Observational Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2019; 25(2): 269-281
Published online Jan 14, 2019. doi: 10.3748/wjg.v25.i2.269
Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome
Yu Zhang, Geng Qin, De-Rong Liu, Yan Wang, Shu-Kun Yao
Yu Zhang, Geng Qin, De-Rong Liu, Yan Wang, Shu-Kun Yao, Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Yu Zhang, Geng Qin, De-Rong Liu, Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Yan Wang, Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
Author contributions: Zhang Y performed the study, analyzed the data and drafted the manuscript; Qin G contributed to the performance of the study and revised the manuscript; Liu DR took part in designing the study and interpreting the data; Wang Y gave guidance and support on experiment operation and data interpretation; Yao SK designed the study, revised the manuscript, supervised the study performance and obtained the funding.
Supported by the National Key Technology Support Program during “12th Five-Year Plan” Period of China, No. 2014BAI08B00; and the Leap-forward Development Program for Beijing Biopharmaceutical Industry (G20), No. Z171100001717008.
Institutional review board statement: The study protocol was approved by the China-Japan Friendship Hospital Ethics Committee (No. 2015-33) and conducted in accordance with the Declaration of Helsinki.
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Shu-Kun Yao, MD, PhD, Professor, Department of Gastroenterology, China-Japan Friendship Hospital, 2nd Yinghua East Road, Chaoyang District, Beijing 100029, China. shukunyao@126.com
Telephone: +86-10-84205288 Fax: +86-10-84205288
Received: October 16, 2018
Peer-review started: October 16, 2018
First decision: November 22, 2018
Revised: December 3, 2018
Accepted: December 13, 2018
Article in press: December 13, 2018
Published online: January 14, 2019
Processing time: 91 Days and 7.1 Hours
Abstract
BACKGROUND

Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome (IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor (BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS (IBS-D).

AIM

To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.

METHODS

Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 age- and sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.

RESULTS

The patients had a higher anxiety score [median (interquartile range), 6.0 (2.0-10.0) vs 3.0 (1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0 (44.0-61.0) vs 21.0 (17.3-30.0), P < 0.001] than controls. The defecating sensation threshold [60.0 (44.0-80.0) vs 80.0 (61.0-100.0), P = 0.009], maximum tolerable threshold [103.0 (90.0-128.0) vs 182.0 (142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0 (20.0-30.0) vs 30.0 (30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46E-2 (3.06E-2-4.44E-2) vs 3.07E-2 (2.91E-2-3.48E-2), P = 0.031] and mRNA [1.57 (1.31-2.61) vs 1.09 (0.74-1.42), P = 0.001] expression and nerve fiber density [4.12E-2 (3.07E-2-7.46E-2) vs 1.98E-2 (1.21E-2-4.25E-2), P = 0.002] were significantly elevated in the patients. Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.

CONCLUSION

Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.

Keywords: Irritable bowel syndrome; Diarrhea; Brain-derived neurotrophic factor; Visceral hypersensitivity; Nerve growth

Core tip: This study comprehensively investigated the psychological and clinical characteristics and visceral sensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and further explored the levels of brain-derived neurotrophic factor (BDNF) protein and mRNA and nerve fiber density in the intestinal mucosa. It was demonstrated that increased mucosal BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters, which provides new evidence that BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity in IBS-D patients.