Relationship between sympathoadrenal and pituitary-adrenal response during colorectal distention in the presence of corticotropin-releasing hormone in patients with irritable bowel syndrome and healthy controls

<div><p>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.</p></div

Features of HRV during each distention and correlation between HRV and neuroendocrine variables.

<p>Features of HRV during each distention and correlation between HRV and neuroendocrine variables.</p

Effects of CRH on HRV during random distention after injection.

<p>(<b>A</b>) HR (beats/min), (<b>B</b>) HF power, and (<b>C</b>) LF/HF ratio in HCs administered with saline (n = 16) or CRH (n = 16); and patients with IBS administered with saline (n = 16) or CRH (n = 16). Results are represented as mean ± SD. GEE analysis of HRV parameters during random distention revealed a significant distention × group × drug interaction for HF power (<i>P</i> = .016). LF, low frequency; HF, high frequency; HCs, healthy controls.</p

Neuroendocrine response models during 40 mmHg distention.

<p>(<b>A</b>) HCs injected with saline (n = 16), (<b>B</b>) HCs injected with CRH (n = 16), (<b>C</b>) patients with IBS injected with saline (n = 16), and (<b>D</b>) patients with IBS injected with CRH (n = 16). *<i>P</i> < .0125 indicate significant paths. The squared multiple correlations (R²) of the variables are reported in the top right corner. There were no significant factor correlations between ACTH and NA. ACTH, plasma ACTH; cortisol, serum cortisol; HCs, healthy controls; NA, plasma noradrenaline; Ad, plasma adrenaline; ACTH, adrenocorticotropic hormone; IBS, irritable bowel syndrome; CRH, corticotropin-releasing hormone.</p

Effects of CRH on HRV during the baseline period after injection.

<p>(<b>A</b>) HR (beats/min), (<b>B</b>) HF power, and (<b>C</b>) LF/HF ratio in HCs administered with saline (n = 16) or CRH (n = 16); and patients with IBS administered with saline (n = 16) or CRH (n = 16). Results are represented as mean ± SD. *<i>P</i> < .05 when compared with placebo; baseline after CRH or saline injection, paired t-test. LF, low frequency; HF, high frequency; HCs, healthy controls.</p

IBS subtype and CRH-BP SNP.

<p>We analyzed the associations between the SNPs and psychometric scores according to IBS subtype. (a) In individuals with diarrhea-type IBS, <i>rs10474485</i> A allele non-carriers showed higher scores than carriers. There were significant differences in the PSS (p = 0.018) and Trait (p = 0.017) scores. (b) In addition, in the IBS group with mixed symptoms, a significant difference was observed in the SDS score (p = 0.030). There was no significant difference in the constipation group. *p <i><</i> 0.05.</p

Genotype Frequencies in the IBS Patients and Controls.

<p>Genotype Frequencies in the IBS Patients and Controls.</p

Self-rating Depression Scale and the CRH-BP SNP.

<p>We analyzed associations between the selected SNP (<i>rs10474485</i>) and psychometric scores according to sex. (a) In male subjects, a significant group (IBS/control) × rs10474485 genotype interaction (p = 0.045) was observed. (b) Further, there was a significant group (IBS/control) × <i>rs10474485</i> A allele interaction (p = 0.017). *p <i><</i> 0.05.</p

Psychometric Scores.

<p>Psychometric Scores.</p

Sample Characteristics.

<p>Sample Characteristics.</p