Brain-derived Neurotrophic Factor Contributes to Abdominal Pain in Irritable Bowel Syndrome

Objective: Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, may play a critical role in many chronic pain conditions. The possible involvement of BDNF in the altered gut sensation in patients with irritable bowel syndrome (IBS) was investigated in the present study.

Methods: Rectosigmoid biopsies were collected from 40 patients with IBS fulfilling the Rome II criteria and 21 healthy controls. Abdominal pain was quantified by a validated questionnaire. The presence of BDNF and nerve fibres in the mucosa was assessed by immunohistochemistry. The structure of mucosal nerve fibres was assessed by transmission electron microscopy. Mucosal BDNF release was measured by ELISA and correlated with abdominal pain scores. Animal studies using BDNF(+/-) mice were carried out to evaluate visceral sensitivity, mucosal nerve fibre density and ultrastructural changes. Alterations of visceral sensitivity and TrkB expression in dorsal root ganglia were examined in BDNF(+/+) mice following different doses of BDNF administration.

Results: Biopsies from patients with IBS revealed a significant upregulation of BDNF (p=0.003), as compared with controls. Total nerve fibres were also substantially increased in patients with IBS. Electron microscopy showed ultrastructural damage on the mucosal nerve fibres (eg, swollen mitochondria and nerve axons). Elevated BDNF release was significantly correlated with the abdominal pain scores. Meanwhile, abdominal withdrawal reflex scores to colorectal distension and mucosal protein gene product 9.5 immunoreactivity were significantly lowered in BDNF(+/-) than in BDNF(+/+) mice. Electron microscopy showed degenerative changes on the mucosal nerve fibres in BDNF(+/-) mice. Exogenous BDNF induced an obvious dose-dependent increase in TrkB expression in dorsal root ganglia and dose-dependent decrease in threshold pressure in BDNF(+/+) mice.

Conclusions: The increased expression of BDNF in colonic mucosa, together with the structural alterations of mucosal innervation, may contribute to the visceral hyperalgesia in IBS.