280 g, were used in this study. The rats were divided into four groups (n = 12): Group 1, control, gastric serosal patch; Group 2, gastric serosal patch + GH; Group 3, gastric serosal patch + HBOT; and Group 4, gastric serosal patch + GH + HBOT. Abdominal access was achieved through a midline incision, and after the 1-cm-long defect was created in the jejunum, a 1 cm × 1 cm patch of the gastric corpus was anastomosed to the jejunal defect. Venous blood samples were taken to determine the insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) basal levels. HBOT was performed in Groups 3 and 4. In Groups 2 and 4, human GH was given subcutaneously at a dose of 2 mg per kg/d for 28 d, beginning on the operation day. All animals were sacrificed 60 d after surgery. The jejunal segment and the gastric anastomotic area were excised for histological examination. The inflammatory process, granulation, collagen deposition and fibroblast activity at the neomucosa formation were studied and scored. Additionally, the villus density, villus height, and crypt depth were counted and recorded. The measurements of villus height and crypt depth were calculated with an ocular micrometer. New vessel growth was determined by calculatingeach new vessel in a 1 mm2 area.
RESULTS: In the histological comparison of groups, no significant differences were observed between the control group and Groups 2 and 3 with respect to epithelialization, granulation, fibroblastic activity and the inflammatory process, but significant differences were present between the control group and all others groups (Groups 2-4) with respect to angiogenesis (P < 0.01) and collagen deposition (P < 0.05, P < 0.01). Significant differences between the control group and Group 4 were also observed with respect to epithelialization and fibroblastic activity (P < 0.01 and P < 0.05, respectively). There were significant differences in villus density in all of groups compared with the control group (P < 0.05). Crypt depth was significantly greater in Group 4 than in the control group (P < 0.05), but no other groups had deeper crypts. However, villus height was significantly longer in Groups 2 and 4 than in the control group (P < 0.05). The comparison of groups revealed, significant difference between control group and Groups 2 and 4) with respect to the levels of IGF-1 and IGFBP-3 (P < 0.01) 3 wk after the operation.
CONCLUSION: HBOT or GH and combined therapy augmented on neomucosal formation. The use of combined therapy produced a synergistic effect on the histological, morphological and functional parameters.
doi:10.3748/wjg.v19.i19.2904
PMCID: PMC3660815  PMID: 23704823
Growth hormone; Hyperbaric oxygen; Neomucosa; Short bowel syndrome; Hypoxia
11.  Distraction-induced intestinal enterogenesis: Preservation of intestinal function and lengthening after re-implantation into normal jejunum 
Annals of Surgery  2012;255(2):302-310.
Background
Significant bowel lengthening can occur in an isolated intestinal segment with the use for linearly directed distractive forces; resulting in increased surface area and epithelial cell proliferation. We hypothesized that re-implantation of this lengthened intestine into normal jejunum would preserve this gain in intestinal length and function similar to normal jejunum.
Methods
An intestinal lengthening device was inserted into isolated jejunal segments in pigs, and fully expanded over 8 days. Lengthened segment were then re-implanted into normal intestinal continuity. Pigs were studied after another 28days. Function was assessed by motility, mucosal enzyme activity, barrier function and intestinal ion transport.
Results
Lengthened segments were significantly longer than control segments, and had nearly 2-fold greater surface area. Bowel lengthening was maintained 4 weeks after re-implantation. Motility after re-implantation was similar to non-operated pigs. Barrier function, mucosal disaccharidase levels and electrophysiologic measures declined immediately after lengthening, but returned to nearly normal levels 28 days after re-implantation.
Conclusion
Bowel lengthening results in a transient decline in mucosal absorptive function and smooth muscle contractility. However, function approaches that of normal bowel after re-implantation into enteric flow. These data may support the use of this technique as a potential new option for the treatment of patients with short bowel syndrome.
doi:10.1097/SLA.0b013e318233097c
PMCID: PMC3259228  PMID: 21997804
12.  Dietary resistant starch dose-dependently reduces adiposity in obesity-prone and obesity-resistant male rats 
Background
Animal studies show that diets containing resistant starch (RS) at levels not achievable in the human diet result in lower body weight and/or adiposity in rodents. We aimed to determine whether RS dose-dependently reduces adiposity in obesity-prone (OP) and obesity-resistant (OR) rats.
Methods
Male Sprague–Dawley rats (n=120) were fed a moderate-fat, high-energy diet for 4 wk. Rats that gained the most weight (40%) were classified as obesity-prone (OP) and obesity-resistant (OR) rats were the 40% that gained the least weight. OP and OR rats were randomly allocated to one of six groups (n=8 for each phenotype). One group was killed for baseline measurements, the other five groups were allocated to AIN-93 based diets that contained 0, 4, 8, 12 and 16% RS (as high amylose maize starch) for 4 wk. These diets were matched for total carbohydrate content. At 0, 4 and 7 wk from the start of the study insulin sensitivity was calculated by homeostasis model assessment of insulin resistance (HOMA-IR) and adiposity was determined by dual-energy X-ray absorptiometry (DXA). At 8 wk, rats were euthanized and fat pad weights, intestinal digesta short chain fatty acid (SCFA) pools and plasma gut hormone levels were determined.
Results
Obesity prone rats gained less weight with 4, 12 and 16% RS compared to 0% RS, but the effect in OR animals was significant only at 16% RS. Irrespective of phenotype, diets containing ≥8% RS reduced adiposity compared to 0% RS. Energy intake decreased by 9.8 kJ/d for every 4% increase in RS. All diets containing RS increased total SCFA pools in the caecum and lowered plasma GIP concentrations compared to the 0% RS, whereas plasma GLP-1 and PYY were increased when the diet contained at least 8% RS. Insulin sensitivity was not affected by RS.
Conclusion
RS in amounts that could be potentially consumed by humans were effective in reducing adiposity and weight gain in OP and OR rats, due in part to a reduction in energy intake, and changes in gut hormones and large bowel carbohydrate fermentation.
doi:10.1186/1743-7075-9-93
PMCID: PMC3541085  PMID: 23098187
Resistant starch; Adiposity; Incretin; Short chain fatty acid; Insulin sensitivity
13.  Impaired meal stimulated glucagon-like peptide 2 response in ileal resected short bowel patients with intestinal failure 
Gut  1999;45(4):559-563.
BACKGROUND—Glucagon-like peptide 2 (GLP-2) is a growth factor for the intestinal epithelium in rodents and may affect intestinal transit.
AIMS—To study the GLP-2 response to nutrient ingestion in seven short bowel patients with intestinal failure and seven controls.
METHODS—The patients and controls were admitted twice for two test meals after a night of fasting. Meal A was liquid (300 ml, 1.88 MJ); meal B was a regular breakfast (755 g, 3.92 MJ). Plasma samples were collected for 180 minutes; GLP-2 immunoreactivity was measured with an NH2 terminal specific radioimmunoassay.
RESULTS—Both meals elicited significant increases in plasma GLP-2 in controls. The magnitude and duration of the responses were dependent on the meal size: the maximum median (25-75%) increases after meal A and B were 24 (3-28) and 48 (33-56) pmol/l. Plasma GLP-2 returned to basal concentrations 180 minutes after meal A, but remained at 50% of peak values after meal B. In the patients neither meal significantly changed the GLP-2 concentration; the maximum median elevation after meal B was 5 (2-8) pmol/l. There were significant differences between patients and controls with respect to the GLP-2 responses to meals A and B.
CONCLUSION—Identification of GLP-2 as a tissue specific intestinal growth factor and demonstration of an impaired meal stimulated GLP-2 response in short bowel patients raises the possibility that GLP-2 administration may constitute a new therapeutic strategy, enhancing jejunal adaptation in ileum resected short bowel patients with intestinal failure.


Keywords: short bowel syndrome; growth factors; intestinal adaptation; human
PMCID: PMC1727702  PMID: 10486365
14.  Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon 
Gut  2000;47(3):370-376.
BACKGROUND—The glucagon-like peptides (GLP) 1 and 2 are secreted postprandially from L cells located mainly in the ileum. Both hormones prolong intestinal transit and GLP-2 is intestinotrophic in rodents. Patients with a jejunostomy have poor adaptation, rapid gastric and intestinal transit, and impaired postprandial GLP-2 secretion. Ileum resected short bowel patients with a preserved colon show evidence of functional adaptation and have normal gastric emptying.
AIM—To investigate if GLP-1 and GLP-2 contribute to the positive effects of a preserved colon in short bowel patients by measuring circulating levels of GLP-1 and GLP-2 in seven ileum resected short bowel patients with a preserved colon and seven age and sex matched controls.
METHODS—GLP-1 and GLP-2 immunoreactivity was measured by specific radioimmunoassays in plasma collected at fasting and at regular intervals 180 minutes after a test meal.
RESULTS—Median (25-75%) fasting GLP-2 values were 72 (69-105) pmol/l versus 23 (19-27) pmol/l (p=0.001) and meal stimulated area under the curve was 21 078 (14 811-26 610) min×pmol/l versus 11 150 (7151-12 801) min×pmol/l (p=0.01) in short bowel patients with a preserved colon compared with control subjects. Fasting GLP-1 values were 10 (6-12) pmol/l versus 5 (3-5) pmol/l (p=0.01) and meal stimulated area under the curve was 3418 (2966-6850) min×pmol/l versus 2478 (1929-3199) min×pmol/l (p=0.04), respectively.
CONCLUSION—Ileum resected short bowel patients with a preserved colon had elevated fasting plasma concentrations of GLP-1 and GLP-2 and significantly larger meal stimulated areas under the curve compared with age and sex matched controls. Elevated GLP-1 and GLP-2 concentrations may contribute to the positive effects of a preserved colon on intestinal motility and functional adaptation in ileum resected short bowel patients.


Keywords: short bowel syndrome; colon; glucagon-like peptides; intestinal adaptation; intestinal transit
doi:10.1136/gut.47.3.370
PMCID: PMC1728028  PMID: 10940274
15.  Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis 
Gut  2000;46(5):694-700.
BACKGROUND—Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known.
AIMS—To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis.
METHODS—Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation).
RESULTS—Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44-60%.
CONCLUSIONS—It seems likely that approximately 30-40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.


Keywords: inflammatory bowel disease; TNBS colitis; growth retardation; insulin-like growth factor 1; interleukin 6
doi:10.1136/gut.46.5.695
PMCID: PMC1727919  PMID: 10764714
16.  Gastrointestinal hormones in short bowel syndrome. Peptide YY may be the 'colonic brake' to gastric emptying. 
Gut  1996;39(2):267-272.
BACKGROUND: Short bowel patients with a jejunostomy have large volume stomal outputs, which may in part be due to rapid gastric emptying of liquid. Short bowel patients with a preserved colon do not have such a high stool output and gastric emptying of liquid is normal. AIMS: To determine if differences in the gastric emptying rate between short bowel patients with and without a colon can be related to gastrointestinal hormone changes after a meal. SUBJECTS: Seven short bowel patients with no remaining colon (jejunal length 30-160 cm) and six with jejunum in continuity with a colon (jejunal length 25-75 cm), and 12 normal subjects. METHODS: The subjects all consumed a 640 kcal meal; blood samples were taken for 180 minutes for measurement of gastrointestinal hormones. RESULTS: Patients with a colon had high fasting peptide YY values (median 71 pmol/l with a colon; 11 pmol/l normal subjects, p < 0.005) with a normal postprandial rise, but those without a colon had a low fasting (median 7 pmol/l, p = 0.076) and a reduced postprandial peptide YY response (p < 0.050). Motilin values were high in some patients without a colon. In both patient groups fasting and postprandial gastrin and cholecystokinin values were high while neurotensin values were low. There were no differences between patient groups and normal subjects in enteroglucagon, pancreatic polypeptide, or somatostatin values. CONCLUSIONS: Low peptide YY values in short bowel patients without a colon may cause rapid gastric emptying of liquid. High values of peptide YY in short bowel patients with a retained colon may slow gastric emptying of liquid and contribute to the "colonic brake'.
PMCID: PMC1383310  PMID: 8977342
17.  Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomised, double blind, crossover, placebo controlled study 
Gut  2000;47(2):199-205.
BACKGROUND—High dose growth hormone, glutamine, and a high carbohydrate diet may improve intestinal function in short bowel patients.
AIMS—To investigate if growth hormone with glutamine and no change in diet improved intestinal function.
PATIENTS AND METHODS—Eight short bowel patients were randomised in a double blind crossover study between placebo and growth hormone (mean 0.12 mg/kg/day) with oral (mean 28 g/day) and parenteral glutamine (mean 5.2 g/day) for 28 days. Balance studies were performed at baseline and five days after placebo and treatment were terminated. Dietary energy, carbohydrate, and fat were maintained as usual.
RESULTS—Growth hormone with glutamine did not improve intestinal absorption of energy (baseline, placebo, treatment, mean: 46%, 48%, 46% of oral intake, respectively), carbohydrate (71%, 70%, 71%), fat (20%, 15%, 18%), nitrogen (27%, 18%, 19%), wet weight (37%, 39%, 31%), sodium (−16%, −16%, −36%), potassium (43%, 47%, 33%), calcium (−16%, −16%, −15%) or magnesium (−3%, 4%, 2%) compared with placebo or baseline (p>0.05) five days after treatment was terminated. All patients experienced adverse effects.
CONCLUSIONS—Combined high dose growth hormone and glutamine administered for four weeks did not improve intestinal absorption five days after treatment was terminated in short bowel patients on their usual diet.


Keywords: growth hormone; glutamine; short bowel syndrome; intestinal failure; intestinal absorption; parenteral nutrition
doi:10.1136/gut.47.2.199
PMCID: PMC1727998  PMID: 10896910
18.  Effects of Growth Hormone and Pioglitazone in Viscerally Obese Adults with Impaired Glucose Tolerance: A Factorial Clinical Trial 
PLoS Clinical Trials  2007;2(5):e21.
Objective:
Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH-induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time.
Design:
Randomized, double-blind, placebo-controlled, 2 × 2 factorial design.
Setting:
Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States.
Participants:
62 abdominally obese adults aged 40–75 with impaired glucose tolerance.
Interventions:
GH (8 μg/kg/d, or placebo) and pioglitazone (30 mg/d, or placebo) for 40 wk.
Outcome Measures:
Baseline and after 40 wk of treatment, VAT content was quantified by CT scan, glucose tolerance was assessed using a 75-g oral glucose tolerance test, and insulin sensitivity was measured using steady-state plasma glucose levels obtained during insulin suppression test.
Results:
Baseline: body mass index (BMI), plasma glucose, and visceral fat content were similar. 40 wk: visceral fat area declined 23.9 ± 7.4 cm2 in GH group, mean difference from placebo: −28.1 cm2 (95% CI −49.9 to −6.3 cm2; p = 0.02). Insulin resistance declined 52 ± 11.8 mg/dl with PIO, mean difference from placebo of −58.8 mg/dl (95% CI −99.7 to −18.0 mg/dl; p = 0.01). VAT and SSPG declined with GH and PIO combined, mean differences from placebo of −31.4 cm2 (95% CI −56.5 cm2 to −6.3 cm2; p = 0.02) and −55.3 mg/dl (95% CI −103.9 to −6.7 mg/dl; p = 0.02), respectively. Fasting plasma glucose increased transiently in GH group. No significant changes in BMI were observed.
Conclusions:
Addition of PIO to GH attenuated the short-term diabetogenic effect of GH; the drug combination reduced VAT and insulin resistance over time. GH plus PIO may have added benefit on body composition and insulin sensitivity in the metabolic syndrome.
Editorial Commentary
Background: People who are overweight are at higher risk of developing type 2 diabetes, particularly if they have impaired glucose tolerance (IGT). When an individual has IGT, their cells are not able to respond properly to insulin in the blood, which means that blood sugar levels can remain high, and fat cells do not take up fatty acids from blood at the rate they should. The term prediabetes is often used to refer to these linked characteristics. However, if such individuals are able to lose weight they can reduce their chances of becoming diabetic in the future. In particular, loss of a particular type of fat, the visceral fat (packed in around the internal organs, as opposed to fat immediately under the skin), is thought to be beneficial for people at risk of developing type 2 diabetes. Some researchers have suggested that giving human growth hormone (GH) to people who are overweight might help reduce their levels of visceral fat. At the same time, drugs known as thiazolidinediones are currently used, in combination with other drugs, diet, and exercise, as a treatment for type 2 diabetes. The researchers carrying out this study wanted to find out whether combining treatment with human GH and a thiazolidinedione, pioglitazone (PIO), would reduce levels of visceral fat and improve glucose metabolism in overweight adults with IGT. The researchers specifically planned to compare the changes in these primary outcomes amongst people receiving both human GH and PIO for 40 weeks with the changes in individuals receiving placebo only; additional comparisons were also done for individuals receiving either drug alone, as compared to placebo.
What this trial shows: A total of 76 participants were randomized and received the treatment allocated to them, but only 62 participants were included in the final analyses due to losses to follow-up. The primary outcomes being compared at baseline and after 40 weeks of treatment were the change in visceral fat levels and change in individuals' sensitivity to insulin. Individuals receiving GH experienced a drop in visceral fat area over the 40 weeks of the trial, as compared to placebo, whilst PIO alone did not seem to have an effect on visceral fat area. Individuals receiving both GH and PIO, however, also showed a decrease in visceral fat area. When examining the effect on insulin resistance, GH alone did not seem to have an effect on the ability to respond to insulin. However, administration of PIO alone did bring about a decrease in insulin resistance levels, as compared to placebo, and individuals receiving both GH and PIO together also experienced a drop in insulin resistance. The trial was not designed to detect statistically significant differences in side effects between the groups studied, but some side effects, such as build-up of fluid in the limbs and joint stiffness, seemed to be more common in the groups receiving drug treatment than in the placebo group.
Strengths and limitations: Although the trial was small, enough participants were recruited to detect statistically significant changes in the primary outcomes. Strengths of the trial include the use of appropriate techniques to conceal the randomization sequence from investigators recruiting participants into the trial and blinding of both participants and investigators to the treatments that an individual would receive. However, one limitation includes the fact that the likelihood of developing diabetes was not directly measured as an outcome in this trial, and it is therefore not possible to conclude from these results that administration of GH, PIO, or both combined, will help prevent diabetes amongst overweight people with IGT. Finally, this trial compared the drug interventions directly with placebo and not with behavioral interventions such as diet and exercise, which are normally recommended for the prevention of diabetes amongst overweight people. It would be important to further investigate the efficacy, harms, and costs of these drugs directly against nondrug interventions before making any recommendations about their clinical use.
Contribution to the evidence: Other studies have shown that PIO administration has beneficial effects on insulin sensitivity in people with type 2 diabetes. This study adds evidence confirming that PIO is likely to have similar effects in people who are not diabetic but who are overweight and who have IGT. The study also adds data regarding the effect of PIO and GH combined in such populations; giving both drugs together seemed to have beneficial effects on visceral fat area and insulin sensitivity, as compared to placebo.
doi:10.1371/journal.pctr.0020021
PMCID: PMC1865086  PMID: 17479164
19.  Small Bowel Transplant 
EXECUTIVE SUMMARY
Objective
The Medical Advisory Secretariat undertook a review of the evidence on the effectiveness and cost-effectiveness of small bowel transplant in the treatment of intestinal failure.
Small Bowel Transplantation
Intestinal failure is the loss of absorptive capacity of the small intestine that results in an inability to meet the nutrient and fluid requirements of the body via the enteral route. Patients with intestinal failure usually receive nutrients intravenously, a procedure known as parenteral nutrition. However, long-term parenteral nutrition is associated with complications including liver failure and loss of venous access due to recurrent infections.
Small bowel transplant is the transplantation of a cadaveric intestinal allograft for the purpose of restoring intestinal function in patients with irreversible intestinal failure. The transplant may involve the small intestine alone (isolated small bowel ISB), the small intestine and the liver (SB-L) when there is irreversible liver failure, or multiple organs including the small bowel (multivisceral MV or cluster). Although living related donor transplant is being investigated at a limited number of centres, cadaveric donors have been used in most small bowel transplants.
The actual transplant procedure takes approximately 12-18 hours. After intestinal transplant, the patient is generally placed on prophylactic antibiotic medication and immunosuppressive regimen that, in the majority of cases, would include tacrolimus, corticosteroids and an induction agent. Close monitoring for infection and rejection are essential for early treatment.
Medical Advisory Secretariat Review
The Medical Advisory Secretariat undertook a review of 35 reports from 9 case series and 1 international registry. Sample size of the individual studies ranged from 9 to 155.
As of May 2001, 651 patients had received small bowel transplant procedures worldwide. According to information from the Canadian Organ Replacement Register, a total of 27 small bowel transplants were performed in Canada from 1988 to 2002.
Patient Outcomes
The experience in small bowel transplant is still limited. International data showed that during the last decade, patient survival and graft survival rates from SBT have improved, mainly because of improved immunosuppression therapy and earlier detection and treatment of infection and rejection. The Intestinal Transplant Registry reported 1-year actuarial patient survival rates of 69% for isolated small bowel transplant, 66% for small bowel-liver transplant, and 63% for multivisceral transplant, and a graft survival rate of 55% for ISB and 63% for SB-L and MV. The range of 1-year patient survival rates reported ranged from 33%-87%. Reported 1-year graft survival rates ranged from 46-71%.
Regression analysis performed by the International Transplant Registry in 1997 indicated that centres that have performed at least 10 small bowel transplants had better patient and graft survival rates than centres that performed less than 10 transplants. However, analysis of the data up to May 2001 suggests that the critical mass of 10 transplants no longer holds true for transplants after 1995, and that good results can be achieved at any multiorgan transplant program with moderate patient volumes.
The largest Centre reported an overall 1-year patient and graft survival rate of 72% and 64% respectively, and 5-year patient and graft survival of 48% and 40% respectively. The overall 1-year patient survival rate reported for Ontario pediatric small bowel transplants was 61% with the highest survival rate of 83% for ISB.
The majority (70% or higher) of surviving small bowel transplant recipients was able to wean from parenteral nutrition and meet all caloric needs enterally. Some may need enteral or parenteral supplementation during periods of illness. Growth and weight gain in children after ISB were reported by two studies while two other studies reported a decrease in growth velocity with no catch-up growth.
The quality of life after SBT was reported to be comparable to that of patients on home enteral nutrition. A study found that while the parents of pediatric SBT recipients reported significant limitations in the physical and psychological well being of the children compared with normal school children, the pediatric SBT recipients themselves reported a quality of life similar to other school children.
Survival was found to be better in transplants performed since 1991. Patient survival was associated with the type of organ transplanted with better survival in isolated small bowel recipients.
Adverse Events
Despite improvement in patient and graft survival rates, small bowel transplant is still associated with significant mortality and morbidity.
Infection with subsequent sepsis is the leading cause of death (51.3%). Bacterial, fungal and viral infections have all been reported. The most common viral infections are cytomegalorvirus (18-40%) and Epstein-Barr virus. The latter often led to ß-cell post-transplant lymphoproliferative disease.
Graft rejection is the second leading cause of death after SBT (10.4%) and is responsible for 57% of graft removal. Acute rejection rates ranged from 51% to 83% in the major programs. Most of the acute rejection episodes were mild and responded to steroids and OKT3. Antilymphocyte therapy was needed in up to 27% of patients. Isolated small bowel allograft and positive lymphocytotoxic cross-match were found to be risk factors for acute rejection.
Post-transplant lymphoproliferative disease occurred in 21% of SBT recipients and accounted for 7% of post-transplant mortality. The frequency was higher in pediatric recipients (31%) and in adults receiving composite visceral allografts (25%). The allograft itself is often involved in post-transplant lymphoproliferative disease. The reported incidence of host versus graft disease varied widely among centers (0% - 14%).
Surgical complications were reported to occur in 85% of SB-L transplants and 25% of ISB transplants. Reoperations were required in 45% - 66% of patients in a large series and the most common reason for reoperation was intra-abdominal abscess.
The median cost of intestinal transplant in the US was reported to be approximately $275,000US (approximately CDN$429,000) per case. A US study concluded that based on the US cost of home parenteral nutrition, small bowel transplant could be cost-effective by the second year after the transplant.
Conclusion
There is evidence that small bowel transplant can prolong the life of some patients with irreversible intestinal failure who can no longer continue to be managed by parenteral nutrition therapy. Both patient survival and graft survival rates have improved with time. However, small bowel transplant is still associated with significant mortality and morbidity. The outcomes are inferior to those of total parenteral nutrition. Evidence suggests that this procedure should only be used when total parenteral nutrition is no longer feasible.
PMCID: PMC3387750  PMID: 23074441
20.  Dietary glutamine and oral antibiotics decrease indices of bacterial translocation and regulate secretory immunoglobulin A after massive bowel resection 
The American journal of physiology  2008;296(2):G348-G355.
Background
Short bowel syndrome (SBS) after massive small bowel resection is associated with gut barrier dysfunction. Our aim was to examine effects of dietary glutamine (GLN) and oral antibiotics gut barrier dysfunction in a rat model of SBS.
Methods
Adult rats underwent 60% distal small bowel + proximal colonic resection (RX) or small bowel transection (TX; control). Rats were pair-fed semi-purified diets, with or without L-GLN supplementation, for 20 days after operation. Oral antibiotics [neomycin, metronidazole, and polymyxin; (ABX)] were given in some RX rats fed control diet. Secretory immunoglobulin-A (sIgA) in stool was measured serially. On day 21, MLN were cultured for gram-negative bacteria in mesenteric lymph nodes (MLN). IgA-positive plasma cells in jejunal lamina propria, stool levels of flagellin- and lipopolysaccharide (LPS)-specific sIgA and serum flagellin- and LPS IgG levels were also determined.
Results
RX caused gram-negativebacterial translocation to MLN and increased stool total sIgA and anti-LPS IgG in serum. Oral ABX eliminated RX-induced bacterial translocation, decreased stool total IgA, increased stool LPS-specific IgA and decreased serum anti-LPS IgG. Dietary GLN blunted bacterial translocation to MLN and decreased anti-LPS IgG levels in serum after RX and increased stool and jejunal mucosal sIgA and stool LPS-specific IgA.
Conclusions
This model of partial small bowel-colonic resection in rats is associated with gram-negative bacterial translocation from the gut and a concomitant adaptive immune response to LPS. These indices of gut barrier dysfunction are ameliorated or blunted by administration of oral antibiotics or dietary GLN, respectively.
doi:10.1152/ajpgi.90233.2008
PMCID: PMC2643904  PMID: 19095767
bacterial translocation; glutamine; intestinal adaptation; short bowel syndrome
21.  Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome 
Short bowel syndrome results from surgical resection, congenital defect or disease-associated loss of absorption. Parenteral support (PS) is lifesaving in patients with short bowel syndrome and intestinal failure who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Together, the symptoms of short bowel syndrome and the inconvenience and complications in relation to PS (e.g. catheter-related blood steam infections, central thrombosis and intestinal failure associated liver disease) may impair the quality of life of patients. The aim of treatment is to maximize intestinal absorption, minimize the inconvenience of diarrhea, and avoid, reduce or eliminate the need for PS to achieve the best possible quality of life for the patient. Conventional treatments include dietary manipulations, oral rehydration solutions, and antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited and treatments that improve the structural and functional integrity of the remaining intestine are needed. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by restoring gastric emptying and secretion, thereby reducing intestinal losses and promoting intestinal absorption. In a 3-week, phase II balance study, teduglutide reduced diarrhea by around 700 g/day and fecal energy losses by around 0.8 MJ/day. In two randomized, placebo-controlled, 24-week, phase III studies, similar findings were obtained when evaluating the fluid composite effect, which is the sum of the beneficial effects of teduglutide – reduction in the need for PS, increase in urine production and reduction in oral fluid intake. The fluid composite effect reflects the increase in intestinal fluid absorption (and the concomitant reduction in diarrhea) and may be used in studies in which metabolic balance assessments are not performed. In studies of up to 24 weeks’ duration, teduglutide appears to be safe and well tolerated. Treatment with teduglutide was associated with enhancement or restoration of the structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for PS in patients with short bowel syndrome and intestinal failure.
doi:10.1177/1756283X11436318
PMCID: PMC3342570  PMID: 22570676
home parenteral nutrition; short bowel syndrome; teduglutide
22.  Immunomodulatory effects of inhaled carbon monoxide on rat syngeneic small bowel graft motility 
Gut  2003;52(9):1278-1285.
Background: Intestinal transplantation provokes an intense inflammatory response within the graft muscularis that causes intestinal ileus. We hypothesised that endogenously produced anti-inflammatory substances could be utilised as novel therapeutics. Therefore, we tested the protective effects of inhaled carbon monoxide (CO) and an endogenous haeme oxygenase 1 (HO-1) anti-inflammatory mediator on transplant induced inflammatory responses and intestinal ileus in the rat.
Methods: Gastrointestinal transit of non-absorbable FITC labelled dextran and in vitro jejunal circular muscle contractions were measured in controls and syngeneic orthotopic transplanted animals with and without CO inhalation (250 ppm for 25 hours). Inflammatory mRNAs for interleukin (IL)-6, IL-1β, tumour necrosis factor α (TNF-α), intercellular adhesion molecule 1 (ICAM-1), inducible nitric oxide (iNOS), cyclooxygenase 2 (COX-2), and IL-10 were quantified by real time reverse transcriptase-polymerase chain reaction and HO-1 by northern blot. Histochemical stains characterised neutrophil infiltration and enterocyte apoptosis.
Results: Transplantation delayed transit and suppressed jejunal circular muscle contractility. Transplantation induced dysmotility was significantly improved by CO inhalation. Transplantation initiated a significant upregulation in IL-6, IL-1β, TNF-α, ICAM-1, iNOS, COX-2, and HO-1 mRNAs with the graft muscularis. CO inhalation significantly decreased expression of IL-6, IL-1β, iNOS, and COX-2 mRNAs. CO also significantly decreased serum nitrite levels (iNOS activity).
Conclusions: CO inhalation significantly improved post-transplant motility and attenuated the inflammatory cytokine milieu in the syngeneic rat transplant model. Thus clinically providing CO, the end product of the anti-inflammatory HO-1 pathway, may prove to be an effective therapeutic adjunct for clinical small bowel transplantation.
PMCID: PMC1773787  PMID: 12912858
transplantation; haeme oxygenase; carbon monoxide; cytokines; small bowel; rat
23.  Intestinal Adaptation for Oligopeptide Absorption via PepT1 After Massive (70%) Mid Small Bowel Resection 
Introduction
Proteins are absorbed primarily as short peptides via PepT1.
Hypothesis
Intestinal adaptation for peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon.
Methods
Peptide uptake was measured in duodenum, jejunum, ileum, and colon using Glycyl-Sarcosine 1 wk (n=9) and 4 wk (n=11) after 70% mid-small bowel resection, and in corresponding segments from unoperated rats (n=12) and after transection and reanastomosis of jejunum and ileum (n=8). Expression of PepT1 (mRNA, protein) and villus height were measured.
Results
Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal peptide uptake (p<0.05) associated with increased villus height (1.13 vs 1.77 and 1.50 mm resp, p<0.01). In ileum although villus height increased at 1 and 4 wk (1.03 vs 1.21 and 1.35 mm resp; p<0.01), peptide uptake was not altered. PepT1 mRNA and protein were decreased at 1 wk, and PepT1 protein continued low at 4 wk. Gene expression, peptide uptake, and histomorphology were unchanged in the colon.
Conclusions
Jejunal adaptation for peptide absorption occurs by hyperplasia. Distal Ileum and colon do not have a substantive role in adaptation for peptide absorption.
doi:10.1007/s11605-010-1320-x
PMCID: PMC3050655  PMID: 21170601
Peptide absorption; short bowel syndrome; PepT1; intestinal adaptation; protein absorption; malabsorption
24.  Reactivation of arthritis induced by small bowel bacterial overgrowth in rats: role of cytokines, bacteria, and bacterial polymers. 
Infection and Immunity  1995;63(6):2295-2301.
Arthritis is often associated with intestinal diseases, but the etiology is not known. We developed a rat model whereby arthritis was reactivated by experimental small bowel bacterial overgrowth (SBBO). Self-limited monoarticular arthritis was induced by intra-articular injection of 2 micrograms of rhamnose peptidoglycan-polysaccharide derived from group A streptococci into the ankle joints in female Lewis rats. Eleven days after intra-articular injection, when swelling was resolving, experimental SBBO induced by surgical creation of jejunal self-filling blind loops reactivated arthritis, but SBBO induced by creation of self-emptying blind loops, which minimally increases luminal bacteria, and sham operation did not (P < 0.001). Increased joint diameters in rats with self-filling blind loops persisted for at least 56 days after surgery. Reactivation of arthritis due to SBBO was prevented by anti-tumor necrosis factor alpha antiserum and interleukin 1 receptor antagonist (P < 0.001), indicating that these cytokines mediate joint swelling secondary to intestinal injury. Recombinant bactericidal/permeability-increasing protein, an agent which neutralizes endotoxin, and metronidazole, which is active against anaerobic bacteria, prevented arthritis (P < 0.001), but polymyxin B (which also neutralizes endotoxin) and gentamicin had no effect. Mutanolysin, an enzyme which degrades peptidoglycan-polysaccharide from group A streptococci, exacerbated arthritis for the first 6 days but then diminished joint swelling from 12 to 21 days after surgery (P < 0.001). These studies introduce a reproducible animal model of reactivation of arthritis secondary to intestinal injury and demonstrate a role for bacterial products from endogenous enteric organisms.
PMCID: PMC173300  PMID: 7768612
25.  Distraction induced Enterogenesis: A unique mouse model using polyethylene glycol 
The Journal of surgical research  2011;170(1):41-47.
Background/Purpose
Recent studies have demonstrated that the small intestine can be lengthened by applying mechanical forces to the bowel lumen – distraction-induced enterogenesis. However, the mechanisms which account for this growth are unknown, and might be best examined using a mouse model. The purpose of this study is to establish the feasibility of developing distractive-induced small bowel growth in mouse.
Methods
12-week old C57BL/6J mice had a jejunal segment taken out of continuity, and distended with polyethylene glycol (PEG: 3350 KDa); this group was compared to a control group without stretching. Segment length and diameter were measured intra-operatively and after 5 days. Villus height, crypt depth, muscle thickness in the isolated segment were assessed. Rate of epithelial cell proliferation (5-bromo-2-deoxyuridine: BrdU incorporation) in crypt was also examined. The mucosal mRNA expression of targeted factors were performed to investigate potential mechanisms of which might lead to distraction-induced enterogenesis.
Results
At harvest, the PEG-stretch group showed a significant increase in length and diameter versus controls. Villus height, crypt depth and muscular layer thickness increased in the PEG group. The PEG group also showed significantly increased rates of epithelial cell proliferation versus controls. Real-time PCR showed a trend toward higher β-catenin and c-myc mRNA expression in the PEG stretched group; however, this difference was not statistically significant.
Conclusions
Radial distraction-induced enterogenesis with PEG is a viable method for increasing small intestinal length and diameter. This model may provide a new method for studying the mechanisms leading to distraction-induced enterogenesis.
doi:10.1016/j.jss.2011.03.041
PMCID: PMC3154514  PMID: 21605872
short bowel syndrome; distraction-induced enterogenesis; polyethylene glycol; proliferation; intestinal morphology

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