IL-25 Regulates Host-Microbial Mutualism in the Intestine

It has previously been shown that intestinal microbiota are critical for interleukin-25 (IL-25) production, yet the role of IL-25 in host-microbe interactions remains unknown. We have shown that IL-25 deficiency results in multiple defects in intestinal immune pathways that regulate microbial handling. Analysis of gut microbial communities revealed key differences in microbial composition in IL-25^-/- mice. To examine the impact of this dysbiosis, intestinal inflammation was induced using dextran sulphate sodium (DSS). IL-25^-/- mice displayed significantly increased intestinal inflammation as compared to C57BL/6 mice, and this dysregulated microbial homeostasis observed in IL-25^-/- mice is transmissible to C57BL/6 mice following cross-fostering. Yet, the defects in intestinal immune homeostasis were still present in IL-25^-/- mice even in the absence of the inflammation-associated gut microbiota, supporting the role of IL-25 in the regulation of these pathways. Inbreeding of cross-fostered C57BL/6 mice restored intestinal and microbial homeostasis, demonstrating that microbial dysbiosis can be rescued through IL-25-mediated maternal regulation of commensal microbiota. In support of this, analysis of breast milk revealed key differences in IL-25^-/- mice. Taken together, these data demonstrate that IL-25 contributes to the maintenance of a healthy commensal microbiota via regulation of key microbial handling pathways.