The enteric microbiome stimulates localized interferon responses and provides preemptive antiviral protection of intestinal epithelial cells through IFNLR1 signaling

Abstract Specialized immune responses have evolved to eliminate pathogens in the gastrointestinal tract. In particular, intestinal epithelial cells (IECs) are uniquely responsive to interferon lambda (IFN-λ) and depend on IFN-λ for antiviral defense to a greater extent than other types of IFN. IFN-λ signaling protects IECs by inducing expression of antiviral IFN-stimulated genes (ISGs), but it is unclear if the intestinal microbiome interacts with the IFN-λ pathway. We find that commensal microbes stimulate a steady-state ISG signal in the gastrointestinal tract that is depleted with broad-spectrum antibiotics, as assessed by whole-tissue RNA sequencing. Steady-state ISG expression is also significantly reduced in mice lacking IFN-λ receptor (IFNLR) specifically in IECs. These data suggest that enteric bacteria stimulate expression of IFN-λ and, subsequently, epithelial ISGs at homeostasis. Strikingly, imaging data reveals that these steady-state ISGs are present in distinct pockets throughout the small intestinal epithelium and are concentrated in IECs at the tips of individual villi. Furthermore, we find that IFNLR protects IECs during initiation of murine rotavirus infection at early time-points post-infection, suggesting that steady-state ISGs are protective against viral infection. Lastly, we find that steady-state ISGs are expressed in a subpopulation of human IECs when we re-analyze publicly available single-cell RNA sequencing datasets. These novel observations indicate that commensal microbes stimulate ISGs in localized regions of the intestinal epithelium at homeostasis and may preemptively activate antiviral defenses in vulnerable IECs to improve host fitness against enteric viruses.