The role of peptide transporter 1 (PepT1) in maintaining health in neonates

Kirupananthan, Dalshini (2022) The role of peptide transporter 1 (PepT1) in maintaining health in neonates. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Peptide transporter 1 (PepT1) carries dietary tri-/dipeptides, bacterial peptides and peptidomimetic drugs in the small intestine (SI). The first study in this thesis describes the interaction between the dipeptide lysyl-lysine and arginine uptake from the SI in Yucatan miniature piglets. This study confirmed that arginine uptake was significantly higher when delivered with lysyl-lysine compared to equimolar amount of free lysine. We speculated that more efficient uptake of lysine as a dipeptide led to enhanced arginine uptake through the trans-stimulation of the b⁰, ⁺ transporter. The activity of PepT1 was preserved during the use of parenteral nutrition (PN). As such, the objective of the second study was to determine if there were advantages to providing lysine as dipeptide in neonatal piglets with PN-induced atrophied gut. PN was provided for four days to induce intestinal atrophy and then piglets were switched to enteral diets. When lysine was provided at 75% of requirement, it was found that providing lysyl-lysine during the transition period from PN to enteral feeding improved villus height, mucosal weight, whole-body protein synthesis and reduced the MPO activity compared to free lysine. The addition of glycyl-sarcosine to competitively inhibit lysyl-lysine uptake completely abolished the beneficial effects of lysyl-lysine. Thus, delivering lysine as dipeptide during the high-risk transition period from PN to enteral feeding may serve to enhance gut recovery and avoid complications related to refeeding. Recently, researchers identified that PepT1 influences the secretion of peptide hormones from the enteroendocrine cells, which may affect appetite regulation and glucose homeostasis in adult rodents. The final part of the thesis characterized the role of PepT1 activation on the protein-mediated gut hormone release and glucose kinetics in neonatal piglets using an in-situ perfusion model. Duodenal casein hydrolysate infusion stimulated the release of incretin hormones GLP-1 and GIP as measured in the portal blood, and the PepT1 inhibitor 4-AMBA hindered this protein-mediated effect on gut hormone release, confirming the involvement of PepT1. Higher baseline plasma insulin and higher insulin response to a glucose challenge strongly suggest that PepT1 activity induces insulin secretion and faster glucose disposal. This mechanism may be advantageous for adults with type 2 diabetes, but in neonates taking in high protein from infant formulas, it contributes to the understanding of the “early protein hypothesis” of childhood obesity. Overall, these studies shed light on the understanding of the role of PepT1 in the neonatal small intestine and characterize novel influences on neonatal metabolism that may be important in conditions of health and disease.

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