Effect of transforming growth factor-alpha on intestinal adaptation in a rat model of short bowel syndrome

OBJECTIVE: TGF-alpha has recently been shown to stimulate enterocyte proliferation. In the present study we investigated the effect of TGF-alpha on enterocyte proliferation and loss via apoptosis and its effects on intestinal adaptation in a rat following massive bowel resection. METHODS: Male Sprague-Dawley rats underwent bowel transection and reanastomosis (sham group) or 75% small bowel resection and anastomosis (SBS group) and were treated with intraperitoneal TGF-alpha (75 microg/kg) from the ninth postoperative day (SBS-TGF-alpha group). Parameters of intestinal adaptation (overall bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth), enterocyte proliferation, and apoptosis were determined on day 15. Statistical significance was determined by ANOVA with a P < 0.05 considered significant. RESULTS: SBS-TGF-alpha rats demonstrated a significant increase (vs SBS) in duodenal, jejunal, and ileal overall bowel and mucosal weights; ileal mucosal DNA and protein; and jejunal and ileal villus height. SBS-TGF-alpha rats also showed an increased cell proliferation index in jejunum (704 +/- 43 vs 499 +/- 63 BrdU-positive cells/10 crypts, P < 0.05) and ileum (715 +/- 84 vs 529 +/- 40 BrdU-positive cells/10 crypts, P < 0.05) and decreased apoptotic index in ileum (8.7 +/- 1.1 vs 21.8 +/- 3.2 apoptotic cells/1,000 villus cells, P < 0.05) compared to SBS animals. CONCLUSIONS: In a rat model of SBS, TGF-alpha enhances intestinal adaptation. Possible mechanisms may include increased cell proliferation and decreased enterocyte loss via apoptosis.     

Low-fat diet impairs postresection intestinal adaptation in a rat model of short bowel syndrome

Background: Low-fat diets (LFD) are utilized frequently in patients with short bowel syndrome (SBS). The purpose of this study was to investigate the effects of LFD on intestinal adaptation, enterocyte proliferation, and enterocyte cell death in a rat model of SBS.Methods: Adult male Sprague-Dawley rats were divided into 3 experimental groups: Sham-NC rats underwent bowel transection and reanastomosis and were fed normal chow (NC), SBS-NC rats underwent 75% small bowel resection and were fed NC, and SBS-rats were fed a low-fat diet (SBS-LFD). Parameters of intestinal adaptation, enterocyte proliferation, and enterocyte apoptosis were determined on day 14 after operation.Results: SBS-NC rats showed a significant increase (v Sham-NC) in jejunal and ileal bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth. A significant 67% increase in crypt cell proliferation rate and 265% increase in villus enterocyte apoptosis was seen in the ileum of SBS-NC rats compared with control animals (P < .05). SBS-LFD animals showed lower ileal mucosal weight (29%; P < .05), jejunal crypt depth (20%; P < .05), and ileal villus height (21%; P < .05). A significant decrease in villus apoptosis in jejunum (74%; P < .05) and ileum (67%; P < .05) and a decrease in cell proliferation in ileum (35%; P < .05) was seen also after exposure to LFD compared with SBS-NC.Conclusions: In a rat model of SBS, early LFD appears to inhibit parameters of intestinal adaptation. A possible mechanisms for this effect may be decreased cell proliferation. Decreased enterocyte loss via apoptosis, found in this study, may reflect a reduced number of enterocyte.     

精氨酸促进短肠综合征肠道代偿及其机制的初步研究

目的研究肠内营养中添加精氨酸对广泛肠切除术后大鼠肠道代偿的影响。方法将30只SD大鼠随机分为Con组（假手术）、SB组（短肠对照）和SB—Arg组（短肠加用精氨酸）,各组大鼠于术后第2。14天分别给予等氮、等热量的肠内营养支持．其中SB-Arg组肠内营养中添加L-精氨酸（300mg·kg^-1·d^-1）。比较术后各组体质量、脂肪吸收率、血浆总游离脂肪酸及必需脂肪酸水平、小肠代偿指标、肠黏膜细胞增殖和凋亡的差异。结果SB组术后早期营养支持2周后,其体质量较Con组低,各项肠道代偿指标均明显升高（P〈0．05）。SB-Arg组大鼠脂肪吸收率[（84．9±3．2）％]、血浆游离脂肪酸水平[（650．0±86．5）mg／L]、回肠黏膜质量[（18．0±3．5）mg·cm^-1·100g^-1]、回肠DNA含量[（29．6±3．3）μg·cm^-1·100g^-1]、小肠蛋白质含量[空肠（65．5＋7．3）μg·cm^-1·100g^-1和回肠（39．2±2．3）μg·cm^-1·100g^-1]和小肠增殖指数（空肠31±4,回肠32±2）均高于SB组的[（81．3±3．9）％、（289．5±76．9）mg／L、（13．5±3．0）mg·cm^-1·100g^-1（26．0＋2．6）μg·cm^-1·100g^-1（59．8±6．2）μg·cm^-1·100g^-1、（35．4±2．3）μg·cm^-1·100g^-1、（22±3）及（25±3）,均P〈0．05];小肠超微结构亦观察到SB-Arg组大鼠小肠绒毛高度、隐窝深度及黏膜厚度均大于SB组大鼠（P〈0．05）。结论肠内营养中添加适量精氨酸能促进短肠综合征大鼠肠道结构及功能的代偿．其机制可能为促进肠黏膜细胞增殖、抑制其凋亡。     

短肠综合征肠道再手术分析

目的 分析手术后短肠综合征（SBS）病人再手术,降低SBS再手术率。方法 回顾性总结2001年1月至2010年12月南京军区南京总医院解放军普通外科研究所收治的短肠综合征病人198例,其中因肠道原因而再次手术治疗病人76例（男59例,女17例）,年龄5~62（37.98±13.75）岁,残存小肠长度0~150（72.53±41.83）cm。结果 76例SBS接受再次手术124（1.63±0.4）例次,再次手术以肠造口还纳（43例次）、腹腔感染引流（28例次）及病变肠袢切除吻合（肠梗阻13例次、肠瘘12例次,蛋白质丢失病7例次、肠穿孔/肠坏死5例次）为主。SBS病人因肠道原因再手术率为38.4%。结论 SBS病人因肠道原因再手术率较高,选择合理的首次手术方式,有助于降低再手术率。     

Comparison of massive vs. repeated resection leading to short bowel syndrome

Short bowel syndrome can result from either a single massive intestinal resection or repeated lesser resections, which might have prognostic implications. The aim of this study was to compare patient populations and outcome of short bowel syndrome caused by massive and repeated resection. The records of 95 adult patients with short bowel syndrome evaluated over a 20-year period were reviewed. Massive resection was performed in 72 patients (76%) and repeated lesser resections in 23 patients (24%). Patients undergoing massive resection were more likely to be more than 70 years of age (26% vs. 9%, P <0.05). Mesenteric vascular disease was more prevalent among patients undergoing massive resection (39% vs. 9%, P <0.05), whereas Crohn’s disease was less prevalent (1% vs. 35%, P <0.05). Distribution of remnant length, presence of the ileocecal junction, and presence of a stoma were similar. Patients undergoing massive resection were more likely to require parenteral nutrition after the first year (56% vs. 23%, P <0.05). Patients with very short remnants (<60 cm) were more likely to receive parenteral nutrition after massive resection (95% vs. 60%, P <0.05). Thirty-day mortality was higher after massive resection (24% vs. 4%, P <0.05). However, those surviving 30 days had similar survival rates at 1 year and 5 years after massive and repeated resections. Patients undergoing massive vs. repeated resections are different with respect to age, underlying condition, and nutritional support needs. These factors may influence overall outcome in short bowel syndrome. The better nutritional prognosis of patients undergoing repeated resection given similar intestinal remnants may be related in part to enhanced intestinal adaptation. Presented at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999.     

Intestinal adaptation after small bowel resection in human infants

Purpose

In animal models, the small intestine responds to massive small bowel resection (SBR) through a compensatory process termed adaptation, characterized by increases in both villus height and crypt depth. This study seeks to determine whether similar morphologic alterations occur in humans after SBR.

Methods

Clinical data and pathologic specimens of infants who had both an SBR for necrotizing enterocolitis and an ostomy takedown from 1999 to 2009 were reviewed. Small intestine mucosal morphology was compared in the same patients at the time of SBR and at the time of ostomy takedown.

Results

For all samples, there was greater villus height (453.6 ± 20.4 vs 341.2 ± 12.4 μm, P < .0001) and crypt depth (178.6 ± 7.2 vs 152.6 ± 6 μm, P < .01) in the ostomy specimens compared with the SBR specimens. In infants with paired specimens, there was an increase of 31.7% ± 8.3% and 22.1% ± 10.0% in villus height and crypt depth, respectively. There was a significant correlation between the amount of intestine resected and the percent change in villus height (r = 0.36, P < .05).

Conclusion

Mucosal adaptation after SBR in human infants is similar to what is observed in animal models. These findings validate the use of animal models of SBR used to understand the molecular mechanisms of this important response.     

谷氨酰胺和生长激素对短肠综合征患者肠道代偿作用

目的探讨谷氨酰胺和生长激素对短肠综合征(SBS)患者的肠道代偿作用。方法26例短肠综合征患者残余小肠长度为0～100(中位数42.5)cm,手术后接受肠外营养(PN)支持3-52个月,联合应用生长激素(GH)(0.10±0.06)mg·kg-1·d-1和谷氨酰胺(GLN)(0.30±0.17)g·kg-1·d-1进行肠道促代偿治疗。结果26例接受GH加GLN治疗的SBS患者,其中9例(34.6%)治疗后近期内完全摆脱PN;8例(30.8%)经治疗后明显减少了PN用量,从每周需要PN(6.0±1.0)d下降至(4.2±1.0)d,每周PN需要量从(13.6±5.2)L降至(8.2±3.3)L;9例(34.6%)在治疗后仍依赖PN维持。结论经过合适的营养支持和肠道促代偿治疗,大多数短肠综合征患者残留肠道能充分代偿,完全摆脱PN或减少PN用量,长期健康生存。     

Living-related bowel transplantation to treat short bowel syndrome in a four-year-old child: a case report

Purpose: Short bowel syndrome (SBS) is an extremely challenging clinical problem in children. Although many patients can be maintained for a period of time on total parenteral nutrition (TPN), many of these children suffer from the morbidity and mortality associated with sequential central line infections, venous thromboses, and TPN-induced liver failure. Intestinal transplantation often is the only chance for long-term survival. Unfortunately, many children die every year waiting for size-matched cadaveric intestine to become available.Methods: After our success with living-related bowel transplantation in adults, the authors successfully transplanted 150 cm of maternal ileum into a 4-year-old 10-kg child with profound malnutrition from SBS and advanced TPN-induced liver failure. Because of the size mismatch, the abdominal cavity could not be closed primarily. The defect was covered with absorbable mesh and subsequently with skin graft.Results: The patient is home with excellent bowel and liver function, off hyperalimentation, and on a regular diet. No rejection has been encountered.Conclusions: Living-related intestinal transplantation is a life-saving alternative to cadaveric intestinal transplantation in children with short bowel syndrome.     

Extreme short bowel syndrome in a full-term neonate--a case report

Massive small bowel resection often leads to long-term parenteral nutrition. The authors present a term-born, 3-day-old boy with midgut volvulus in whom only 17 cm of small bowel was left after resection. This patient was weaned from parenteral nutrition after 7 months. Temporary parenteral nutrition-associated cholestasis was treated with ursodeoxycholic acid.     

谷氨酰胺对短肠综合征大鼠结肠黏膜细胞凋亡的影响

目的 探讨谷氨酰胺联合肠内营养对动物模型结肠黏膜凋亡的影响。方法 将大鼠随机分为3组，即正常组，模型组、谷氨酰胺组2l天两个时间点进行观察。结果 谷氨酰胺组BCl-2的平均灰度值及表达阳性的面积明显大于其他组，Bax基因蛋白平均灰度值及表达阳性的面积明显小于其他组（P〈0．05）。结论 谷氨酰胺能抑制结肠黏膜细胞的凋亡，促进结肠的代偿。     

胰高血糖素样肽-2对短肠大鼠残留小肠代偿的影响

目的　研究胰高血糖素样肽 2 (GLP 2 )对短肠大鼠残留小肠代偿的影响及机制。方法　 75 %小肠切除大鼠随机分成空白 (SB)组、生长激素 (GH )组和GLP 2组。术后 6d行残留回肠黏膜形态学检测、细胞增殖核心抗原 (PCNA)测定及原位末端标记 (INST法 )染色。结果　GLP 2组回肠黏膜形态学指标显著高于SB组 (P <0 .0 5 ) ,并且其黏膜厚度显著高于GH组 (P <0 .0 5 )。GLP 2组PCNA指数显著高于SB组 (0 .5 1± 0 .0 9与 0 .40± 0 .0 6比较 ,P <0 .0 5 ) ,但和GH组比较差异无统计学意义 (P >0 .0 5 )。GLP 2组细胞凋亡显著低于SB组 (67.7± 10 .1与 81.7± 12 .9比较 ,P <0 .0 5 ) ,但和GH组比较差异无统计学意义 (P >0 .0 5 )。结论　GLP 2能刺激小肠黏膜上皮增生 ,抑制凋亡 ,显著促进短肠大鼠残留小肠黏膜的形态代偿。     

短肠综合征时结肠的代偿研究

目的　观察及评价短肠大鼠结肠代偿性增生及结肠对营养物质吸收的促进作用。　方法　制作切除（80～85）%的超短肠大鼠模型,用百普素(Pepti-2000)做肠内营养（EN）治疗,观察全身营养状况和结肠形态学的改变,并在术后第21天用木糖和15N-甘氨酸混合液对带血管蒂的结肠进行封闭式灌注,观察结肠对水、碳水化合物和氨基酸的吸收情况。　结果　EN组于术后第21天净氮平衡与对照组（CONT）无差异,体重仅比术前减轻(10±18)g。结肠壁明显增厚,皱襞增大增粗,结肠壁的厚度、粘膜厚度、皱襞高度和皱襞表面积与CONT组相比差异具有非常显著性意义（P＜0.01）。EN组与CONT组相比DNA指数1.21±0.11vs.1.01±0.15(P＜0.05),S期细胞百分比（52.6±5.5）%vs.（42.9±4.1）%（P＜0.05）。连续循环灌注3h之后EN组对水、木糖和氨基酸的吸收明显高于CONT组（P＜0.05）。　结论　大鼠结肠在短肠综合征时发生了明显的形态和功能上的代偿。早期适当的肠内营养不但可使超短肠大鼠获得足够营养支持,并且能够促进短肠大鼠结肠代偿。     

The effect of growth hormone supplementation on late nutritional independence in pediatric patients with short bowel syndrome

Purpose

The use of growth hormone (GH) supplementation for intestinal adaptation among adult patients with short bowel syndrome (SBS) has provided mixed results. This report examines the effect of GH supplementation on SBS in pediatric patients.

Methods

Two girls with SBS from neonatal gastrointestinal catastrophes received exogenous GH at 0.3 mg/kg per week subcutaneously and concurrent glutamine supplementation, beginning at 6 and 6½ years of age. Changes in growth (height and weight) and changes in enteral and parenteral energy requirements were evaluated.

Results

Treatment duration was 8 and 2.5 years, respectively. Patient weights increased from the 5th to the 41st percentile and from the 17th to the 23rd percentile, respectively. Height increased from the 1st to the 57th percentile in the former patient and increased from less than the 1st to the 17th percentile in the latter. Both patients are independent of parenteral nutrition and take enteral nutrition alone. Tolerance for enteral diets was significantly improved in each girl, with only 2 stools per day maintained in one patient.

Conclusions

The data show that late exogenous treatment with GH and glutamine supplementation improved growth parameters in pediatric patients with SBS. Growth hormone and glutamine supplementation may be beneficial in promoting late intestinal adaptation in pediatric patients with SBS. These data also suggest that these adjuncts may be useful in the early phases of intestinal adaptation.     

胰高血糖素样肽-2对短肠大鼠残留小肠代偿的影响

目的研究胰高血糖素样肽-2(GLP-2)对短肠大鼠残留小肠形态及功能代偿的影响。方法将20只切除小肠75%的大鼠随机分成对照组和GLP-2组,术后1-5 d内自由进食。GLP-2组每日2次腹腔注射GLP-2(250μg·kg~(-1)·d~(-1))；对照组每日2次腹部皮下注射生理盐水0．5 ml；另设1组正常进食大鼠作空白对照。术后第6天行残留小肠黏膜形态学检测、细胞增殖核心抗原(PCNA)测定,钠葡萄糖共同转运体(SGLT1)和二肽转运体(PEPT1)的mRNA表达检测以及在体小肠循环灌流实验测定大鼠回肠的单位长度及单位重量的葡萄糖吸收率。结果GLP-2组残留小肠黏膜形态学指标、PCNA指数显著高于对照组；而小肠黏膜细胞凋亡显著低于对照组；残留回肠SGLT1和PEPT1的mRNA表达显著高于对照组；均P＜0．05。但两组灌洗段回肠每g湿重葡萄糖吸收率差异无统计学意义(P＞0．05)。结论GLP-2能刺激小肠黏膜上皮增生、抑制凋亡,促进短肠大鼠残留小肠黏膜的形态及功能代偿。     

Functional liver recovery parallels autologous gut salvage in short bowel syndrome

Background/purpose

Parenteral nutrition (PN) is life saving in short bowel syndrome. However, long-term parenteral nutrition is frequently complicated by a syndrome of progressive cholestatic liver disease that is considered to be irreversible beyond the early stages of cholestasis, particularly in the presence of any degree of fibrosis in the liver. The purpose of this study was to examine apparent improvement in PN-associated liver dysfunction in a cohort of children with short bowel syndrome.

Methods

A retrospective case-record review of all patients managed within a dedicated Intestinal Rehabilitation Program (IRP) identified 13 patients with short bowel who had PN-associated liver dysfunction, defined for this purpose as hyperbilirubinemia or an abnormal liver biopsy.

Results

At referral, 12 of the 13 patients were exclusively on PN, and one was on 50% PN. At current follow-up, 3 patients have achieved complete enteral autonomy from PN, and 7 patients have had smaller decrements in PN requirements. Specific operative procedures to improve intestinal function were undertaken in 11 patients; 4 patients also underwent cholecystectomies with biliary irrigation at the time of intestinal reconstruction. The median highest bilirubin level in these 13 patients was 10.7 mg% (range, 3.2 to 24.5 mg%). Liver biopsy results indicated that 5 patients were cirrhotic, 3 had bridging fibrosis, and 4 had severe cholestasis or lesser degrees of fibrosis. Of 10 survivors in this series, 9 patients currently have a serum bilirubin less than 1 mg% with a median bilirubin in the group of 0.6 mg% (range, 0.3 to 6.4 mg%). Twelve of the 13 patients in this series were initially referred for liver-small bowel transplantation.

Conclusions

This preliminary experience suggests that PN-dependent patients with advanced liver dysfunction in the setting of the short bowel syndrome may, in some instances, experience functional and biochemical liver recovery. The latter appears to parallel autologous gut salvage in most cases. As a corollary, the authors believe that even advanced degrees of liver dysfunction should not preclude attempts at autologous gut salvage in very carefully selected patients. Such a policy of “aggressive conservatism” may help avoid the need for liver/intestinal transplantation in some patients who appear to be not responding to PN.     

短肠综合征的肠内营养支持

目的探讨短肠综合征患者肠内营养支持的临床意义、疗效及注意事项。方法回顾性总结1999至2005年收治的40例短肠综合征患者的临床资料。所有患者均存活至今,并随访2年以上。统计分析其肠内营养用量、费用、脱离肠外营养时间及目前营养状况。结果40例患者平均残存小肠（50．8±29．4）cm,脱离肠外营养平均时间为（29．1±9．2）个月。肠内营养用量为（3284．0±1408．8）kJ／d,其费用显著低于肠外营养（P〈0．01）。目前本组患者平均体质指数为（17．8±3．2）kg,／m^2,血红蛋白（113．3±14．8）g／L,血清白蛋白（35．0±4．1）g／L。平均大便次数为（3．4±1．7）次／d,平均大便量为（720．2±350．3）ml／d。结论肠内营养对于维持短肠综合征患者营养状况、减少并发症具有重要意义,但在具体实施时需掌握方法。     

短肠综合征患者的肠道代偿及康复治疗

目的 总结短肠综合征(SBS)的治疗经验。方法 分析38例SBS患者的治疗过程,随访其目前饮食情况,肠外营养(PN)或肠内营养(EN)的时间,了解并发症情况,对部分患者作有关检测,并联合应用生长激素(GH)和谷氨酰胺(GLN)治疗,采用稳定核素示踪检测残余肠道对单糖、脂肪酸及氨基酸的吸收情况。结果 本组患者死亡5例;存活33例,存活时间为6个月～17年,平均(5.9±4.3)年。目前有3例长期接受家庭PN,6例需部分或间歇性接受PN或EN补充,完全摆脱PN的有24例,其平均摆脱PN的时间为(9.5±6.6)个月。GH加GLN治疗只能在短时间内促进残余肠道对营养物质的吸收能力。结论 经过合适的肠道康复治疗,大多数SBS患者残留肠道能充分代偿,可完全摆脱PN或减少PN用量,长期健康地生存。