Gut-derived cholecystokinin contributes to visceral hypersensitivity via nerve growth factor-dependent neurite outgrowth

• Published in: Journal of gastroenterology and hepatology Vol. 31; no. 9; pp. 1594 - 1603
• Main Authors: Hsu, Luo-Ting, Hung, Kuan-Yang, Wu, Hsiu-Wei, Liu, Wei-Wen, She, Meng-Ping, Lee, Tsung-Chun, Sun, Chin-Hung, Yu, Wei-Hsuan, Buret, Andre G, Yu, Linda Chia-Hui
• Format: Journal Article
• Language: English
• Published: Australia Blackwell Publishing Ltd 01.09.2016
• Subjects: Abdominal Pain - etiology; Abdominal Pain - metabolism; Abdominal Pain - pathology; Animals; Cells, Cultured; Cholecystokinin - pharmacology; Cholecystokinin - physiology; Coculture Techniques; Colon - innervation; Colon - metabolism; colon hyperalgesia; Culture Media, Conditioned; Dilatation; Giardia lamblia; Giardiasis - complications; Humans; Hyperalgesia - etiology; Hyperalgesia - metabolism; Hyperalgesia - pathology; Intestinal Mucosa - innervation; Intestinal Mucosa - metabolism; irritable bowel syndrome; Male; Mice, Inbred C57BL; Nerve Fibers - drug effects; Nerve Fibers - pathology; Nerve Growth Factor - antagonists & inhibitors; Nerve Growth Factor - metabolism; neuroendocrine; Neuronal Outgrowth - drug effects; Neuronal Outgrowth - physiology; post-giardiasis; psychological stress; Recombinant Proteins - pharmacology; Stress, Psychological - complications; neuroendocrine; irritable bowel syndrome; post-giardiasis; psychological stress; colon hyperalgesia
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.13296

Background and Aim: Irritable bowel syndrome is characterized by abdominal pain and altered bowel habits and may occur following stressful events or infectious gastroenteritis such as giardiasis. Recent findings revealed a link between cholecystokinin (CCK), neurotrophin synthesis, and intestinal hyperalgesia. The aim was to investigate the role of CCK in visceral hypersensitivity using mouse models challenged with a bout of infection with Giardia lamblia or psychological stress, either alone or in combination. Methods: Abdominal pain was evaluated by visceromoter response to colorectal distension. Nerve fibers in intestinal tissues were stained using immunohistochemistry (PGP9.5). Human neuroblastoma SH‐SY5Y cells incubated with bacterial‐free mouse gut supernatant or recombinant CCK‐8S were assessed for neurite outgrowth and nerve growth factor (NGF) production. Results: Intestinal hypersensitivity was induced by either stress or Giardia infection, and a trend of increased pain was seen following dual stimuli. Increased CCK levels and PGP9.5 immunoreactivity were found in colonic mucosa of mice following stress and/or infection. Inhibitors to the CCK‐A receptor (L‐364718) or CCK‐B receptor (L‐365260) blocked visceral hypersensitivity caused by stress, but not when induced by giardiasis. Nerve fiber elongation and NGF synthesis were observed in SH‐SY5Y cells after incubation with colonic supernatants from mice given the dual stimuli, or after treatment with CCK‐8S. Increased nerve fiber length by colonic supernatant and CCK‐8S was attenuated by L‐365260 or neutralizing anti‐NGF. Conclusions: This new model successfully recapitulates intestinal hypernociception induced by stress or Giardia. Colonic CCK contributes to visceral hypersensitivity caused by stress, but not by Giardia, partly via NGF‐dependent neurite outgrowth.