新生儿短肠综合征外源性胰高血糖素样肽与肠内营养对肠道适应的不同影响

　　目前，胰高血糖素样肽-2（GLP-2）对儿科短肠综合征（SBS）的治疗作用仍不明确。加拿大阿尔伯塔大学、多伦多大学、多伦多病童医院通过对幼猪进行研究，发现GLP-2能显著增加小肠绒毛高度，增加空肠黏膜重量和隐窝深度。此外，添加肠内营养（EN）可增加回肠的长度。但是，这些作用存在肠道解剖学上的异质性。

JPEN J Parenter Enteral Nutr. 2016;40(4):118.

Differential Effects on Intestinal Adaptation Following Exogenous Glucagon-Like Peptide-2 Therapy With and Without Enteral Nutrition in Neonatal Short Bowel Syndrome.

David Lim; Diane Abdoulaye; Mitsuru Muto; Donna Vine; Patrick Nation; Pamela Wizzard; David Bigam; Paul Pencharz; Justine Turner; Paul Wales.

University of Alberta, Edmonton, Alberta, Canada; University of Toronto, Toronto, Ontario, Canada; The Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: Our understanding of the efficacy of glucagon-like peptide-2 (GLP-2) therapy in pediatric short bowel syndrome (SBS) is limited. Many key questions remain unanswered: (1) Can GLP-2 stimulate adaptation in neonatal SBS? (2) If an adaptive effect is present, will it vary depending on anatomy? and (3) Will an adaptive effect be potentiated by the addition of enteral nutrition (EN)? We aim to study the efficacy of exogenously administered GLP-2 on structural and functional adaptation in 2 preclinical models of neonatal SBS representing the spectrum of disease and whether this adaptive effect can be potentiated with EN at a level reported to stimulate adaptation.

Methods: Piglets (3-5 days old) were block randomized to a 75% midintestinal resection (JI group; retains ileum), distal-intestinal resection (JC group; has no ileum), or no resection (sham control) and either GLP-2 treatment (11 nmol/kg/d) or saline control for 7 days. Piglets also received nutrition support at 100% parenteral nutrition (PN; n = 32 in total) or 80% PN + 40% EN (n = 28 in total). Structural adaptation was assessed by morphologic changes (in intestinal length and intestinal/mucosal weights) and histologic changes. Functional adaptation was assessed by qRT-PCR for the relative gene expression of nutrient transporters (SGLT1, GLUT5, CD36, FATP4) and epithelial tight junction proteins (occludin and claudins 3, 7, and 15) as well as fecal fat absorption in pigs receiving 40% EN. Data are analyzed by 2-way analysis of variance for a 2 × 2 factorial design of surgery and treatment factors; post hoc testing was performed by Bonferroni's method.

Results: Body weight gain: In pigs on 100% PN, there was no difference in the change in total body weight gain among groups. In the pigs receiving 40% EN, the JC group gained the least amount of weight vs the sham control (P < .01). Structural adaptation: In pigs receiving 100% PN (no EN), there was no difference in the change in intestinal length. GLP-2 therapy increased normalized bowel weight (P = .04) and jejunal mucosal weight (P < .01) in the JI but not the JC group. GLP-2 therapy increased villus height in the jejunum of the JC group and ileum of the JI group (P < .01). Jejunum crypt depth was increased in both groups with GLP-2 treatment (P < .01). In piglets receiving 40% EN, intestinal length increased in the JI group and did not change in the JC group, irrespective of GLP-2 treatment (P < .01). There was no difference in jejunal mucosal weight. Jejunum villus height increased in the JC group (P < .01), while ileum crypt depth was increased in the JI group (P < .01) with GLP-2 therapy. Functional adaptation: There was no difference in the relative expression of nutrient transporters or tight junction proteins as a function of either GLP-2 treatment or surgical anatomy or receiving EN. In pigs receiving 40% EN, GLP-2 treatment did not affect fecal fat absorption (P = .76).

Conclusions: In piglets receiving no EN on 100% PN, GLP-2 induced structural adaptation more robustly in the JI group than the JC group; the JC group nevertheless had histologic adaptation. However, while 40%-60% EN is reported in the literature as the minimum enteral requirement for adaptation in healthy piglets, our data suggest that, in the setting of SBS, 40% EN had differential effects on adaptation depending on anatomy. In the JI group, bowel lengthening occurred, while the JC group did not show evidence of enhanced adaptation. Together, our studies illustrate that even without EN, GLP-2 has an intestinotrophic effect. The optimal amount of EN necessary to potentiate the adaptive effect of GLP-2 in neonatal SBS may depend on remnant intestinal anatomy, which is relevant considering the heterogeneous nature of the human neonatal SBS population.

Financial support: Canadian Institutes of Health Research, SickKids Foundation.