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

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 IFNγ ⁺ 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.