Short-Chain Fatty Acids and Glucagon -Like Peptide-2 Enhance Intestinal Development and Adaptation

In 2002, 43% of the ∼470,822 preterm infants were born at a low birth weight. These infants have a higher risk for intestinal dysfunctions indicating the use of total parenteral nutrition (TPN) to meet their nutritional needs. Despite its benefits, TPN is associated with many complications; hence, treatments aimed at minimizing the need for TPN are necessary. Glucagon-like peptide-2 (GLP-2) may be a therapeutic agent as it reduces TPN associated atrophy and increases enzyme and transporter activity. To examine this, we coinfused GLP-2 with TPN and found increased ileal mRNA and protein abundance of the brush border sodium-dependent glucose cotransporter, SGLT-1. However, the minimum effective dose that is necessary to enhance intestinal function is unknown. Therefore, GLP-2 was coinfused with TPN at three physiological doses: low, moderate and high. Results show that the mRNA abundance of the basolateral sodium-independent glucose transporter, GLUT2, was increased to enteral levels by all GLP-2 doses. Furthermore, the low GLP-2 dose increased brush border membrane (BBM) protein abundance of GLUT2. This increase corresponded with an increase in glucose uptake, indicating that GLP-2 may be enhancing neonatal intestinal function through the translocation of GLUT2 from the basolateral to the BBM. Systemic short-chain fatty acids and dietary fiber are reported to stimulate the secretion of GLP-2. Therefore, we supplemented TPN with butyrate and found increases in structural adaptation. The most marked effects were in the intestinal epithelium, with increased crypt-villus architecture resulting from increased proliferation and decreased apoptosis. Additionally, butyrate increased the plasma GLP-2 concentration through a rapid and specific increase in ileal and colonic mRNA abundance of proglucagon, the gene that encodes GLP-2. Thus, GLP-2 may mediate the intestinotrophic effects of butyrate. Further evidence for the intestinotrophic effects of GLP-2 was investigated using a degradation-resistant GLP-2 analog, teduglutide, in adult patients with short-bowel syndrome. Teduglutide increased crypt-villus architecture, glucose and glutamine transport and the protein expression of nutrient transporters. The provision of GLP-2 and supplementation of TPN with butyrate, which augments endogenous levels of GLP-2, may benefit patients with intestinal dysfunctions by maximizing their intestinal absorptive capacity, thereby enabling them to successfully transition to enteral feedings.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Nutritional Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Bartholome, Anne Louise

Contributors dc:contributor

• Kelly A. Tappenden

• Health Sciences, Human Development

Language dc:language

eng

Identifier

(MiAaPQ)AAI3153243

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/84937