Brain and gut CRF signaling: biological actions and role in the gastrointestinal tract
Open accessAbstract
Background Corticotropin-releasing factor (CRF) pathways coordinate behavioral, endocrine, autonomic and visceral responses to stress. Convergent anatomical, molecular, pharmacological and functional experimental evidence supports a key role of brain CRF receptor (CRF-R) signaling in stress-related alterations of gastrointestinal functions. These include the inhibition of gastric acid secretion and gastric-small intestinal transit, stimulation of colonic enteric nervous system and secretorymotor function, increase intestinal permeability, and visceral hypersensitivity. Brain sites of CRF actions to alter gut motility encompass the paraventricular nucleus of the hypothalamus, locus coeruleus complex and the dorsal motor nucleus while those modulating visceral pain are localized in the hippocampus and central amygdala. Brain CRF actions are mediated through the autonomic nervous system (decreased gastric vagal and increased sacral parasympathetic and sympathetic activities). The activation of brain CRF-R2 subtype inhibits gastric motor function while CRF-R1 stimulates colonic secretomotor function and induces visceral hypersensitivity. CRF signaling is also located within the gut where CRF-R1 activates colonic myenteric neurons, mucosal cells secreting serotonin, mucus, prostaglandin E2, induces mast cell degranulation, enhances mucosal permeability and propulsive motor functions and induces visceral hyperalgesia in animals and humans. CRF-R1 antagonists prevent CRF- and stressrelated gut alterations in rodents while not influencing basal state. Discussion These preclinical studies contrast with the limited clinical positive outcome of CRF-R1 antagonists to alleviate stress-sensitive functional bowel diseases such as irritable bowel syndrome. Conclusion The translational potential of CRF-R1 antagonists in gut diseases will require additional studies directed to novel anti-CRF therapies and the neurobiology of brain-gut interactions under chronic stress.
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CRF acts on enteric peristalsis, secretion, and the mucosal barrier, playing a role in functional and organic disorders, such as IBS and IBD.
“CRF acts on enteric peristalsis, secretion, and the mucosal barrier, playing a role in functional and organic disorders, such as IBS and IBD (23).”
From Stress triggers flare of inflammatory bowel disease in children and adults (2019) · cites this paper as [23]
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References 9 · Cited by 147
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- Authors
- Tache, Y., Larauche, M., Yuan, P.-Q., & Million, M.
- Affiliations
- CURE/Digestive Diseases Research Center, G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
- University of California, Los Angeles (US)
- Venue
- Current Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2018-01-03
- Volume
- 11
- Issue
- 1
- Pages
- 51-71
- ISSN
- 1874-4672 (ISSN-L)
- PMC
- PMC8091865
- OpenAlex
- W2594882031
- Cited by
- 147
- References
- 9
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 14 · 2023: 19 · 2022: 25 · 2021: 18 · 2020: 16 · 2019: 10 · 2018: 9 · 2017: 5
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P50DK064539, R01DK078676, P30DK041301, K01DK088937, R01DK057236)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- corticotropin-releasing factor, CRF1 receptor, CRF receptor 2, gut-brain axis, stress, gastrointestinal motility, gastric acid secretion, visceral hypersensitivity, intestinal permeability, enteric nervous system, paraventricular nucleus, locus coeruleus, dorsal motor nucleus of the vagus, hippocampus, central amygdala, autonomic nervous system, mast cell degranulation, serotonin, prostaglandin E2, irritable bowel syndrome, functional bowel disorders, chronic stress
- MeSH terms
- Animals, Brain, Corticotropin-Releasing Hormone, Humans, Motor Activity, Signal Transduction, Gastrointestinal Tract
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