Disease tolerant mice shelter a pathogenic intestinal microbiota able to trigger lethal disease in low tolerant hosts

Abstract

Disease tolerance is a defensive strategy that limits tissue damage during infection. Macrophage migration inhibitory factor (MIF)-deficient mice (Mif-/-) are protected in different models of infection and intestinal inflammation due to unclear disease tolerance mechanisms, whereas low disease-tolerant Il10-/-mice develop microbiota-dependent spontaneous gut inflammation. Here, we examined whether IL-10 is required for the phenotype seen in Mif-/-mice and, conversely, the contribution of MIF during IL-10 deficiency. While breeding for double-deficient Mif-/-Il10-/- mice, we unexpectedly observed that Il10-/- individuals died within days after co-housing with Mif-/- mice. We found that healthy Mif-/-hosts endure a highly diverse, unique and dysbiotic-like microbiota composition, including antibiotic-resistant Enterobacteriaceae species, which were sufficient to cause acute and lethal Th1-driven colitis in Il10-/- recipients. The disease was characterized by increased frequencies of IFN{gamma}+ cells and neutrophils within colonic lamina propria. Mif-/-Il10-/-mice died prematurely, and survivors developed communicable disease, - indicating that lack of IL-10 is a dominant trait. These findings suggest that tolerant individuals harbor a gut microbiota enriched in pathogens/pathobionts, which can trigger disease in susceptible hosts.