Peptide transport in the neonatal Yucatan miniature pig

Nosworthy, Matthew G. (2015) Peptide transport in the neonatal Yucatan miniature pig. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The H⁺-coupled transporter peptide transporter 1 (PepT1) is found primarily in the intestine and is capable of transporting dietary di- and tripeptides as well as peptides produced by bacteria. However, little is known about the ontogeny of PepT1 in the piglet. The first part of this thesis describes the investigation of the effects of development and diet on peptide transport in the intestine of the Yucatan miniature piglet. Dipeptide transport was significantly higher in the ileal section in the youngest age group (1 week) compared to the other suckling groups (p<0.05); however, all suckling piglet groups demonstrated lower ileal transport compared to post-weaned pigs. These results suggest that peptide transport in the small intestine is important during the first week of suckling and again with diet transition following weaning. The objective of the second part of this thesis was to determine the impact of enterally delivered dipeptide-containing diets on indices of intestinal adaptation in neonatal piglets after intestinal resection, as PepT1 is preferentially maintained over free amino acid transporters in situations of gut stress such as short bowel syndrome. In this model no evidence was found that enteral dipeptides provide specific adaptive benefits compared to constituent amino acids. However, the dipeptide-containing diets reduced pro-inflammatory cytokine concentrations in the mucosa (p<0.05). One dipeptide in particular, cysteinyl-glycine, supported greater villus height compared to all other dipeptides and greater crypt depth compared to alanyl-glutamine yet no dipeptide diet altered intestinal morphology compared to the free amino acid control diet. This study demonstrated that while there was no explicit morphological benefit of enteral dipeptides over their constituent free amino acids, there was the potential for the amelioration of intestinal inflammation by reducing pro-inflammatory cytokines. As PepT1 is also capable of transporting bacterial peptides were then investigated intestinal response to a pro-inflammatory peptide, formyl-methionyl-leucyl-phenylalanine (fMLP) alone or in combination with cysteinyl-glycine in a model of intestinal atrophy. Piglets received parenteral nutrition (PN) for 4 d to induce atrophy while littermates remained with the sow. In both dietary treatments, intestinal segments exposed to fMLP had higher mucosal pro-inflammatory cytokines with this inflammatory effect being attenuated when cysteinyl-glycine was co-perfused with this bacterial peptide (p<0.05). Morphologically, fMLP exposure did not alter villus height or crypt depth in sow-fed animals; in contrast, intestinal segments from PN-fed piglets exposed to fMLP had reduced villus height compared to unexposed loops. Inclusion of cysteinyl-glycine was effective at attenuating a bacterial peptide-induced inflammatory response in the injured SI. This may be due to efficient dipeptide uptake in a situation of impaired free amino acid absorption, and/or competitive inhibition of fMLP uptake. Through the use of in vivo piglet models, these studies have contributed to the understanding of peptide transport in health and disease states in addition to demonstrating the potential benefits of enteral dipeptide provision.

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