Differential jejunal and colonic adaptation due to resection and IGF-I in parenterally fed rats

Patients with severe short-bowel syndrome (SBS) often require long-term total parenteral nutrition (TPN) to maintain their nutritional status because of limited intestinal adaptation. Growth factors, including insulin-like growth factor I (IGF-I), are under investigation to promote intestinal adaptation and tolerance to oral feeding. We investigated structural and functional adaptation of the jejunum and colon in four groups of rats maintained with TPN for 7 days after a 60% jejunoileal resection and cecectomy or sham surgery and treatment with IGF-I or vehicle. Resection alone did not stimulate jejunal growth. IGF-I significantly increased jejunal mucosal mass, enterocyte proliferation, and migration rates. IGF-I decreased jejunal sucrase specific activity and reduced active ion transport and ionic permeability; resection alone had no effect. In contrast, resection significantly increased colonic mass and crypt depth but had no effect on active ion transport or ionic permeability. IGF-I had minimal effects on colonic structure. IGF-I but not resection stimulates jejunal adaptation, whereas resection but not IGF-I stimulates colonic growth in rats subjected to a model for human SBS. IGF-I treatment may improve intestinal adaptation in humans with SBS.     

Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

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.     

Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection

To elucidate the role of luminal nutrients and glucagon-like peptide-2 (GLP-2) in intestinal adaptation, rats were subjected to 70% midjejunoileal resection or ileal transection and were maintained with total parenteral nutrition (TPN) or oral feeding. TPN rats showed small bowel mucosal hyperplasia at 8 h through 7 days after resection, demonstrating that exogenous luminal nutrients are not essential for resection-induced adaptation when residual ileum and colon are present. Increased enterocyte proliferation was a stronger determinant of resection-induced mucosal growth in orally fed animals, whereas decreased apoptosis showed a greater effect in TPN animals. Resection induced significant transient increases in plasma bioactive GLP-2 during TPN, whereas resection induced sustained increases in plasma GLP-2 during oral feeding. Resection-induced adaptive growth in TPN and orally fed rats was associated with a significant positive correlation between increases in plasma bioactive GLP-2 and proglucagon mRNA expression in the colon of TPN rats and ileum of orally fed rats. These data support a significant role for endogenous GLP-2 in the adaptive response to mid-small bowel resection in both TPN and orally fed rats.     

Resection upregulates the IGF-I system of parenterally fed rats with jejunocolic anastomosis

Rats maintained with parenteral nutrition following 60% jejunoileal resection plus cecectomy exhibit minimal adaptive growth in the residual jejunum but a dramatic adaptive growth in the residual colon. Coinfusion of insulin-like growth factor I (IGF-I) with parenteral nutrition induces jejunal growth but has minimal effects in the colon. Our objective was to study the role of the endogenous IGF-I system in the differential responses of jejunum and colon to resection and/or IGF-I during parenteral nutrition. We measured concentrations of immunoreactive IGF-I in plasma, jejunum, and colon, IGF-I receptor binding, and levels of IGF receptor, IGF-I, IGF binding protein (IGFBP)-3 and IGFBP-5 mRNA in residual jejunum and colon 7 days after resection and/or IGF-I treatment. IGF-I receptor number was increased (74-99%) in jejunum and colon due to resection; IGF-I mRNA was increased 5-fold in jejunum and 15-fold in colon due to resection. Resection increased circulating IGFBPs but did not alter plasma IGF-I concentration. Resection induced colonic growth in association with significantly greater colonic IGFBP-5 mRNA and significantly lower colonic immunoreactive IGF-I. IGF-I treatment had no significant effect on IGF-I mRNA or IGF-I receptor number. Concentrations of plasma and jejunal immunoreactive IGF-I were significantly increased in rats given IGF-I in association with jejunal growth. IGF-I treatment significantly increased IGFBP-5 mRNA in the jejunum, which also correlated with jejunal growth. Thus resection upregulated IGF-I receptor number and IGF-I mRNA in residual jejunum and colon, but differential adaptation of these segments correlated with differential regulation of IGFBP-5 mRNA.     

Greater potency of IGF-I than IGF-I/BP-3 complex in catabolic parenterally fed rats

We compared the anabolic effects of recombinant human insulin-like growth factor I (rhIGF-I, 2.5 mg/kg) and equimolar amounts of rhIGF-I prebound to rhIGF binding protein-3 (rhIGF-I/BP-3) coinfused continuously with total parenteral nutrition (TPN) solution in dexamethasone (Dex, 70 microg/day ip)-treated male rats for 6 days. The four TPN groups included control, Dex, Dex + IGF-I, and Dex+IGF-I/BP-3. Pharmacokinetic analysis indicated reduced clearance of IGF-I when infused as IGF-I/BP-3 compared with free IGF-I (0.91 +/- 0.09 vs. 2.01 +/- 0.19 ml serum/min, P < 0.001) and this was associated with significantly greater serum IGF-I concentrations in the Dex+IGF-I/BP-3 group. Despite greater total serum IGF-I levels, infusion of free IGF-I produced greater anabolic responses than IGF-I/BP-3 based on body weight, nitrogen balance, and jejunal cellularity. Treatment with free IGF-I, but not IGF-I/BP-3, significantly reduced serum insulin and glucose levels that were elevated due to Dex. There were no significant differences in liver IGF-I mRNA levels between groups. Serum IGFBP-3 levels were elevated with infusion of IGF-I/BP-3 compared with IGF-I. These results indicate greater anabolic potency of IGF-I compared with IGF-I/BP-3 when administered by continuous parenteral infusion with TPN solution in catabolic rats.     

Intestinotrophic effects of exogenous IGF-I are not diminished in IGF binding protein-5 knockout mice

IGF binding protein-5 (IGFBP-5) modulates the availability of IGF-I to its receptor and potentiates the intestinotrophic action of IGF-I. Our aim was to test the hypothesis that stimulation of intestinal growth due to coinfusion of IGF-I with total parenteral nutrition (TPN) solution is dependent on increased expression of IGFBP-5 through conducting our studies in IGFBP-5 knockout (KO) mice. IGFBP-5 KO, heterozygote (HT) and wild type (WT) male and female mice were maintained with TPN or TPN plus coinfusion of IGF-I [recombinant human (rh)IGF-I; 2.5 mg x kg(-1) x day(-1)] for 5 days. The concentration of IGF-I in serum was 73% greater (P < 0.0001) in mice given TPN + IGF-I infusion compared with TPN alone. IGF-I attenuated the 2-3 g loss of body weight associated with TPN in WT mice, whereas KO and HT mice did not show improvement in body weight with IGF-I treatment. KO and HT mice had significantly greater levels of circulating IGF-I binding proteins (IGFBPs) compared with WT mice. Intestinal growth due to IGF-I was observed in all groups treated with IGF-I based on greater concentrations of protein and DNA in small intestine and colon and significantly greater crypt depth and muscularis thickness in jejunum. Jejunal expression of IGFBP-5 mRNA was greater in WT mice, whereas IGFBP-3 mRNA was greater in KO mice treated with IGF-I. In summary, the absence of the IGFBP-5 gene did not block the ability of IGF-I to stimulate intestinal growth, possibly because greater jejunal expression of IGFBP-3 compensates for the absence of IGFBP-5.     

Free oxygen radical-induced lipid peroxidation and antioxidant in infants receiving total parenteral nutrition

OBJECTIVE: Increased oxygen-derived free radical activity has been reported during total parenteral nutrition (TPN) in infants particularly linked to the fat infusion. It is possible that partial enteral feeding can ameliorate some of the complications of TPN. By this study we aimed to investigate free radical formation and antioxidant activity in term and preterm infants during TPN and/or enteral feeding. STUDY DESIGN: We had 6 groups of term and preterm infants made up of 10 patients each. Group I had only enteral feeding, Group II enteral plus parenteral feeding, Group III only parenteral feeding. Plasma malondialdehyde (MDA), superoxide dismutase (SOD), vitamin E and vitamin C levels were measured in all infants. Blood samples of infants receiving only TPN and TPN plus enteral feeding were measured on the 1st and 5th days, and 3h after the end of lipid infusion. RESULTS: There was no difference between the term and preterm infants in terms of MDA, SOD, vitamin C and E levels taken baseline and after parenteral, and enteral plus parenteral feeding on the 1st and 5th days. When 3 groups of both term and preterm infants were compared with each other none of the parameters showed a statistically significant difference. In addition, we compared baseline and 1st and 5th days of TPN therapy in both term and preterm infants fed only parenterally and enteral plus parenteral feedings. In term infants fed both parenterally and parenteral plus enterally, the MDA levels before TPN were significantly higher than that of the levels of patients on parenteral nutrition on the 5th day. On the 1st and 5th days of TPN therapy, the levels of vitamin C was significantly decreased, in term and preterm infants fed only parenterally, levels of vitamin E was increased, in term and preterm infants fed both parenterally and parenteral plus enterally. Also, when compared to their base line the SOD levels of the term infants detected on the 1st and 5th days were significantly high. CONCLUSION: Free radical production is increased by the administration of TPN and may be linked to its adverse effects. It may be assumed that long-term complications of preterm infants receiving TPN may be reduced by further strengthening the antioxidant capacities of the TPN solutions.     

Selective decontamination by antimicrobials during long term treatment: perspectives for saving host indigenous microbiota

Short bowel syndrome (SBS) occurs in patients fed total parenteral nutrition (TPN) after massive intestinal resection. TPN weaning is often associated with occlusion or sepsis. In the present study the intestinal biotope was investigated in young patients (n = 14) with massive intestinal resection and recurrent symptoms of sepsis or occlusion during enteral food introduction. They were treated by aminosides for a long term period. Ileal effluents were collected for enumerating bacteria. In some case, blood and rectal specimen were also collected. A few patients developed bacterial overgrowth (1), occlusion (1), sepsis (4), osteoarthritis (1) or pneumonia (1) during the survey. A drastic drop of bifidobacteria that was not prevented by human milk feeding was observed prior occlusion or respiratory infection. Detection of clostridial vegetative forms preceded sepsis and decrease in clostridia parallelled recovery. In conclusion, onset of symptoms was related with extreme imbalance of the ileal flora. Supplementation with bifidobacterial compounds that were well tolerated in two patients could be of interest in children with recurrent symptoms.     

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 microg.kg(-1).h(-1) GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals (P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression (P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.     

Acidomucin goblet cell expansion induced by parenteral nutrition in the small intestine of piglets

Total parenteral nutrition (TPN) impairs small intestine development and is associated with barrier failure, inflammation, and acidomucin goblet cell expansion in neonatal piglets. We examined the relationship between intestinal goblet cell expansion and molecular and cellular indices of inflammation in neonatal piglets receiving TPN, 80% parenteral + 20% enteral nutrition (PEN), or 100% enteral nutrition (control) for 3 or 7 days. Epithelial permeability, T cell numbers, TNF-alpha and IFN-gamma mRNA expression, and epithelial proliferation and apoptosis were compared with goblet cell numbers over time. Epithelial permeability was similar to control in the TPN and PEN jejunum at day 3 but increased in the TPN jejunum by day 7. By day 3, intestinal T cell numbers were increased in TPN but not in PEN piglets. However, goblet cell expansion was established by day 3 in both the TPN and PEN ileum. Neither TNF-alpha nor IFN-gamma mRNA expression in the TPN and PEN ileum correlated with goblet cell expansion. Thus goblet cell expansion occurred independently of overt inflammation but in association with parenteral feeding. These data support the hypothesis that goblet cell expansion represents an initial defense triggered by reduced epithelial renewal to prevent intestinal barrier failure.     

Indications for total parenteral nutrition in the hospitalized patient: a prospective review of evolving practice

The indications for initiating total parenteral nutrition (TPN) were prospectively evaluated in 100 consecutive patients at a tertiary referral hospital with a long-standing Nutritional Support Service to illustrate the reasons why the parenteral route was chosen at this unique institution in terms of patient population. Sixty male and 40 female patients, average age 59 +/- 17 years (range 22-86 years), were classified a priori as to the underlying reasons for initiation of TPN. The study was conducted by a Nutrition Support Service at this hospital without pediatric, trauma, or burn services specializing in the care of patients with diabetes mellitus. Of the 100 patients, 63% were from the surgical service; 24% had diabetes mellitus. Their mean weight (118 +/- 29% of ideal), body mass index (25 +/- 6 kg/m(2)), and serum albumin (2.8 +/- 0.7 g/dL) indicated a reasonable body composition with a moderate systemic inflammatory response. Six patients received preoperative TPN for an average of 5 +/- 3 days with a variety of diagnoses including malignancy, Crohn's disease, bowel obstruction, and gastrointestinal bleeding. The underlying reasons for initiating nutritional support were related to three factors that largely determine the need for involuntary feeding: preexisting protein calorie malnutrition, actual or anticipated semistarvation for a prolonged period, and the presence of a systemic inflammatory response. The choice of TPN was based on anticipated or proven intolerance to full enteral feeding. The duration of time before initiation of TPN postoperatively was 6 +/- 5 days, which reflects our policy that initially well-nourished patients who are experiencing a systemic inflammatory response should not undergo more than 5 to 7 days of inadequate feeding. The duration of TPN overall was 11 +/- 10 days, which primarily illustrates the dramatic reduction in length of hospital stay that has occurred throughout the health care system and the willingness to provide TPN in alternative settings including transitional care units, rehabilitation hospitals, and for short-term care, the patient's home. The most common specific reasons identified for initiating TPN rather than enteral nutrition were ileus (25%), an underlying acid-base or electrolyte/mineral disorder (13%) requiring correction, and the convenience of TPN because a central venous catheter was in place (12%). The usual indication for nutritional support at this tertiary referral and specialty hospital was actual or impending protein calorie malnutrition. TPN was chosen for a variety of reasons related to actual or anticipated tolerance to enteral feeding. This audit demonstrates that our TPN practice has evolved in relation to time of initiation and duration of feeding, which reflect a clearer appreciation of the risks and benefits of TPN.     

Acute alcohol administration inhibits the refeeding response after starvation in rat skeletal muscle

This study determined whether an acute alcohol dose could inhibit the refeeding response in starved muscle. Rats starved for 24 h were pretreated with alcohol or saline before refeeding by intragastric or intravenous infusion of enteral diet (ENT), total parenteral nutrition (TPN), or saline. Refeeding by TPN or ENT stimulated increases in the fractional rate of protein synthesis (k(s)) in skeletal muscle. Alcohol prevented the increase in k(s) when refeeding occurred intragastrically (TPN or ENT) (P < 0.001) but not intravenously (TPN). Upon intragastric refeeding, alcohol inhibited the increase in both eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and p70 S6 kinase (p70(S6K)) phosphorylation in plantaris but caused only partial inhibition in soleus muscle (ENT only). When rats were refed intravenously, alcohol had no effect on the increased 4E-BP1 or p70(S6K) phosphorylation in either muscle. Plasma insulin levels were augmented by alcohol. Alcohol-related changes in plasma amino acid concentrations were similar irrespective of the route of feeding, whereas IGF-I levels showed differential changes. This is the first study to demonstrate that acute alcohol ingestion impedes the starved-to-fed response in skeletal muscle.     

Glucagon-like peptide-2 protects against TPN-induced intestinal hexose malabsorption in enterally refed piglets

Premature infants receiving chronic total parenteral nutrition (TPN) due to feeding intolerance develop intestinal atrophy and reduced nutrient absorption. Although providing the intestinal trophic hormone glucagon-like peptide-2 (GLP-2) during chronic TPN improves intestinal growth and morphology, it is uncertain whether GLP-2 enhances absorptive function. We placed catheters in the carotid artery, jugular and portal veins, duodenum, and a portal vein flow probe in piglets before providing either enteral formula (ENT), TPN or a coinfusion of TPN plus GLP-2 for 6 days. On postoperative day 7, all piglets were fed enterally and digestive functions were evaluated in vivo using dual infusion of enteral ((13)C) and intravenous ((2)H) glucose, in vitro by measuring mucosal lactase activity and rates of apical glucose transport, and by assessing the abundances of sodium glucose transporter-1 (SGLT-1) and glucose transporter-2 (GLUT2). Both ENT and GLP-2 pigs had larger intestine weights, longer villi, and higher lactose digestive capacity and in vivo net glucose and galactose absorption compared with TPN alone. These endpoints were similar in ENT and GLP-2 pigs except for a lower intestinal weight and net glucose absorption in GLP-2 compared with ENT pigs. The enhanced hexose absorption in GLP-2 compared with TPN pigs corresponded with higher lactose digestive and apical glucose transport capacities, increased abundance of SGLT-1, but not GLUT-2, and lower intestinal metabolism of [(13)C]glucose to [(13)C]lactate. Our findings indicate that GLP-2 treatment during chronic TPN maintains intestinal structure and lactose digestive and hexose absorptive capacities, reduces intestinal hexose metabolism, and may facilitate the transition to enteral feeding in TPN-fed infants.     

Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs

Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly described metabolic hormone fibroblast growth factor-19 (FGF19) and also glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN + CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG) content. CDCA treatment improved direct bilirubin levels by almost fourfold compared with the TPN group and also normalized serum bile acids and liver TG. FGF19, GLP-1, and GLP-2 were decreased in plasma of the TPN group compared with the EN group but were all induced by CDCA treatment. Intestinal mucosal growth marked by weight and villus/crypt ratio was significantly reduced in the TPN group compared with the EN group, and CDCA treatment increased both parameters. These results suggest that decreased circulating FGF19 during TPN may contribute to PNALD. Moreover, we show that enteral CDCA not only resolves PNALD but acts as a potent intestinal trophic agent and secretagogue for GLP-2.     

早期肠内营养和肠外营养对ICU中重症肺炎患者预后的影响

目的:研究早期肠内和肠外营养对ICU中重症肺炎患者预后的影响。方法:选取2013年1月-2014年1月我院重症医学科60例重症肺炎患者随机分为肠内营养组30例(enteral nutrition,EN组)和完全肠外营养支持组30例(total parenteral nutrition,TPN组),经过营养支持治疗后,将两组的免疫、营养以及有创机械通气的时间等指标进行比较。结果:肠内营养组与肠外营养组对比发现,在第5天、第10天EN组血清免疫球蛋白和T细胞亚群细胞数显著升高(P0.05);血红蛋白(HGB)、白蛋白(ALB)和血清前白蛋白(PAB)明显升高(P0.05);有创机械通气时间缩短(P0.05),差异具有统计学意义。结论:ICU中重症肺炎应选择肠内营养支持方式,肠内营养能有效的改善营养状态,并能改善患者的免疫功能,减少有创机械通气时间。     

Antioxidants in patients receiving total parenteral nutrition after gastrointestinal cancer surgery

Total parenteral nutrition (TPN) is essential for patients with postoperative impairing gastrointestinal function who are unable to receive and absorb oral/enteral feeding for at least 7 days. Oxidative stress plays a major role in the ethiopathogenesis of cancers. In this study, total antioxidant status (TAS), glutathione peroxidase (GPx), superoxide dismutase, malondialdehyde and ascorbic acid were studied in patients operated because of small intestine, colorectal or pancreatic cancer and subsequently receiving TPN in comparison with patients receiving standard nutrition after the operation. TAS level and GPx activity were decreased in patients with small intestine cancer but did not differ in patients with colorectal and pancreatic cancer before and after surgery. In all patient groups receiving TPN, superoxide dismutase activity after the surgery was kept at the same level as before. On the fifth day after the surgery, malondialdehyde concentration in each group was restored to the value observed before surgery. On the fifth day of TPN treatment, ascorbic acid concentration was increased in every group of patients. TPN applied during the postoperative period alleviates oxidative stress resulting from surgery. In the case of small intestine cancer, the addition of vitamins and antioxidants to the nutrition mixture seems to result in depletion of antioxidant enzymes' activities.     

Vagal afferents are essential for maximal resection-induced intestinal adaptive growth in orally fed rats

Small bowel resection stimulates intestinal adaptive growth by a neuroendocrine process thought to involve both sympathetic and parasympathetic innervation and enterotrophic hormones such as glucagon-like peptide-2 (GLP-2). We investigated whether capsaicin-sensitive vagal afferent neurons are essential for maximal resection-induced intestinal growth. Rats received systemic or perivagal capsaicin or ganglionectomy before 70% midjejunoileal resection or transection and were fed orally or by total parenteral nutrition (TPN) for 7 days after surgery. Growth of residual bowel was assessed by changes in mucosal mass, protein, DNA, and histology. Both systemic and perivagal capsaicin significantly attenuated by 48-100% resection-induced increases in ileal mucosal mass, protein, and DNA in rats fed orally. Villus height was significantly reduced in resected rats given capsaicin compared with vehicle. Sucrase specific activity in jejunal mucosa was not significantly different; ileal mucosal sucrase specific activity was significantly increased by resection in capsaicin-treated rats. Capsaicin did not alter the 57% increase in ileal proglucagon mRNA or the 150% increase in plasma concentration of bioactive GLP-2 resulting from resection in orally fed rats. Ablation of spinal/splanchnic innervation by ganglionectomy failed to attenuate resection-induced adaptive growth. In TPN rats, capsaicin did not attenuate resection-induced mucosal growth. We conclude that vagal afferents are not essential for GLP-2 secretion when the ileum has direct contact with luminal nutrients after resection. In summary, vagal afferent neurons are essential for maximal resection-induced intestinal adaptation through a mechanism that appears to involve stimulation by luminal nutrients.     

Enteral feeding induces diet-dependent mucosal dysfunction, bacterial proliferation, and necrotizing enterocolitis in preterm pigs on parenteral nutrition

Preterm neonates have an immature gut and metabolism and may benefit from total parenteral nutrition (TPN) before enteral food is introduced. Conversely, delayed enteral feeding may inhibit gut maturation and sensitize to necrotizing enterocolitis (NEC). Intestinal mass and NEC lesions were first recorded in preterm pigs fed enterally (porcine colostrum, bovine colostrum, or formula for 20-40 h), with or without a preceding 2- to 3-day TPN period (n = 435). Mucosal mass increased during TPN and further after enteral feeding to reach an intestinal mass similar to that in enterally fed pigs without TPN (+60-80% relative to birth). NEC developed only after enteral feeding but more often after a preceding TPN period for both sow's colostrum (26 vs. 5%) and formula (62 vs. 39%, both P < 0.001, n = 43-170). Further studies in 3-day-old TPN pigs fed enterally showed that formula feeding decreased villus height and nutrient digestive capacity and increased luminal lactic acid and NEC lesions, compared with colostrum (bovine or porcine, P < 0.05). Mucosal microbial diversity increased with enteral feeding, and Clostridium perfringens density was related to NEC severity. Formula feeding decreased plasma arginine, citrulline, ornithine, and tissue antioxidants, whereas tissue nitric oxide synthetase and gut permeability increased, relative to colostrum (all P < 0.05). In conclusion, enteral feeding is associated with gut dysfunction, microbial imbalance, and NEC in preterm pigs, especially in pigs fed formula after TPN. Conversely, colostrum milk diets improve gut maturation and NEC resistance in preterm pigs subjected to a few days of TPN after birth.     

Loss of exocrine pancreatic stimulation during parenteral feeding suppresses digestive enzyme expression and induces Hsp70 expression

Luminal nutrients are essential for the growth and maintenance of digestive tissue including the pancreas and small intestinal mucosa. Long-term loss of luminal nutrients such as during animal hibernation has been shown to result in mucosal atrophy and a corresponding stress response characterized by the induction of heat shock protein (Hsp)70 expression. This study was conducted to determine if the loss of luminal nutrients during total parenteral nutrition (TPN) would result in atrophy of the exocrine pancreas and small intestinal mucosa as well as an induction of Hsp70 expression in rats. In experiment 1, the treatment groups included an orally fed control, a saline-infused surgical control, or TPN treatment for 7 days. In experiment 2, the treatment groups included an orally fed control and TPN alone or coinfused with varying doses of glucagon-like peptide (GLP)-2, a mucosal proliferation agent, for 7 days. In experiment 1, TPN resulted in a 40% reduction in pancreatic mass that was associated with a dramatic reduction in digestive enzyme expression, enhanced apoptosis, and a 200% increase in Hsp70 expression. Conversely, heat shock cognate 70, Hsp27, and Hsp60 expression was not changed in the pancreas. In experiment 2, TPN resulted in a 30% reduction in jejunal mucosa mass and a similar induction of Hsp70 expression. The inclusion of GLP-2 during TPN attenuated jejunal mucosal atrophy and inhibited Hsp70 expression, suggesting that Hsp70 induction is sensitive to cell growth. These data indicate that pancreatic and intestinal mucosal atrophy caused by a loss of luminal nutrient stimulation is accompanied by a compensatory response involving Hsp70.     

Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, intestinotrophic hormone derived from posttranslational processing of proglucagon in the distal bowel. GLP-2 is thought to act through indirect mediators, such as IGF-I. We investigated whether intestinal expression of GLP-2 and IGF-I system components are increased with the mucosal growth induced by enteral nutrient (EN) and/or a low dose of GLP-2 in parenterally fed rats. Rats were randomized to four treatment groups using a 2 x 2 design and maintained with parenteral nutrition (PN) for 7 days: PN alone, EN, GLP-2, and EN+GLP-2; n = 7-9. The two main treatment effects are +/-GLP-2 (100 microg.kg body wt(-1).day(-1)) and +/-EN (43% of energy needs, days 4-6). Combination treatment with EN+GLP-2 induced synergistic intestinal growth in ileum, resulting in greater mucosal cellularity, sucrase segmental activity, and gain of body weight (ENxGLP-2, P < 0.04). In addition, EN+GLP-2 induced a significant 28% increase in plasma concentration of bioactive GLP-2, a significant 102% increase in ileal proglucagon mRNA with no change in ileal dipeptidyl peptidase-IV (DPP-IV) specific activity, and significantly reduced plasma DPP-IV activity compared with GLP-2. This indicates that EN potentiates the intestinotrophic action of GLP-2. Proliferation of enterocytes due to GLP-2 infusion was associated with greater expression of ileal proglucagon, GLP-2 receptor, IGF-I, IGF binding protein-3 mRNAs, and greater IGF-I peptide concentration in ileum (P < 0.032). Ileal IGF-I mRNA was positively correlated with expression of proglucagon, GLP-2R, and IGFBP-5 mRNAs (R2 = 0.43-0.56, P < 0.0001). Our findings support the hypothesis that IGF-I is one of the downstream mediators of GLP-2 action in a physiological model of intestinal growth.