Tamira K. Klooker

The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome

Background Mast cell activation is thought to be involved in visceral hypersensitivity, one of the main characteristics of the irritable bowel syndrome (IBS). A study was therefore undertaken to investigate the effect of the mast cell stabiliser ketotifen on rectal sensitivity and symptoms in patients with IBS. Methods 60 patients with IBS underwent a barostat study to assess rectal sensitivity before and after 8 weeks of treatment. After the initial barostat, patients were randomised to receive ketotifen or placebo. IBS symptoms and health-related quality of life were scored. In addition, mast cells were quantified and spontaneous release of tryptase and histamine was determined in rectal biopsies and compared with biopsies from 22 age- and gender-matched healthy volunteers. Results Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity. This effect was not observed in normosensitive patients with IBS. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life. The number of mast cells in rectal biopsies and spontaneous release of tryptase were lower in patients with IBS than in healthy volunteers. Spontaneous release of histamine was mostly undetectable but was slightly increased in patients with IBS compared with healthy volunteers. Histamine and tryptase release were not altered by ketotifen. Conclusions This study shows that ketotifen increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-related quality of life. Whether this effect is secondary to the mast cell stabilising properties of ketotifen or H1 receptor antagonism remains to be further investigated. Trial Registration Number NTR39, ISRCTN22504486.

Essential role for TRPV1 in stress‐induced (mast cell‐dependent) colonic hypersensitivity in maternally separated rats

Abstract  Irritable bowel syndrome is in part characterized by an increased sensitivity to colonic distension. Stress is an important trigger factor for symptom generation. We hypothesized that stress induces visceral hypersensitivity via mast cell degranulation and transient receptor ion channel 1 (TRPV1) modulation. We used the rat model of neonatal maternal separation (MS) to investigate this hypothesis. The visceromotor response to colonic distention was assessed in adult MS and non‐handled (NH) rats before and after acute water avoidance (WA) stress. We evaluated the effect of the mast cell stabilizer doxantrazole, neutralizing antiserum against the mast cell mediator nerve growth factor (NGF) and two different TRPV1 antagonists; capsazepine (non‐specific) and SB‐705498 (TRPV1‐specific). Immunohistochemistry was used to assess post‐WA TRPV1 expression in dorsal root ganglia and the presence of immunocytes in proximal and distal colon. Retrograde labelled and microdissected dorsal root ganglia sensory neurons were used to evaluate TRPV1 gene transcription. Results showed that acute stress induces colonic hypersensitivity in MS but not in NH rats. Hypersensitivity was prevented by prestress administration of doxantrazole and anti‐NGF. Capsazepine inhibited and SB‐705498 reversed poststress hypersensitivity. In MS rats, acute stress induced a slight increase in colonic mast cell numbers without further signs of inflammation. Post‐WA TRPV1 transcription and expression was not higher in MS than NH rats. In conclusion, the present data on stress‐induced visceral hypersensitivity confirm earlier reports on the essential role of mast cells and NGF. Moreover, the results also suggest that TRPV1 modulation (in the absence of overt inflammation) is involved in this response. Thus, mast cells and TRPV1 are potential targets to treat stress‐induced visceral hypersensitivity.

Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study.

OBJECTIVES:Stressful events during early life have been suggested to play an important role in the development of the irritable bowel syndrome (IBS). In this study, we evaluate whether an exposure to severe wartime conditions during gestation and in early life are associated with an increased prevalence of IBS.METHODS:We assessed the prevalence of IBS using the Rome II questionnaire among 816 men and women (aged 58±1 years) who were born as term singletons in Wilhelmina Gasthuis, Amsterdam, The Netherlands around the time of World War II.RESULTS:Of a total of 816 participants, 9.6% (n=78, 52F) met the criteria for IBS. Exposure to severe wartime conditions in utero was not associated with the prevalence of IBS in adulthood (8.3%). Early-life exposure to severe wartime conditions was associated with an increased prevalence of IBS. The prevalence of IBS among individuals exposed up to 0.5 years of age, 1 year of age, and 1.5 years of age was 8.1%, 12.5%, and 15.3%, respectively. The increased IBS prevalence was not associated with an increased stress response.CONCLUSIONS:Our data indicate that exposure to severe wartime conditions in early life is associated with an increased risk of developing IBS. To what extent this is attributable to the stressful environment of war, to severe undernutrition, or to the increased prevalence of infectious diseases is, however, unclear.

Mucosal Immune Cell Numbers and Visceral Sensitivity in Patients With Irritable Bowel Syndrome: Is There Any Relationship?

OBJECTIVES:Repeated exposure to stress leads to mast cell degranulation, microscopic inflammation, and subsequent visceral hypersensitivity in animal models. To what extent this pathophysiological pathway has a role in patients with the irritable bowel syndrome (IBS) has not been properly investigated. The objective of this study was to assess the relationship between visceral hypersensitivity, microscopic inflammation, and the stress response in IBS.METHODS:Microscopic inflammation of the colonic mucosa was evaluated by immunohistochemistry in 66 IBS patients and 20 healthy volunteers (HV). Rectal sensitivity was assessed by a barostat study using an intermittent pressure-controlled distension protocol. Salivary cortisol to a psychological stress was measured to assess the stress response.RESULTS:Compared with HV, mast cells, T cells, and macrophages were decreased in IBS patients. Similarly, λ-free light chain (FLC)-positive mast cells were decreased but not immunoglobulin E (IgE)- and IgG-positive mast cells. There were no differences between hypersensitive and normosensitive IBS patients. No relation was found between any of the immune cells studied and the thresholds of discomfort, urge, first sensation, or IBS symptoms (e.g., abdominal pain, stool-related complaints, bloating). Finally, stress-related symptoms and the hypothalamic–pituitary–adrenal-axis response to stress were not correlated with the number of mast cells or the presence of visceral hypersensitivity.CONCLUSIONS:Although the number of mast cells, macrophages, T cells, and λFLC-positive mast cells is decreased in IBS compared with HV, this is not associated with the presence of visceral hypersensitivity or abnormal stress response. Our data question the role of microscopic inflammation as an underlying mechanism of visceral hypersensitivity, but rather suggest dysregulation of the mucosal immune system in IBS.

Randomised clinical trial: the effects of amitriptyline on drinking capacity and symptoms in patients with functional dyspepsia, a double-blind placebo-controlled study.

Aliment Pharmacol Ther 2011; 34: 638–648

The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients

Background  Visceral hypersensitivity to distension is thought to play an important role in the pathophysiology of the irritable bowel syndrome (IBS). Cannabinoids are known to decrease somatic pain perception, but their effect on visceral sensitivity in IBS remains unclear. Therefore, we evaluated the effect of the mixed CB1/CB2 receptor agonist delta‐9‐tetrahydrocannabinol (Δ9‐THC, dronabinol) on rectal sensitivity.

Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity.

What is the central question of this study? Supernatants from colonic mucosal biopsies from patients with irritable bowel syndrome (IBS) activate enteric and dorsal root ganglion (DRG) neurons. Based on the discomfort/pain threshold during rectal distension, IBS patients may be subtyped as normo‐ or hypersensitive. However, the link between neuronal activation and visceral sensitivity remains unknown. What is the main finding and its importance? We found that supernatants from hypersensitive IBS patients caused stronger activation of enteric and DRG neurons than supernatants from normosensitive IBS patients. The level of activation correlated with the individual discomfort/pain threshold pressure values. We therefore conclude that mucosal biopsy supernatants have biomarker potential and may, in the future, help to personalize treatment of IBS patients with different visceral sensitivities.

Excitation of Enteric Neurons by Supernatants of Colonic Biopsies From Irritable Bowel Syndrome Patients (IBS) is Linked to Visceral Sensitivity

but DAT and NET contribute to 5-HT clearance. As the animals mature beyond 3 weeks, SERT function increases while DAT function declines. NET and SERT both contribute to 5-HT clearance in the mucosa of 6 week old guinea pigs. These data indicate that there are redundant transport mechanisms for 5-HT clearance in the gut mucosa. Monoamine transport inhibitors used to treat behavioral problems in pediatric patients could have unanticipated effects on gut function. (Supported by DK57039, DK082967, HD05197)