Inflammation-induced epigenetic imprinting regulates intestinal stem cells

It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges. [Display omitted] •Inflammation from GI GVHD alters ISCs after Allo-HSCT•ISCs show succinate accumulation•Succinate regulates DNA methylation and reprograms its epigenome•The epigenetic changes linger and alter ISC regeneration capacity Zhao et al. demonstrate that exposure to T cell-mediated inflammation changes the metabolism of Lgr5+ intestinal stem cells (ISCs). The metabolic alteration increases succinate in the ISCs and reprograms their epigenome by regulating DNA methylation. The changes in ISC DNA methylation affect the function of ISCs, and these effects linger in vitro and in vivo, despite the absence of the initial inflammation.