Steady-state interferon-stimulated gene expression in the intestinal epithelium depends on interferon lambda and the bacterial microbiome

Abstract

Abstract Distinct cellular responses have evolved that are specialized for eliminating pathogens in mucosal surfaces, such as the gastrointestinal tract. In particular, intestinal epithelial cells (IECs) are uniquely responsive to interferon lambda (IFN-λ) and depend on this cytokine for antiviral defense to a greater extent than other types of interferon. IFN-λ signaling protects IECs by inducing expression of antiviral IFN-stimulated genes (ISGs), but it is unclear how this signaling pathway interacts with the intestinal microbiome. We find that depletion of the intestinal microbiome with broad spectrum antibiotics significantly reduces steady-state ISGs in the gastrointestinal tract when assessed by whole-tissue RNA sequencing. Steady-state ISG expression is also significantly reduced in mice with conditional knockout of IFN-λ receptor (IFNLR) in IECs. These data suggest that enteric bacteria stimulate expression of IFN-λ and, subsequently, epithelial ISGs at homeostasis. Strikingly, imaging data reveals distinct pockets of IFNLR-dependent ISGs throughout the small intestinal epithelium. These highly localized ISGs are also dependent on the presence of bacteria and IFNLR expression by IECs. Notably, in addition to localized ISG expression along the length of the gastrointestinal tract, ISG expression is concentrated in the most mature IECs at the tips of individual villi. These novel observations indicate that ISGs are robustly expressed in localized regions of the intestinal epithelium at homeostasis. This robust ISG expression depends on the bacterial microbiome and may preemptively activate antiviral defenses in vulnerable IECs to improve host fitness against enteric viruses.