Abstract
Corticotropin-releasing hormone (CRH) mediates stress responses in the brain-gut axis. Administration of CRH modulates brain activation, for example by controlling the autonomic nervous system in response to colorectal distention. Here, we investigated the relationship between sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to colorectal distention in patients with irritable bowel syndrome (IBS). We enrolled 32 patients with IBS (16 women and 16 men) and 32 healthy subjects (16 women and 16 men), and randomly divided them between CRH and saline injection groups. The patients randomly underwent no (0 mmHg), mild (20 mmHg), or strong (40 mmHg) colorectal distension. CRH (2 μg/kg) or saline was then administered via injection, and the distention protocol was repeated. The heart rate (HR) and HR variability (HRV; calculated as the low [LF] to high frequency [HF] peak ratio, LF/HF) were analyzed using electrocardiography. Plasma noradrenaline, adrenaline, adrenocorticotropic hormone (ACTH), and cortisol levels were measured at the time of each distention. Plasma adrenaline levels were shown to be associated with plasma ACTH levels in HCs injected with CRH during distention using structural equation modeling analysis. Patients with IBS injected with placebo during distention displayed a closer association between these two parameters than those injected with CRH. Generalized estimating equation analysis revealed a significant distention × group × drug interaction for HF power. Moreover, there was a strong correlation between adrenaline and HRV upon CRH injection in controls, but not patients with IBS. The relationship between HPA-sympathoadrenal responses and CRH levels during colorectal distention differs between patients with IBS and controls. Modulation of adrenal gland activity in response to ACTH stimulation may contribute to the brain-gut pathophysiology characteristic of IBS.
Highlights
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel function in the absence of structural or inflammatory abnormalities [1, 2]
We showed an association between plasma adrenaline adrenocorticotropic hormone (ACTH) levels in healthy controls (HCs) injected with Corticotropin-releasing hormone (CRH) during strong distention
Patients with IBS injected with placebo displayed a closer association between these two parameters than those injected with CRH during strong distention
Summary
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel function in the absence of structural or inflammatory abnormalities [1, 2]. Corticotropin-releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis, and it increases colonic motility and sensitivity [4,5,6]. Stress results in CRH release in the paraventricular nucleus of the hypothalamus, as well as secretion of adrenocorticotropic hormone (ACTH) from the pituitary, which stimulates the adrenal gland to release cortisol [7]. We have found that activity in brain regions implicated in CRH secretion is suppressed during strong colorectal distention in men with IBS [10]. Sex differences in central nervous system responses to visceral stress, perception, and motility have been reported in patients with IBS. It has been reported that male patients with IBS likely exhibit a ceiling effect with regard to their responses to colorectal distention both in the amygdala and in plasma noradrenaline levels following CRH injection [10]
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