Background & aims: Brain-derived neurotrophic factor (BDNF) may play a critical role in gut motility. We aimed to investigate BDNF's physiologic effects on gut motility in slow-transit constipation (STC) and to explore the underlying molecular mechanisms.
Methods: BDNF expression and alterations of colonic nerve fibre density in STC patients were first investigated. BDNF's effects on gastrointestinal motility of both BDNF(+/-) mice and loperamide-induced constipation mice were then examined in vivo and in vitro. Smooth muscle α-actin (α-SMA) expression, and nerve fibre, neuromuscular junction (NMJ) and smooth muscle cell (SMC) alterations were investigated. Finally, the effects of BDNF-induced TrkB-phospholipase C/inositol trisphosphate (TrkB-PLC/IP3) pathway activation on gut motility were investigated.
Results: In STC patients, BDNF expression and nerve fibre density were decreased, and mucosal nerve fibre ultrastructural degenerations were demonstrated. Gut motility was decreased in vivo and in vitro in BDNF(+/-) and constipation mice, with BDNF dose-dependently increasing gut motility. In BDNF(+/-) mice, α-SMA expression and nerve fibre density were decreased, and nerve fibre, NMJ and SMC ultrastructural degenerations were observed. Finally, TrkB-PLC/IP3 pathway antagonists dramatically attenuated BDNF's excitatory effect on gut motility, and exogenous BDNF induced an obvious increase in IP3 expression.
Conclusions: BDNF plays an important regulatory role in gut motility in STC. It was mediated by altering the intestinal innervation structure, as well as smooth muscle secondary degeneration through a mechanism involving TrkB-PLC/IP3 pathway activation.
Keywords: BDNF; STC; TrkB-PLC/IP3 pathway; gut motility; nerve fibre.
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.