Disease tolerance licenses a transmissible pathogenic microbiota

Disease tolerance preserves tissue integrity without necessarily limiting microbial burden, yet its consequences for microbiota ecology and host-to-host interactions remain poorly understood. Unlike previously described models in which host pathology drives the emergence of colitogenic communities, we demonstrate that disease tolerance alone, in the absence of overt inflammation, is sufficient to generate a transmissible pathogenic microbiota. Mice deficient in macrophage migration inhibitory factor (MIF), a regulator of inflammatory damage, remained clinically healthy despite harboring a unique microbiota enriched in pathobionts. Microbiota transmission through co-housing or fecal gavage revealed that this tolerance-permissive community was lethal to disease-susceptible Il10^-/- hosts, inducing rapid, microbiota-dependent colitis characterized by expansion of IFNγ-producing CD4⁺ T cells and neutrophilic infiltration. Longitudinal 16S rRNA gene sequencing showed that each genotype sheltered distinct baseline fecal communities, which followed divergent trajectories under co-housing conditions. Isolation experiments further identified specific members of the Enterobacteriaceae and Enterococcaceae as key drivers of pathology in Il10^-/- hosts. Mechanistically, Mif^-/- hosts offset microbiota pathogenicity through enhanced barrier-protective programs, including increased expression of Il22 and Epiregulin, and enrichment of IL-22⁺ leukocytes, particularly within CD45⁺ Tαβ⁻ compartment. This protection was critically dependent on IL-10: Mif^-/-Il10^-/- mice were recovered far below Mendelian expectations, showed poor survival and developed severe spontaneous colitis that remained transmissible to Il10^-/- recipients. Thus, disease tolerance can relax ecological constraints on the microbiota, licensing the silent persistence of pathogenic communities that reveal their virulence only upon transmission to susceptible individuals.