Recent investigations have begun to reveal the impact host-microbe mutualism has on both health and disease. Inappropriate immune-microbe interactions are known to contribute to the pathogenesis of a growing number of chronic inflammatory diseases. Understanding host regulation of gut microbiota may provide critical targets for the development of novel therapeutics to treat immune mediated diseases.
To further probe the complex network of immune pathways involved in the regulation of gut microbiota, we employed IL-25-/- mice to identify the role of this cytokine in this process. Expression of IL-25 has been shown to be induced by gut microbiota but the role of IL-25 in host-microbe interactions remains unknown. IL-25 deficiency resulted in multiple defects in the intestinal immune pathways that regulate microbial handling. Analysis of gut microbiota communities discovered key differences in microbial composition in IL-25-/- mice, further supporting the role of IL-25 in regulation of host-microbe interactions. To examine the impact of these host-microbial defects in IL-25-/- mice, dextran sulphate sodium (DSS)-induced intestinal inflammation was performed. IL-25-/- mice displayed significantly increased intestinal inflammation as compared to DSS treated C57BL/6 mice. To obtain evidence that the gut microbiota was sufficient to drive DSS-induced intestinal inflammation, we utilized antibiotic treatment and carried out cross-fostering experiments. Pre-treatment with broad-spectrum antibiotics in both IL-25-/- and C57BL/6 mice prevented DSS-induced intestinal inflammation, demonstrating that microbial signals contribute to disease pathogenesis. Further, the increased susceptibility to DSS-induced inflammation in IL-25-/- mice is transmissible to C57BL/6 mice following cross-fostering. Most importantly, the defects in intestinal immune pathways in IL-25-/- mice were still present even in the absence of their inflammation-associated gut microbiota. Taken together, these data demonstrate that IL-25 contributes to the maintenance of a healthy commensal microbial community via regulation of key microbial handling pathways in the intestine.