Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome

Michiko Kano,Shin Fukudo,Shunji Mugikura,Huynh Giao Ly,Kei Takase,Makoto Yoshizawa,Joe Morishita,Motoyori Kanazawa,Yukari Tanaka,Patrick Dupont,Tomohiko Muratsubaki,Keiji Kohno,Lukas Van Oudenhove,Mao Yagihashi

doi:10.1038/s41598-017-09635-x

Abstract

Stress is a known trigger of irritable bowel syndrome (IBS) and exacerbates its gastrointestinal symptoms. However, underlying the physiological mechanism remains unknown. Here, we investigated hypothalamic–pituitary–adrenal (HPA) axis, colonic motility, and autonomic responses to corticotropin-releasing hormone (CRH) administration as well as brain activity alterations in IBS. The study included 28 IBS patients and 34 age and sex-matched healthy control subjects. IBS patients demonstrated greater adrenocorticotropic hormone (ACTH) responses to CRH than control subjects. Male IBS patients had greater increases in colonic motility than male HCs after CRH. Female IBS patients showed altered sympathovagal balance and lower basal parasympathetic tone relative to female control subjects. Brain responses to rectal distention were measured in the same subjects using functional magnetic resonance imaging, and their associations with individual ACTH responses to CRH were tested. A negative association between ACTH response to CRH and activity in the pregenual anterior cingulate cortex (pACC) during rectal distention was identified in controls but not in IBS patients. Impaired top-down inhibitory input from the pregenual ACC to the HPA axis may lead to altered neuroendocrine and gastrointestinal responses to CRH. Centrally acting treatments may dampen the stress induced physical symptoms in IBS.

Highlights

Irritable bowel syndrome (IBS) is characterized by idiopathic, chronic recurrent abdominal pain associated with altered bowel habits[1]
We examined whether intravenous Corticotropin-releasing hormone (CRH) administration increases adrenocorticotropic hormone (ACTH) and cortisol responses, exaggerates colonic motility, and alters sympathovagal balance in patients with IBS compared to healthy control subjects, taking into account the putative sex differences
The study is the first to comprehensively assess HPA axis, autonomic, and colonic responses to CRH in IBS and healthy controls and link these responses to brain responses to rectal distension in regions known to be involved in top-down control of the abovementioned peripheral stress responses

Summary

Introduction

Irritable bowel syndrome (IBS) is characterized by idiopathic, chronic recurrent abdominal pain associated with altered bowel habits[1]. CRH-mediated colonic hypermotility and hyper-responsiveness of the HPA axis have been reported in patients with IBS17–19, though possible sex differences are involved[19] Together, these data suggest that dysregulation of the CRH system is a pathophysiological mechanism of IBS. We evaluated patients with IBS and age-matched controls after peripheral administration of CRH, determining HPA axis responsiveness, colonic motility, and autonomic reactivity; we conducted a brain imaging (functional magnetic resonance imaging; fMRI) study during rectal balloon distention in both groups. We tested the hypothesis that rectal distention-induced brain activity in HPA axis-regulating cortical regions including the medial PFC, ACC, hippocampus, and amygdala correlates with HPA axis reactivity as assessed by ACTH responsiveness to CRH. We examined whether intravenous CRH administration increases ACTH and cortisol responses, exaggerates colonic motility, and alters sympathovagal balance in patients with IBS compared to healthy control subjects, taking into account the putative sex differences

Methods

Results

Conclusion