The gut microbiota as a regulator of intestinal stem-cell fate: bacterial and fungal control of differentiation and regeneration

Abstract

Abstract Intestinal stem cells (ISCs) sustain epithelial homeostasis and regeneration in a niche that is shaped by epithelial, stromal, immune, and microbial inputs. This review examines how bacterial and fungal signals influence ISC activity and epithelial repair through microbial metabolites, immune relays, and epithelial sensing. Bacterial metabolites and structural ligands act through Wnt/β-catenin, AHR, IL-22–STAT3, Hippo–YAP, and related pathways, and the effects vary according to the ligand involved, responding cell type, and tissue state. Evidence for fungi is more limited: some fungal products engage repair-associated pathways, whereas improved barrier function or reduced inflammation have been observed without directly measuring ISC fate. Therefore, we distinguish direct changes in stem-cell self-renewal, lineage allocation, or regenerative state from indirect evidence based on epithelial repair. This evidence-based framework evaluates how multi-kingdom microbial signals may shape intestinal renewal and identifies key mechanistic gaps.