A cellular basis for heightened gut sensitivity in females, 2025, Venkataraman et al.

[SNT Gatchaman]

A cellular basis for heightened gut sensitivity in females

Spoiler: Authors

Archana Venkataraman; Eric E Figueroa; Joel Castro; Fernanda Castro Navarro; Deepanshu Soota; Stuart M Brierley; David Julius; Holly A Ingraham

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.

Web | DOI | PDF | Science | Paywall

 

[SNT Gatchaman]

Science commentary at Why are women more likely to get irritable bowel syndrome? New study provides clues

In a study published today in Science, the team showed that the female sex hormone estrogen increases communication between two cell types in the gut lining, in turn increasing pain signaling to the brain.

Holly Ingraham, a molecular physiologist at the University of California San Francisco, wondered whether estrogen might be activating a rare group of cells in the lining of the colon known as enterochromaffin cells. These cells respond to certain irritants and other stimuli by releasing the neurotransmitter serotonin, which in turn activates nerves that send pain signals to the brain.

But when the team analyzed slices of mouse gut, they couldn’t find estrogen receptors on enterochromaffin cells. Instead, such receptors showed up on another rare cell type called L cells, which help detect compounds made by gut bacteria. These cells secrete a peptide called PYY, which some research has linked to control of appetite.

Mice injected with estrogen had higher concentrations of PYY in their blood. And additional experiments using cells in a dish showed PYY directly triggers enterochromaffin cells to release serotonin. Giving mice a drug to block enterochromaffin cells’ receptors for PYY reduced their sensitivity to gut discomfort.

The team’s findings could hint at an evolutionary reason for the higher IBS rates in women, Ingraham says. Estrogen rises to extremely high levels in late-stage pregnancy—exactly when “you want to have this heightened sensitivity in the gut,” which could help deter consumption of toxic foods that may harm the fetus, she says. Perhaps a higher risk of IBS is the trade-off for this useful sensitivity, she speculates.

Her team now plans to study mice during pregnancy. The work could help provide insight into how big changes in estrogen, such as those that occur in people during pregnancy and perimenopause, for example, might set the stage for IBS, she adds.

Getting to the bottom of female-specific pathways is critical for learning how to treat disorders that disproportionately affect women, she argues. “If we don’t understand the basic physiological pathways, I don’t see how we ever come up with any new ways to think about curing some of these chronic diseases that have plagued women for decades.”

 

[Jonathan Edwards]

Seems another interesting way of thinking about female predisposition.

 

[SNT Gatchaman]

Yes, and exogenous olfactory receptors.

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.

I would be intrigung if there was a signalling system hiding throughout the body that made use of primitive olfactory (i.e. chemical) recognition.

 

[Jonathan Edwards]

Yes, and exogenous olfactory receptors.

Indeed.

The issue of female preponderance continues to puzzle me, because the mechanism of female traits is so complex.

It seems that it is just the absence of a Y chromosome that encodes for general female habitus in the newborn but Turner's syndrome (XO) shows that you need two Xs (with presumably incomplete suppression) to get normal female oestrogen production. And oestrogen production depends on the CYP19A1 gene on chromosome 15, not on X. So there is a gene on X that you need two of (unsuppressed) to get 15 to make oestrogen?

Part of the lupus sex ratio seems to be due to incomplete suppression of X, independent of oestrogen. But maybe the general autoimmunity sex ratio is oestrogen dependent. This olfactomedin story would be yet another oestrogen-related route.