Investigating effect of dietary lipids on jejunal afferent sensitivity in the Mouse

Enteral nutrients, especially lipid, have been well recognized as signalling molecules which control various cellular processes and play an important role in food intake, metabolisms, inflammation and pain. Loss of appetite and altered functional property of TRPV1 ion channel have been found ageing. However, the transduction mechanism of extrinsic intestinal afferent nerves in lipid sensing from the gut remains poorly understood. Thus, the primary objective of this thesis was to investigate effect of lipid-containing nutrients on different subpopulations of jejunal afferents using an in vitro nerve-gut preparation from adult and aged mice using a sophisticated and comprehensive single unit analysis. The contribution of TRPV1 in aged related changes was also examined. In adult mice, both lipid-low and lipid-rich containing nutrients were found to increase intraluminal distension-induced afferent response in three functional different subpopulations; Low threshold (LT), wide dynamic range (WDR) and high threshold (HT) units. The effects were lipid concentration dependent. Only the response of LT unit to lipids was significantly attenuated by CCK-1 antagonist devazepide which also effectively inhibited exogenous applied CCK, strongly suggesting that lipids-induced enhanced mechanosensitivity was predominately mediated by CCK-1 vagal nerve pathway. Lipid rich-induced mechanosensitivity was further examined in aged mice. Response of both LT and HT was gradually reduced with ageing compared with adult. The reduced mechanosensitivity was restored in 12 months TRPV1-knockout mice, suggesting down-regulation role of TRPV1 in gut ageing. Finally, the role of lipid in modulating jejunal afferent mechanosensitivity, its changing and function of TRPV1 as a sensor during ageing process was discussed. Thus this study has advanced our understanding of biological mechanisms underlying gut afferent signalling in nutrient sensing at single nerve fibre level.