AUTHOR=Fagundes Raphael R. , Bravo-Ruiseco Gabriela , Hu Shixian , Kierans Sarah J. , Weersma Rinse K. , Taylor Cormac T. , Dijkstra Gerard , Harmsen Hermie J. M. , Faber Klaas Nico 

TITLE=Faecalibacterium prausnitzii promotes intestinal epithelial IL-18 production through activation of the HIF1α pathway

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1298304

DOI=10.3389/fmicb.2023.1298304

ISSN=1664-302X

ABSTRACT=<sec><title>Introduction</title><p>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 <italic>IL18</italic> expression in inflammatory bowel disease (IBD).</p></sec><sec><title>Methods</title><p>Mucosal samples from patients with IBD (<italic>n</italic> = 760) were analyzed for bacterial composition, <italic>IL18</italic> levels and HIF1α pathway activation. Wild-type Caco-2 and CRISPR/Cas9-engineered Caco-2-<italic>HIF1A</italic>-null cells were cocultured with <italic>Faecalibacterium prausnitzii</italic> in a “Human oxygen-Bacteria anaerobic” <italic>in vitro</italic> system and analyzed by RNA sequencing.</p></sec><sec><title>Results</title><p>Mucosal <italic>IL18</italic> mRNA levels correlated positively with the abundance of mucosal-associated butyrate-producing bacteria, in particular <italic>F. prausnitzii</italic>, and with HIF1α pathway activation in patients with IBD. HIF1α-mediated expression of <italic>IL18</italic>, either by a pharmacological agonist (dimethyloxallyl glycine) or <italic>F. prausnitzii</italic>, was abrogated in Caco-2-<italic>HIF1A</italic>-null cells.</p></sec><sec><title>Conclusion</title><p>Butyrate-producing gut bacteria like <italic>F. prausnitzii</italic> regulate mucosal <italic>IL18</italic> expression in a HIF1α-dependent manner that may aid in mucosal healing in IBD.</p></sec>