Dual effect of butyrate on IL-1β-mediated intestinal epithelial cell inflammatory response

Butyrate (NaBu), a product of intestinal microbial metabolism, has been proposed as an anti-inflammatory agent for treating inflammatory bowel diseases. However, the molecular mechanisms implicated in the modulation of intestinal epithelial cell inflammatory response to NaBu remain unknown. Here, microarray analysis performed on nontransformed human crypt intestinal epithelial cells (HIEC) shows that NaBu regulated specifically the short-term IL-1 beta-dependent induction of different inflammatory genes. While NaBu significantly increased the IL-1 beta-induction of genes like SAA2, C3, and IL-1 alpha, other inflammatory genes like CXCL5, CXCL11, and IL-1 beta were decreased. Induction of various genes such as CXCL8, CCL20, and IL-6 was unaffected by NaBu. We show that, compared to genes that are upregulated or downregulated by NaBu, genes that are unaffected by NaBu were induced more rapidly after IL-1 beta treatment and contained a higher concentration of transcription factor binding sites in their promoter region. In addition, transient treatment with IL-1 beta was sufficient for subsequent induction of NaBu-upregulated and NaBu-unaffected classes of genes, while a continuous presence of IL-1 beta was required for NaBu-downregulated gene expression. In conclusion, our results suggest that fundamental differences predispose inflammatory genes to specific regulation by NaBu in intestinal epithelial cells, thereby allowing precise control of inflammation.