Case Control Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 7, 2018; 24(1): 46-57
Published online Jan 7, 2018. doi: 10.3748/wjg.v24.i1.46
Increased intestinal mucosal leptin levels in patients with diarrhea-predominant irritable bowel syndrome
De-Rong Liu, Xiao-Juan Xu, Shu-Kun Yao
De-Rong Liu, Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
De-Rong Liu, Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Xiao-Juan Xu, Department of Gastroenterology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Author contributions: Liu DR performed the study, analyzed the data, and drafted the manuscript; Xu XJ contributed to study design and data interpretation; Yao SK designed the study, revised the manuscript, supervised the study performance, and obtained the funding.
Supported by National Key Technology Support Program during the “12th Five-Year Plan” Period of China, No. 2014BAI08B02.
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, or their legal guardian, provided written informed consent prior to study enrollment.
Conflict-of-interest statement: All authors have no conflict of interest related to this manuscript.
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:
Correspondence to: Shu-Kun Yao, MD, PhD, Professor, Department of Gastroenterology, China-Japan Friendship Hospital, No. 2, Yinghua East Road, Chaoyang District, Beijing 100029, China.
Telephone: +86-10-84205288 Fax: +86-10-84205288
Received: September 29, 2017
Peer-review started: September 30, 2017
First decision: October 17, 2017
Revised: November 8, 2017
Accepted: November 21, 2017
Article in press: November 21, 2017
Published online: January 7, 2018
Research background

Irritable bowel syndrome (IBS) is a commonly diagnosed functional gastrointestinal disease. Symptoms may worsen over time and significantly impact patient quality of life and work productivity. A major subtype of IBS is IBS with diarrhea (IBS-D). The pathogenesis of IBS-D is complex and poorly understood. Leptin not only exerts significant biological effects, such as appetite control, by signaling satiety and increasing energy expenditure, but also modulates the immune system and gastrointestinal function. Few studies have specifically addressed the role of leptin in the pathogenesis of IBS. To our knowledge, this was the first study to preliminarily investigate the possible role of leptin in the pathophysiology of IBS-D.

Research motivation

The main topics of the present study include evaluating clinical symptoms, psychological characteristics, and visceral sensitivity of IBS-D patients and healthy controls; examining leptin expression, mast cells, and PGP9.5 nerve fibres in IBS-D and healthy controls; and performing correlation analyses between these parameters. Our study proposed a mechanism by which leptin may contribute to the pathophysiology of IBS.

Research objectives

This study aimed to measure leptin expression in both the serum and intestinal mucosa of patients with IBS-D subtype disease and to analyze the relationship of leptin with the clinical features, visceral sensitivity, and number of mast cells and nerve fibers in these patients.

Research methods

Participants underwent clinical and psychological evaluations using validated questionnaires (including IBS Symptom Severity Scale, IBS-specific Quality of Life, Hamilton Anxiety Scale and Hamilton Depression Scale), along with colonoscopy, colonic mucosal biopsy, and visceral sensitivity testing. Serum leptin levels were assayed using enzyme-linked immunosorbent assay. Mucosal leptin expression and localization were evaluated using immunohistochemistry and immunofluorescence. Mucosal leptin mRNA levels were quantified using quantitative real-time reverse transcription polymerase chain reaction. Mast cell counts and activation rates were investigated by toluidine blue staining. Correlation analyses between these parameters were performed. All statistical analyses were performed using SPSS for Windows software, version 24.0 (SPSS Inc, Chicago, IL).

Research results

The authors found that IBS-D patients had significantly increased psychological symptoms and visceral hypersensitivity, and their mucosal leptin expression, leptin mRNA levels, and mast cell activation rates were significantly increased. Also, leptin expression was positively correlated with anxiety, depression, and the mast cell activation rate, but negatively correlated with the defecation sensation threshold and the maximum tolerance threshold during visceral sensitivity testing. Increased levels of mucosal leptin may interact with mast cells and the nervous system to contribute to the pathogenesis of IBS-D.

Research conclusions

This study presents evidence that leptin levels are increased in the intestinal mucosa of IBS-D patients, proposes a mechanism by which leptin may contribute to the pathophysiology of IBS, and provides some potential avenues for more specific and effective treatments in these patients. The authors believe that this study makes a significant contribution to the literature because it is an original research that provides information that not only contributes to the understanding of the pathogenesis and pathophysiology of IBS, but also suggests area for future research and therapeutic intervention.

Research perspectives

This study preliminarily investigated the possible role of leptin involved in the pathogenesis of IBS-D. Future studies should focus on the following aspects. First, the present study focused on patients with the IBS-D subtype. Therefore, the findings may not be generalizable to constipation-predominant IBS, mixed-type IBS, and unsubtyped IBS patients. Future research should investigate the possible role of leptin in the pathophysiology of the other three subtypes. Second, leptin has been shown to increase during the process of inflammation. However, we cannot be sure that all postinfective IBS patients were excluded from the study. Because these two subgroups may be different in pathogenesis, future experiments should study these two types separately. Finally, we cannot make a cause and effect inference on the basis of our findings, therefore, additional studies of the effects of leptin on mast cells and the nervous system as well as larger clinical studies are needed.