Maladaptive Inflammatory Signaling in Old Mice Impairs Colonic Regeneration by Promoting a Sustained Fetal-Like Epithelial State.

Abstract

Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake a comprehensive assessment of age-related changes in the mouse colon at single-cell resolution. A survey of immune and epithelial compartments revealed a hyperactivated inflammatory state in the colon of old mice characterized, among other changes, by the induction of an interferon γ (IFNγ) response signature in immune cells. This does not result in increased inflammatory signatures in the epithelium under homeostasis but triggers a disproportionate inflammatory response that disrupts regeneration and epithelial integrity after challenge with the enteropathogen Citrobacter rodentium. Colons of old mice exhibit higher production of IFNγ by T and innate lymphoid cells (ILCs) that are associated with reduced Lgr5⁺ stem cells and decreased epithelial proliferation. Interestingly, we find that aged intestinal epithelial cells express an elevated regeneration-associated fetal-like gene expression signature that, in turn, renders these cells more sensitive to IFNγ-induced apoptosis. Our findings reveal an age-related imbalance in the interaction between the immune and epithelial compartments in the colon, priming the system for excessive inflammatory responses and the emergence of a hypersensitive epithelial cell state thus derailing proper repair of the intestinal epithelium after injury.