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A cellular basis for heightened gut sensitivity in females.

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Title: A cellular basis for heightened gut sensitivity in females.
Authors: Venkataraman, Archana (AUTHOR), Figueroa, Eric E. (AUTHOR), Castro, Joel (AUTHOR), Navarro, Fernanda Castro (AUTHOR), Soota, Deepanshu (AUTHOR), Brierley, Stuart M. (AUTHOR), Julius, David (AUTHOR), Ingraham, Holly A. (AUTHOR)
Source: Science. 12/18/2025, Vol. 390 Issue 6779, p1285-1291. 7p.
Subjects: Females, Estrogen regulation, Enteroendocrine cells, Neuropeptide Y, Irritable colon, Serotonin, Visceral pain
Abstract: Visceral pain disorders, such as irritable bowel syndrome, exhibit a marked female prevalence. Enhanced signaling between enterochromaffin (EC) cells in the gut epithelium and mucosal sensory nerve fibers likely contributes to this sex bias. We identified an estrogen-responsive paracrine pathway in which two enteroendocrine cell types, peptide YY (PYY)–expressing L cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that estrogen signaling up-regulates the bacterial metabolite short-chain fatty acid receptor Olfr78 on colonic L cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells by means of NPY1R, thereby enhancing serotonin release and gut pain. We propose that hormonal fluctuations, in conjunction with internal (stress) or environmental (diet) factors, amplify this local estrogen-responsive colonic circuit, resulting in maladaptive gut sensitivity. Editor's summary: Gastrointestinal and other visceral pain disorders are more common in female patients, but the underlying reasons remain poorly understood. By comparing male and female mouse models, including animals subjected to ovariectomy and/or estrogen supplementation, Venkataraman et al. uncovered an estrogen-dependent pathway that promotes gut sensitivity to noxious stimuli (see the Perspective by Joly and Miguel-Aliaga). In this pathway, estrogen up-regulates a bacterial metabolite receptor, which then stimulates L cells in the colon to release peptide YY, triggering serotonin release from enterochromaffin cells and resulting in a sensation of gut pain. If these findings are confirmed in humans, then dietary modifications and/or antagonists of peptide YY signaling may help to improve the treatment of visceral pain disorders such as irritable bowel syndrome. —Yevgeniya Nusinovich [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: A cellular basis for heightened gut sensitivity in females.
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  Data: <searchLink fieldCode="AR" term="%22Venkataraman%2C+Archana%22">Venkataraman, Archana</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Figueroa%2C+Eric+E%2E%22">Figueroa, Eric E.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Castro%2C+Joel%22">Castro, Joel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Navarro%2C+Fernanda+Castro%22">Navarro, Fernanda Castro</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Soota%2C+Deepanshu%22">Soota, Deepanshu</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Brierley%2C+Stuart+M%2E%22">Brierley, Stuart M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Julius%2C+David%22">Julius, David</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ingraham%2C+Holly+A%2E%22">Ingraham, Holly A.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 12/18/2025, Vol. 390 Issue 6779, p1285-1291. 7p.
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  Data: <searchLink fieldCode="DE" term="%22Females%22">Females</searchLink><br /><searchLink fieldCode="DE" term="%22Estrogen+regulation%22">Estrogen regulation</searchLink><br /><searchLink fieldCode="DE" term="%22Enteroendocrine+cells%22">Enteroendocrine cells</searchLink><br /><searchLink fieldCode="DE" term="%22Neuropeptide+Y%22">Neuropeptide Y</searchLink><br /><searchLink fieldCode="DE" term="%22Irritable+colon%22">Irritable colon</searchLink><br /><searchLink fieldCode="DE" term="%22Serotonin%22">Serotonin</searchLink><br /><searchLink fieldCode="DE" term="%22Visceral+pain%22">Visceral pain</searchLink>
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  Data: Visceral pain disorders, such as irritable bowel syndrome, exhibit a marked female prevalence. Enhanced signaling between enterochromaffin (EC) cells in the gut epithelium and mucosal sensory nerve fibers likely contributes to this sex bias. We identified an estrogen-responsive paracrine pathway in which two enteroendocrine cell types, peptide YY (PYY)–expressing L cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that estrogen signaling up-regulates the bacterial metabolite short-chain fatty acid receptor Olfr78 on colonic L cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells by means of NPY1R, thereby enhancing serotonin release and gut pain. We propose that hormonal fluctuations, in conjunction with internal (stress) or environmental (diet) factors, amplify this local estrogen-responsive colonic circuit, resulting in maladaptive gut sensitivity. Editor's summary: Gastrointestinal and other visceral pain disorders are more common in female patients, but the underlying reasons remain poorly understood. By comparing male and female mouse models, including animals subjected to ovariectomy and/or estrogen supplementation, Venkataraman et al. uncovered an estrogen-dependent pathway that promotes gut sensitivity to noxious stimuli (see the Perspective by Joly and Miguel-Aliaga). In this pathway, estrogen up-regulates a bacterial metabolite receptor, which then stimulates L cells in the colon to release peptide YY, triggering serotonin release from enterochromaffin cells and resulting in a sensation of gut pain. If these findings are confirmed in humans, then dietary modifications and/or antagonists of peptide YY signaling may help to improve the treatment of visceral pain disorders such as irritable bowel syndrome. —Yevgeniya Nusinovich [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – SubjectFull: Enteroendocrine cells
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      – SubjectFull: Neuropeptide Y
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      – SubjectFull: Irritable colon
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      – SubjectFull: Visceral pain
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              Text: 12/18/2025
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