Abstract
The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF+/− mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation.
Highlights
Sex ratio (M/F) Mean age Abdominal pain scores Severity Frequency HAD depression scale HAD anxiety scale
Our study demonstrates that increased colonic BDNF may contribute to visceral hypersensitivity in Irritable bowel syndrome (IBS) patients, likely via interacting with the EGC-enteric nerve unit
We found that glial fibrillary acidic protein (GFAP), an EGC activation marker, together with tyrosine receptor kinase B (TrkB) and substance P (SP) expressed by EGCs significantly increased in the colonic mucosa of IBS patients and the increased GFAP and SP are positively correlated with abdominal pain scores
Summary
Sex ratio (M/F) Mean age (years) Abdominal pain scores Severity Frequency HAD depression scale HAD anxiety scale. Tyrosine receptor kinase B (TrkB), the high-affinity receptor of BDNF20, has been identified to be expressed in the EGCs of humans[21] and mice[22], which implies a possible functional link between BDNF and EGCs. whether BDNF-EGC interaction exists and contributes to IBS-like visceral hypersensitivity has yet to be examined. Previous studies have shown that BDNF has no direct effect on the excitability of enteric nerves but can increase their chemical sensitivity[23,24]. Whether BDNF can influence enteric nerve mechanosensitivity remains to be defined. We sought to investigate the effect of colonic BDNF on EGC activation and enteric nerve mechanosensitivity to explore the link between BDNF-challenging EGCs, enteric nerves and IBS-like visceral hypersensitivity
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