Introduction

Visceral hypersensitivity is a hallmark of irritable bowel syndrome (IBS). Transient receptor potential (TRP) channels are known as molecules involved in the pathogenesis of visceral hypersensitivity. A putative role for the Transient Receptor Potential Ankyrin 1 (TRPA1) channel in colonic nociceptor activation and mechanosensitation has been shown in animal studies. We hypothesize there is a correlation in TRPA1 mRNA expression and the symptom-severity in IBS patients.

Aims & Methods

The main objective of this study was to determine TRPA1 mRNA expression in the colonic mucosa and ascertain its correlation with symptom-severity in IBS patients. Second, difference in TRPA1 mRNA expression between IBS patients and healthy controls along with regional differences in TRPA1 mRNA expression was analyzed.
IBS patients (Rome III) and healthy controls were included. Sigmoid biopsies were obtained in all subjects. Additional biopsies of the proximal colon were obtained in 24/30 IBS patients. TRPA1 mRNA levels were measured in duplicate by quantitative reverse-transcriptase–polymerase-chain-reaction (Biorad), using primers from Biolegio and normalized to GAPDH. Levels of mRNA were expressed as relative mRNA values using the -2^ΔCt method. A multivariate regression was utilized to compare mRNA-expression between IBS patients vs healthy controls. Symptoms in IBS patients were assessed using the Gastrointestinal Symptom Rating Scale (GSRS).

Results

30 IBS patients (median age 39.0 yrs, 80% female) and 23 healthy controls (median age 22.7 yrs, 43.5% female) were included. Relative TRPA1 mRNA expression in the sigmoid was significantly higher in IBS patients compared to healthy controls (P<0.001), independent of age and gender. There was no significant difference in relative TRPA1 mRNA expression between IBS subtypes (P>0.05). Within IBS patients expression of TRPA1 mRNA of sigmoid-biopsies was significantly higher compared to biopsies of the proximal colon (p<0.001). No significant correlation between TRPA1 expression in sigmoid or proximal colon in GSRS scales (n=27) was found.

Conclusion

In IBS patients relative TRPA1 mRNA expression in colonic biopsies is significantly elevated compared to healthy controls. Furthermore, relative TRPA1 mRNA expression is higher in sigmoid colonic biopsies than in proximal colonic biopsies of IBS patients. These findings suggest a potential for the TRPA1 pathway as a target for IBS treatment in the future. However, no correlation between TRPA1 mRNA expression and symptom severity was found. Therefore, further research towards the clinical relevance of the increased TRPA1 mRNA-expression in IBS-patients along with its location-specific expression is warranted.

Introduction

Irritable bowel syndrome (IBS) has a profound impact on health-related quality of life. Increasing evidence suggests psychological factors have a large impact in the development and course of IBS, and in particular quality of life, with large individual heterogeneity. This observational study aims to investigate the influence of personality traits using the Big Five Inventory (BFI) and examine their associations with abdominal pain, general and gastrointestinal-specific anxiety, and quality of life in patients with IBS.

Aims & Methods

Data from a large observational study in patients with IBS (Rome III criteria) was used, in which patients completed questionnaires with regards to personality traits (BFI-44), symptom severity, general anxiety, GI-specific anxiety, and quality of life. Multivariable regression models and a network correlation analysis were used to determine underlying associations.

Results

194 patients were included for analysis (74.7% female, mean age 51.36 years). There was a positive association of neuroticism to GI-specific anxiety (B 7.234, P = 0.040) and general anxiety (B 0.954, P = 0.040) with a strong negative association to mental quality of life (B – 3.576, P = 0.007). In addition, a strong negative association of agreeableness to mental quality of life was found (B – 4.266, P = 0.001). Although there were no significant associations of personality traits to abdominal pain, positive associations were found regarding general anxiety (B 6.304, p < 0.001) and GI-specific anxiety (B 0.034, P <0.001) of abdominal pain. There were no associations found with regards to the other personality traits openness, conscientiousness or extroversion.

Conclusion

IBS patients with a higher level of neuroticism were more likely to experience higher levels of GI-specific and general anxiety. The trait neuroticism and/or agreeableness was more likely to have a significant lower mental quality of life in IBS. These findings emphasize the contribution of personality traits in the pathophysiology and course of IBS, pleading for a more personalized approach in patient management.

Introduction

The pathophysiological mechanisms of irritable bowel syndrome (IBS) are complex and incompletely known. Studies investigating the role of colonic volumes and their relation with symptoms and measurements of gut physiology in IBS are sparse.

Aims & Methods

The aim of this study was to explore the associations between colonic volume and symptoms and measurements of gut physiology in IBS and healthy individuals. We included 18 IBS patients (4 IBS-diarrhea, 5 IBS-constipation, 9 IBS-mixed or IBS-unspecified) and 19 healthy individuals. Total and segmental colonic volumes were determined by magnetic resonance imaging (MRI). The GSRS-IBS was used to measure gastrointestinal symptoms and a stool diary (Bristol Stool Form Scale) was completed 14 days before the MRI. Oro-anal transit time (radiopaque markers) and rectal sensitivity (rectal barostat, including pressure thresholds for first perception, defecation, and discomfort) were measured.

Results

The total colonic volume did not differ between IBS patients and healthy individuals (736 ml [528-903] vs 597 [498-939] (median [IQR]); p=0.44). In the IBS group, there were trends towards inverse associations between total colonic volume and the perceived severity of diarrhea (r_s= -0.43; p=0.08), as well as the volume of the descending colon and stool frequency (r_s= -0.48; p=0.07). Other GI symptoms and stool consistency were not associated with colonic volumes. When investigating the physiological parameters in IBS, the total colonic volume was positively associated with oro-anal transit time (r_s=0.54; p=0.02) and negatively associated with rectal pressure thresholds for sensations (first perception: r_s= -0.51; p=0.04, defecation: r_s= -0.44; p=0.09), Table 1. A similar pattern was seen when investigating individual colonic segments, with tendencies towards positive associations between segmental colonic volumes and oro-anal transit time, and negative associations with rectal sensory thresholds. The associations in healthy individuals between colonic volumes and oro-anal transit time and rectal sensitivity, respectively, were overall weaker (all p>0.05).

Conclusion

In this pilot study, we have shown that larger colonic volumes, measured with MRI, seem to be associated with slower oro-anal transit and rectal hypersensitivity in IBS. This suggests a potential role for measuring colonic volumes in IBS pathophysiology studies, but larger studies are needed to better appreciate subtype differences and their relevance for symptoms.

Introduction

Irritable bowel syndrome (IBS) is a multifactorial disorder characterized by recurrent abdominal pain associated with defecation or a change in bowel habits. The pathophysiology of IBS involves alterations in the epithelial barrier, but data on the intestinal vascular barrier are lacking.

Aims & Methods

The aims of this study were to investigate the morpho-functional integrity of the vascular barrier and to correlate barrier dysfunction with IBS symptoms. Forty-eight healthy subjects (AC) and 144 patients with IBS (61 IBS-D, 51 IBS-C and 32 IBS-M) were enrolled in the study. Rome IV criteria, Bowel disease questionnaire, Short Form 12, Hospital Anxiety Depression Scale were used to phenotype patients. Immunohistochemistry, western blot and electron microscopy were used to characterize the vascular barrier. Vascular permeability was evaluated by assessing two markers: plasmalemma vesicle–associated protein-1 (PV1) and vascular endothelial cadherin (VEC). A translational model based on HUVEC was used to evaluate permeability changes induced by mediators spontaneously released by mucosal biopsies, and to highlight the underlying molecular mechanisms. Correlation analyses between experimental and clinical data were performed.

Results

Mucosal vessel density was significantly increased by 1.5 fold in the colonic mucosa of IBS patients compared to AC (P<0.01). PV1 expression was increased (P<0.01) while VEC expression was decreased in the colonic mucosa of IBS patients compared to AC (P<0.05). Compared to AC, IBS mucosal mediators increased permeability in the HUVEC monolayer through the activation of protease-activated receptor (PAR)-2 and histone deacetylase (HDAC)11, resulting in VEC downregulation. PV1 expression significantly correlated with anxiety and depression scores and health-related quality of life reported by IBS patients.

Conclusion

The vascular barrier is impaired in IBS and contributes to clinical manifestations

Introduction

Irritable bowel syndrome (IBS) is a complex multifactorial disorder characterized by recurrent abdominal pain associated with defecation or a change in bowel habits. Patients with IBS often complain of extra-intestinal symptoms resulting in impaired related quality of life. Growing evidence support the hypothesis that intestinal barrier dysfunction has a central role in the pathophysiology of IBS being the interface between the gut lumen and the deeper intestinal layers as well as the brain.

Aims & Methods

The aims of this study were: to characterize the epithelial and vascular barriers; to correlate molecular, morphological and functional aspects of epithelial and vascular barriers with IBS symptoms. 66 healthy subjects (AC) and 223 patients with IBS (112 IBS-D, 58 IBS-C and 53 IBS-M) were enrolled in the study. Rome IV criteria, Bowel disease questionnaire, Short Form 36, Hospital Anxiety Depression Scale were used to phenotype patients. Sugar test was used to evaluate in vivo permeability. The vascular barrier was characterized by using immunohistochemistry, western blot and electron microscopy. Vascular permeability was evaluated by assessing two markers: plasmalemma vesicle–associated protein-1 (PV1) and vascular endothelial cadherin (VEC). A translational model based on Caco-2 cells or HUVEC was used to evaluate permeability changes induced by mediators spontaneously released by mucosal biopsies and to highlight the underlying molecular mechanisms. Correlation analyses have been performed among experimental and clinical data.

Results

Compared to AC, lactulose (P<0.05), sucralose (P<0.01), sucrose (P<0.01) excretion and the L/M ratio (P<0.01) were significantly increased in IBS patients. Soluble mediators released by mucosal biopsies of IBS patients increased Caco-2 permeability compared to AC mediators (P<0.05) via a down-regulation of tight junction gene expression. Blood vessels were significantly increased by 1.5 fold in the colonic mucosa of IBS patients compared to AC (P<0.01). PV1 expression was increased (P<0.01) while VEC expression was decreased in the colonic mucosa of IBS group compared to AC (P<0.05). IBS mucosal mediators increased HUVEC permeability compared to AC mediators. The HUVEC changes associated with IBS samples were mediated by a protease-activated receptor (PAR)2 dependent mechanism resulting in VEC down-regulation. Significant correlations emerged among permeability changes and intestinal, extra-intestinal symptoms and health-related quality of life reported by IBS patients.

Conclusion

Epithelial and vascular barriers are compromised in IBS and are likely involved in symptom development.

Disclosure

Nothing to disclose

Introduction

Sleep disturbances are more common in individuals with Irritable Bowel Syndrome (IBS) compared to healthy subjects. Sleep quality is an independent factor affecting gastrointestinal (GI) symptoms but the directionality of effects is unknown.

Aims & Methods

Our aim was to investigate relationships between subjective sleep quality, objective sleep measures and GI symptoms using actigraphy and the Experience Sampling Method (ESM). Single-centre, prospective, cross-sectional study conducted at the Wingate Institute of Neurogastroenterology in London, from March 2020 to May 2021. IBS patients were recruited from a tertiary neurogastroenterology clinic and the community. GI symptoms and mood were recorded on a smartphone application, ten times per day, over seven consecutive days (i.e. ESM). Subjective sleep quality was recorded every morning to reflect the night before. Objective measures of sleep quality were estimated from wrist-worn actigraphy. Cross-lagged structural equation models were built to assess the directionality of sleep-symptom relationships over time.

Results

Eighty IBS patients completed the study (mean age: 37 (range 20 – 68), 89% female, 78% community). The median IBS - Symptom Severity Score (IBS-SSS) score indicated moderate IBS severity (279 (IQR: 237-350)). Sixty-six % had a Pittsburgh Sleep Quality Index (PSQI) score ≥ 8 indicating a clinically significant sleep disturbance. Eighty-two % (95% CI: 72-90) screened positive for a sleep disorder, most commonly insomnia. Sleep efficiency, measured by actigraphy, was at the lower end of normal range (median: 86% (CI 95%: 85-87). In cross-lagged analysis, poor subjective sleep quality predicted next day abdominal pain (0.036 < p < 0.040) and lower GI symptoms (0.030 < p < 0.032), but not vice versa. Although the direction of the effect was the same for abdominal pain and lower GI symptoms, it was not significant for upper GI symptoms. No significant relationship with GI symptoms was found for any objective sleep measure.

Conclusion

Poor subjective sleep quality is associated with higher next day abdominal pain and lower GI symptom scores in IBS patients, but not vice versa. Objective sleep measures did not predict next day abdominal symptoms, potentially supporting the conclusion that it is the perception of sleep quality which is most influential. This study supports the use of real-time patient reported outcome measures when interpreting potential influencers of IBS symptoms and may be used to guide future research into the effect of sleep interventions on GI symptoms.

Disclosure

DK has received research funding from Grunenthal, Allergan, Will Pharma, Rome Foundation, ZonMw, MLDS, UEG, Horizon 2020, Horizon Europe, and speaker’s fee from Dr Falk (paid to host institution).
QA undergoes consulting work for Takeda Pharmacueticals, and Classado Biosciences Ltd.