Faecalibacterium prausnitzii promotes intestinal epithelial IL-18 production through activation of the HIF1 pathway

Introduction Intestinal epithelial cells produce interleukin-18 (IL-18), a key factor in promoting epithelial barrier integrity. Here, we analyzed the potential role of gut bacteria and the hypoxia-inducible factor 1 alpha (HIF1 alpha) pathway in regulating mucosal IL18 expression in inflammatory bowel disease (IBD).Methods Mucosal samples from patients with IBD (n = 760) were analyzed for bacterial composition, IL18 levels and HIF1 alpha pathway activation. Wild-type Caco-2 and CRISPR/Cas9-engineered Caco-2-HIF1A-null cells were cocultured with Faecalibacterium prausnitzii in a "Human oxygen-Bacteria anaerobic" in vitro system and analyzed by RNA sequencing.Results Mucosal IL18 mRNA levels correlated positively with the abundance of mucosal-associated butyrate-producing bacteria, in particular F. prausnitzii, and with HIF1 alpha pathway activation in patients with IBD. HIF1 alpha-mediated expression of IL18, either by a pharmacological agonist (dimethyloxallyl glycine) or F. prausnitzii, was abrogated in Caco-2-HIF1A-null cells.Conclusion Butyrate-producing gut bacteria like F. prausnitzii regulate mucosal IL18 expression in a HIF1 alpha-dependent manner that may aid in mucosal healing in IBD.