Abstract
Short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, modulate immune responses in the gut. However, the effect of SCFAs on mucosal vaccine-induced immune cell migration is poorly understood. Here, we investigated whether SCFAs modulate chemokine expression induced by the killed whole-cell oral cholera vaccine, Shanchol™, in human intestinal epithelial cells. Shanchol™ induced expression of CCL2, CCL5, CCL20, and CXCL10 at the mRNA level, but not at the protein level. Interestingly, CCL20 secretion was substantially increased by co-stimulation with Shanchol™ and butyrate, while neither acetate nor propionate showed such effect. Enhanced CCL20 secretion was associated with GPR109A activation, and histone deacetylase (HDAC) inhibition. In addition, co-treatment with Shanchol™ and butyrate synergistically increased the secretion of adenosine triphosphate (ATP). Moreover, CCL20 secretion was decreased by inhibiting the extracellular ATP receptor P2X7. However, neither inflammasomes nor caspases were involved in CCL20 production. The culture supernatant of cells treated with Shanchol™ and butyrate augmented human immature dendritic cell migration. Collectively, these results suggest that butyrate enhances Shanchol™-induced CCL20 production in human intestinal epithelial cells via HDAC inhibition and ATP-P2X7 signaling by activating GPR109A. These effects potentially enhance the mucosal immune responses in the gut induced by this oral cholera vaccine.
Highlights
Cholera is an acute diarrheal disease that can cause life-threatening dehydration and shock if not treated appropriately
These results indicate that ShancholTM treatment potently induces mRNA synthesis of chemokines but barely induces protein secretion from human intestinal epithelial cells
To examine whether short-chain fatty acid (SCFA) alter chemokine secretion, Caco-2 cells were treated with ShancholTM in the presence of major intestinal SCFAs such as acetate, butyrate, and propionate for 24 h, and chemokine secretion was determined by using Enzyme-Linked Immunosorbent Assay (ELISA)
Summary
Cholera is an acute diarrheal disease that can cause life-threatening dehydration and shock if not treated appropriately. It is caused by ingestion of water or food contaminated with Vibrio cholerae [1]. ShancholTM includes formalin-killed V. cholerae O139 and heat-killed or formalin-killed V. cholerae O1, but does not include the recombinant CTB subunit [3]. Both cholera vaccines have been successfully licensed, their low immunogenicity, short-term protection, and high dose requirement leave a room for further improvement [4, 5]. Enhancement of intestinal mucosal immunity has been suggested to be one of the most efficient approaches by which the development of modern oral vaccines against cholera can be improved [6]
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