Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome

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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.

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Most cited references 36

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The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress.

C. FRANCIS, J. Morris, P J Whorwell (1997)

The clinical assessment and investigation of irritable bowel syndrome would be greatly facilitated by the introduction of a simple, easy to use severity scoring system. Such a system, developed in our department over a number of years, has been submitted to validation in a total of 141 patients and 40 healthy controls. The system, incorporating pain, distension, bowel dysfunction and quality of life/global well-being, was assessed for its ability to reliably score patients previously classified as mild, moderate or severe. The reproducibility and sensitivity to change of the system was also assessed. The maximum achievable score was 500. Mild, moderate and severe cases were indicated by scores of 75 to 175, 175 to 300 and > 300 respectively. Controls scored below 75 and patients scoring in this range can be considered to be in remission. There was a highly significant difference between controls and patients as a whole (P = 0.0001) as well as significant differences (P < 0.01) between all severity categories. Scores repeated within 24 h were very reproducible and sensitivity to change was also extremely good (P < 0.001) with a change of 50 reliably indicating improvement. These results suggest that this scoring system should prove to be a valuable instrument in helping to meet the many challenges offered by irritable bowel syndrome.

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Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.

Giovanni Barbara, Vincenzo Stanghellini, Roberto De Giorgio … (2004)

The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.

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Effect of gender on prevalence of irritable bowel syndrome in the community: systematic review and meta-analysis.

Kimberly M. Lovell, Talitha C. Ford (2012)

Irritable bowel syndrome (IBS) is thought to be commoner in women. However, no systematic review has confirmed whether this is the case, or assessed whether any proposed female preponderance remains stable according to geography and criteria used to define IBS. Nor has effect of gender on subtype of IBS been examined systematically. MEDLINE, EMBASE, and EMBASE Classic were searched (up to October 2011) to identify population-based studies reporting prevalence of IBS in adults (≥15 years) according to gender, and defined using symptom-based criteria, or questionnaire. The prevalence of IBS in women and men was extracted for all studies, and according to study location and diagnostic criteria used, and compared using odds ratios (ORs) with 95% confidence intervals (CIs). Prevalence of each subtype of IBS, according to predominant stool pattern, was compared in women and men with IBS. Of the 390 papers evaluated, 56 studies containing 188,229 subjects were eligible. The OR for IBS in women, compared with men, in all studies was 1.67 (95% CI: 1.53-1.82). Prevalence of IBS was not significantly higher in women, compared with men, in South Asian, South American, or African studies. The OR was highest with the Rome I criteria (1.99; 95% CI: 1.76-2.25), and lowest with the Rome II criteria (1.40; 95% CI: 1.24-1.59). Women with IBS were more likely to exhibit the constipation-predominant subtype (OR: 2.38; 95% CI: 1.45-3.92), and less likely to meet criteria for the diarrhea-predominant subtype (OR: 0.45; 95% CI: 0.32-0.65) than men with IBS. Prevalence of IBS appeared modestly higher in women, and this remained relatively stable according to geography and criteria used to define its presence. However, among individuals with IBS, subtypes varied according to gender.

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Author and article information

Contributors

Yu Zhang

Geng Qin

De-Rong Liu

Yan Wang

Shu-Kun Yao

Journal

Journal ID (nlm-ta): World J Gastroenterol

Journal ID (iso-abbrev): World J. Gastroenterol

Journal ID (publisher-id): WJG

Title: World Journal of Gastroenterology

Publisher: Baishideng Publishing Group Inc

ISSN (Print): 1007-9327

ISSN (Electronic): 2219-2840

Publication date (Print): 14 January 2019

Publication date (Electronic): 14 January 2019

Volume: 25

Issue: 2

Pages: 269-281