Glucocorticoids and Androgens Protect From Gastric Metaplasia by Suppressing Group 2 Innate Lymphoid Cell Activation

Busada, Jonathan T.; Peterson, Kylie N.; Khadka, Stuti; Xu, Xiaojiang; Oakley, Robert H.; Cook, Donald N.; Cidlowski, John A.

doi:10.1053/j.gastro.2021.04.075

Cited by 34 publications

(40 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, we observed a tendency that the female patients were more prone to high‐grade atrophy and SPEM, which is consistent with several previous studies 18,25,29 . A mouse model demonstrated that simultaneous depletion of glucocorticoids and androgen triggered spontaneous pathogenic gastric inflammation and SPEM 30 …”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Atrophic gastritis in Helicobacter pylori‐infected children

et al. 2022

View full text Add to dashboard Cite

Helicobacter pylori infection is the leading cause of peptic ulcer diseases and chronic gastritis. Chronic H. pylori infection may initiate a cascade of progressive inflammation, mucosal atrophy, intestinal metaplasia (IM), and ultimately result in gastric cancer. 1 The World Health Organization classified H. pylori as a group I carcinogen for gastric cancer in 1994. H. pylori-infected patients with atrophic

show abstract

Section: Discussionsupporting

confidence: 93%

“…and androgen triggered spontaneous pathogenic gastric inflammation and SPEM. 30 This male protective effect may at least partially explain the female predominance of SPEM in H. pylori-infected children.…”

Section: Ack N Owled G Em Entsmentioning

confidence: 99%

Atrophic gastritis in Helicobacter pylori‐infected children

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Overall, our observations establish androgen-AR signaling as a critical pathway in the normal regulation of colonic motility and suggest that it should be considered in the pathophysiology of any disorder affecting the gut-brain axis. Emerging studies are revealing new roles for androgens in the gut, including dampening inflammatory responses in a specific subset of gastric lymphocytes ( 43 ) and modulating stromal cell effects on the small intestinal epithelium ( 44 ). These advances combine to suggest that androgen signaling is a complex, highly regulated pathway playing crucial homeostatic roles in the gut, and that these roles need to be broadly considered in human health as well as disease.…”

Section: Discussionmentioning

confidence: 99%

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice

Rastelli¹,

Robinson²,

Lagomarsino³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5-10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.

show abstract

“…Indeed, the expansion of the tuft cell and ILC2 populations required to overcome parasite infections are also cellular hallmarks of epithelial metaplasia in the stomach. Meanwhile, tuft cell and ILC2 numbers have separately been found to increase during gastric colonization with H. pylori infection, and chemically induced gastric metaplasia ( 36–38 ), precursors of chronic gastritis and associated progression to gastric cancer ( 33, 34 ). In agreement with our findings, genetic or antibody-mediated depletion of ILC2s has been demonstrated to protect against chemically induced gastric metaplasia ( 37, 38 ), although this was shown in the context of IL13 and IL33 signaling, while IL25 was not investigated ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Intestinal metaplasia is the leading risk factor for gastric cancer, while increased abundance of tuft cells and ILC2s have been reported in the gastric mucosa in response to H. pylori infection (33,34) and metaplasia (35)(36)(37)(38). The latter is experimentally replicated following a 3-day exposure to high dose tamoxifen (HDTmx; 250mg/kg) (39) and results in the loss of parietal cells and H + /K + ATPase expression, with a concomitant trans-differentiation of gastric chief cells into a spasmolytic polypeptide-expressing metaplasia (SPEM) characterized by TFF2 expression (Fig.…”

Section: Tuft Cells and Ilc2s Are Increased During Spasmolytic Polype...mentioning

confidence: 99%

Inhibition of the tuft cell/ILC2 axis reduces gastric tumor development in mice

O’Keefe

Carli

Baloyan

et al. 2022

Preprint

View full text Add to dashboard Cite

Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here we explore a metabolite-triggered circuit between epithelial tuft cells and innate lymphoid type 2 cells (ILC2) that is evolutionarily optimized for intestinal remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) acts as an alarmin on ILC2s to induce the release of IL13 as a growth factor for tuft cells, and propose that this model drives early metaplastic remodeling and gastric tumor formation. Genetic ablation of tuft cells, ILC2s or antibody-mediated neutralization of IL13 or IL25 reduces the growth of established tumors. Thus, the tuft cell/ILC2 axis provides an opportunity to therapeutically inhibit preneoplastic lesions and early-stage gastric cancer through repurposing of antibody-mediated therapies.

show abstract

Glucocorticoids and Androgens Protect From Gastric Metaplasia by Suppressing Group 2 Innate Lymphoid Cell Activation

Cited by 34 publications

References 57 publications

Atrophic gastritis in Helicobacter pylori‐infected children

Atrophic gastritis in Helicobacter pylori‐infected children

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice

Inhibition of the tuft cell/ILC2 axis reduces gastric tumor development in mice

Contact Info

Product

Resources

About