From inflammation to regeneration: immune control of intestinal stem cell state transitions

The intestinal epithelium is continuously exposed to microbial and inflammatory perturbations yet retains a remarkable capacity to restore tissue integrity after injury. Traditionally, this regenerative ability has been attributed largely to the survival and proliferative recovery of LGR5 + intestinal stem cells (ISCs). Emerging evidence instead reveals regeneration as a dynamic state-transition process in which stemness is redistributed across a plastic epithelial compartment and immune signals actively shape the entry, maintenance and resolution of injury-adapted states. In this Review, we discuss how inflammation reshapes ISC identity and distinguish permissive immune functions that preserve regenerative competence from instructive signals that actively redirect epithelial cell state. We highlight macrophage-derived regenerative cues, lymphoid cytokine networks and epithelial innate immune sensing, and examine how these extracellular signals are integrated through TGFβ–Hippo–YAP/TAZ–SOX9, JAK–STAT and related regulatory modules. We further consider how chromatin state, metabolism and tissue mechanics determine regenerative competence, how fetal-like, revival and wound-associated programmes are terminated, and how inflammatory experience can persist as epithelial memory or durable post-inflammatory niche remodelling. Failure to appropriately enter, sustain or exit regenerative states provides a unifying framework for understanding chronic intestinal inflammation, defective mucosal healing and inflammation-associated tumorigenesis. We propose that intestinal regeneration is best viewed as an immune-regulated, context- and history-dependent trajectory rather than a simple return to a fixed stem-cell state. This framework provides a conceptual basis for what we term ‘precision mucosal regeneration’, a proposed treatment-design framework aimed at guiding the injured intestine through appropriate regenerative states while ensuring their timely resolution.