A risk variant within the ‘interferon induced with helicase C domain 1ʹ (IFIH1) gene render epithelial cells susceptible for microbial stimuli

Background Variants in the gene for IFIH1 have been associated with an increased risk for both Crohn’s disease (CD) and ulcerative colitis (UC). IFIH1 represents a member of the RIG-I-like-receptor family capable of recognizing intracellular viral and bacterial double-stranded RNAs. Thus, we hypothesized that IFIH1 may be involved in microbe-host interaction particularly in intestinal epithelial cells (IEC), the major cell type of the intestinal mucosal border.

Methods Mucosal biopsy samples were collected from patients with CD, UC and healthy controls and stained immunohistochemically for IFIH1. Mucosal expression of IFIH1 was quantified by qPCR. For functional experiments Caco2 cells were silenced for IFHI1 (and/or RIG-I) and features of epithelial cell biology were determined after stimulation with Salmonella enterica serovar typhimurium and synthetic RNAs. Finally, colonic organoids were derived from healthy biopsy samples obtained from patients expressing different IFIH1 variants, namely wt/wt, wt/mut, and mut/mut.

Results Our data highlight strong IFIH1 expression in IECs in CD and UC. However, mRNA expression revealed a wide distribution within all studied groups, namely healthy controls, UC and CD patients from involved and non-involved mucosal sites. In cell culture experiments we found that IFIH1-silenced Caco2 cells are hardly responsive to major microbial stimuli both in terms of cytokine expression and induction of autophagosomes. Strikingly, by developing human organoid models from patients wildtype, heterozygous, or homozygous for the IFIH1 risk locus, we were able to reproduce and verify major mechanistic aspects.

Conclusion Herein, we provide a mechanistic explanation of how the human IBD risk variant in the IFIH1 gene links to an increased risk for the development of inflammation in IBD.

Publication History

Article published online:
01 September 2021