Faecalibacterium prausnitzii promotes intestinal epithelial IL-18 production through activation of the HIF1α pathway
Raphael R. Fagundes, Gabriela Bravo‐Ruiseco, Shixian Hu, Sarah J. Kierans, Rinse K. Weersma, Cormac T. Taylor, Gerard Dijkstra, Hermie J. M. Harmsen, Klaas Nico Faber
Abstract
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 1α (HIF1α) 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 HIF1α 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 HIF1α pathway activation in patients with IBD. HIF1α-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 HIF1α-dependent manner that may aid in mucosal healing in IBD.