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

doi:10.3389/fmicb.2023.1298304

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

Front Microbiol. 2023 Dec 14:14:1298304. doi: 10.3389/fmicb.2023.1298304. eCollection 2023.

Authors

Raphael R Fagundes¹, Gabriela Bravo-Ruiseco², Shixian Hu¹, Sarah J Kierans³, Rinse K Weersma¹, Cormac T Taylor³, Gerard Dijkstra¹, Hermie J M Harmsen², Klaas Nico Faber¹

Affiliations

¹ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
² Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
³ School of Medicine and Medical Science and the Conway Institute, University College Dublin, Dublin, Ireland.

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.

Keywords: Faecalibacterium; HIF1α; HoxBan in vitro coculture system; IBD; IL-18; epithelial-bacteria interaction; intestine.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. RW is supported by a research grant from the Seerave Foundation and by the collaborative TIMID project (LHSM18057-SGF) financed by the PPP allowance made available by Top Sector Life Sciences & Health Samenwerkende Gezondheidsfondsen (SGF). The research position of RF was supported by the Graduate School of Medical Sciences of the University of Groningen. The funders had no role in the design of the study, collection, analysis, interpretation of data or writing the manuscript.