Sex hormones play a critical role in regulating gastric inflammation and metaplasia, according to study results published in Gastroenterology.

Researchers removed endogenous glucocorticoids and male sex hormones from male and female mice via adrenalectomy and castration to investigate how these hormones function in relation to gastric inflammation in both sexes.

Postadrenalectomy female mice had prominent mucosal thickening and chronic inflammation along the entire gastric corpus lesser curvature, while male mice were histologically normal.


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Male mice then underwent either castration alone or along with adrenalectomy to determine if male resistance to adrenalectomy-induced gastric inflammation involved the sex hormones. Castrated males alone did not show gross histological abnormities but castrated males with adrenalectomy appeared identical to the female mice undergoing adrenalectomy.

Spasmolytic polypeptide-expressing metaplasia (SPEM) was confirmed in adrenalectomized females and castrated plus adrenalectomized males, suggesting an essential role of male sex hormones in suppressing inflammation and metaplasia.

Female mice were also adrenalectomized and simultaneously implanted with a 5α-dihydrotestosterone (DHT) pellet, to test for preventative effects of androgens. Treatment with DHT prevented the development of gastric inflammation, the loss of parietal and chief cells, and blocked SPEM development in adrenalectomized females. Furthermore, DHT treatment administered 1 month after adrenalectomy completely reversed the development of gastric inflammation and SPEM.

Using single-cell RNA sequencing, researchers identified cell populations that respond to androgens and found abundant levels of both glucocorticoids and androgen receptors in type 2 innate lymphoid cells. Researchers also revealed that the expression of proinflammatory cytokines by type 2 innate lymphoid cells was powerfully suppressed by DHT, and that depletion of type 2 innate lymphoid cells had a protective effect in the stomach against the development of SPEM.

According to researchers, these results highlight a novel mechanism for the overlapping effects of glucocorticoids and androgens in regulating gastric inflammation. They concluded, “This work revealed a critical role for sex hormones in regulating gastric inflammation and metaplasia.”

Reference

Busada JT, Peterson KN, Khadka S, et al. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterol. Published online May 7, 2021. doi: 10.1053/j.gastro.2021.04.075