GLP-2 Delays but Does Not Prevent the Onset of Necrotizing Enterocolitis in Preterm Pigs

Autor: Nancy M. Benight, Oluyinka O. Olutoye, Douglas G. Burrin, Jens J. Holst, Barbara Stoll
Rok vydání: 2013
Předmět:
Zdroj: Journal of Pediatric Gastroenterology & Nutrition. 56:623-630
ISSN: 0277-2116
Popis: As improvements in neonatal care have allowed for the survival of more preterm infants, the incidence of necrotizing enterocolitis (NEC) has risen (1). Preterm infants enter the world with immature organ systems, including the gastrointestinal tract (GIT). The GIT is not fully matured until the end of the third trimester, so prematurity represents a significant risk factor for the development of NEC (1). NEC is a complex disease whose etiology is not completely understood; however, it is thought to occur as a result of a combination of factors dominated by an immature innate immunity, bacterial colonization, maldigestion of enteral feeds, as well as genetic predisposition, dysmotility, and poor barrier function (2). The incidence of NEC is inversely proportional to birth weight, with approximately 12% of very-low-birth-weight infants (500–750 g) developing NEC (1); however, despite advances in prevention and treatment, significant proportions of neonates who develop NEC do not survive or require surgery to remove large portions of the bowel. Recently, many studies have begun to identify biomarkers associated with disease progression. One such study found several plasma proteins elevated in human infants with NEC compared with non-NEC control infants, including transthyretin and serum amyloid A (SAA). The identification and validation of biomarkers may assist physicians in determining a definitive NEC diagnosis, which is notoriously difficult to predict and diagnose (2). Furthermore, identification of markers of NEC severity in animal models provides justification to test these markers in human patients. A common standard of clinical care used to circumvent enteral feeding intolerance and prevent NEC is to nourish preterm neonates with total parental nutrition (TPN) before the introduction of enteral feeds. TPN allows for normal weight gain and somatic growth, and a recent report from a multicenter study of NICU admissions indicated that 69% of neonates received parenteral nutrition for up to 14 days (3–5). Our studies in neonatal pigs also have shown that administration of TPN induces mucosal atrophy, reduces barrier function, and reduces digestive and absorptive capacity (6–9). These data suggest that although TPN administration provides critical nutrition, it may also reduce the functional capability of the intestine, which may increase the risk of developing NEC during the initiation of enteral feeds. More important, piglet studies have also shown that administration of intravenous glucagon-like peptide-2 (GLP-2) prevented the mucosal atrophy and restored digestive function associated with TPN administration (6,10,11). GLP-2 is a member of the glucagon superfamily and is produced by the enzymatic cleavage of proglucagon in entero-endocrine L cells and some neurons. The hormone has multiple actions in the intestine, including fortifying the intestinal barrier (12,13), reducing inflammation, and augmenting intestinal growth (14,15). There is a wealth of published literature on the intestinotrophic effects of GLP-2 (16). Given the beneficial effects of GLP-2, it has been studied in multiple GI diseases, including inflammatory bowel disease (IBD) and short bowel syndrome (SBS). In patients with IBD, circulating GLP-2 has been shown to be increased in patients with active disease (17), whereas animal models have found that either providing exogenous GLP-2 (18) or blocking degradation (19) reduces clinical and histological manifestations in experimental colitis. Vasoactive intestinal peptide (VIP), a secreted factor involved in intestinal motility, has been identified as the signal mediator for the anti-inflammatory actions of GLP-2 in rodent colitis models (20,21). GLP-2 has been most extensively tested in animal models and human patients with SBS in which it has shown promise to enhance intestinal adaptation and improve absorptive function (22–29). A GLP-2 analogue (teduglutide) is in clinical studies for the treatment of SBS, with early results finding teduglutide was well tolerated, reduced the amount of parenteral nutrition required in adults, and improved bowel morphology (25). The ability of GLP-2 to suppress mucosal inflammation and increase intestinal growth makes it an attractive therapy for the prevention of NEC. Because preterm infants are provided with TPN to support growth, TPN also causes mucosal atrophy and may lead to an increased risk of developing NEC. Thus, we hypothesized that providing GLP-2 during TPN and before enteral feeds may be protective against NEC. The aim of this study was to test whether administration of GLP-2 in a preterm pig NEC-like model would lead to a reduction in both clinical and molecular NEC parameters through increased mucosal growth and reduction in inflammation. Our results show that although GLP-2 was able to delay the onset of NEC in our piglet model, it was unable to completely prevent the occurrence of NEC and had minimal effects on inflammation; however, GLP-2 administration did have protective effects on histological damage and increased morphometric intestinal endpoints.
Databáze: OpenAIRE
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