Fasting primes small intestinal regeneration after damage via a microbiome-metabolite-chromatin axis

Fasting protects the small intestine epithelial cells from high-dose radiation injury, yet the mechanisms linking fasting to epithelial regeneration remain incompletely understood. Akkermansia muciniphila (AKK) is both necessary and sufficient for fasting-induced radioprotection. Selective depletion of AKK abolishes fasting-mediated preservation of SI stem cells, while recolonization restores epithelial integrity and survival. AKK produces the short-chain fatty acid propionate, which, together with host-derived β-hydroxybutyrate (β-OHB), induces histone H3 acetylation (H3K27ac, H3K9ac) and β-hydroxybutyrylation (H3K9bhb) in crypt epithelial cells, remodeling enhancer–promoter landscapes. CUT&Tag and single-cell ATAC-seq analyses show that fasting, in an AKK-dependent manner, expands a Clu⁺Olfm4⁺ “revival” stem cell (persister cells) population enriched for HNF, FOXA, GATA and KLF transcription factor motifs, establishing a pro-regenerative chromatin state that persists through injury-repair phases. CTCF and BORIS activities persist, suggesting a role in maintaining epigenetic memory for intestinal regeneration after radiation. This microbiota–metabolite–chromatin axis primes persister cells for rapid regeneration after damage and offers a strategy to protect normal tissues during radiation therapy.