Tursun Turapov

Background: Eosinophilic esophagitis (EoE) is an inflammatory disorder characterized by impaired swallowing. Eosinophils are key mediators in the progression of EoE and can respond to microbial metabolites. One group of microbial metabolites shown to play an immunomodulatory role in eosinophilic inflammation are short chain fatty acids (SCFAs) produced within the gastrointestinal tract. IL-33, a member of the IL-1 family of cytokines, has been shown to play a pro-inflammatory role in eosinophils. Previous work has demonstrated that SCFAs can reduce IL-33-induced activation of eosinophils and attenuate eosinophil survival. The mechanism by which SCFAs do this has, however, not clearly been elucidated and both the SCFA receptor GPR43 and histone deacetylases have been mechanistically implicated.

Methods: Hematopoietic stem cells isolated from patient blood were stimulated with IL-3, IL-6, GM-CSF, and SCF for 5 days, followed by IL-3, IL-5, and GM-CSF for an additional 15 days to promote eosinophil differentiation. Differentiated eosinophils were treated with IL-33 and acetate, propionate, or butyrate, with or without GLPG-0974, a GPR43 antagonist. Differentiated eosinophils were treated with Trichostatin A, a potent inhibitor of histone deacetylase, and IL-33.

Results: Propionate and butyrate induce eosinophil apoptosis despite activation with IL-33. Addition of GPR43i to SCFA/IL-33-treated eosinophils failed to rescue eosinophil apoptosis, suggesting a GPR43-independent signaling mechanism. HDACi potently induced eosinophil apoptosis despite concomitant IL-33 stimulation. These findings suggest that SCFAs regulate eosinophil survival independently of GPR43 agonism and implicate HDAC inhibition as a major driver of eosinophilic apoptosis.

Conclusions: These findings highlight the importance of SCFAs in eosinophilic esophagitis.