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

Abstract

Fasting enhances small intestinal regeneration after radiation, but the contribution of the gut microbiome to this process remains uncharacterized. We identify <i>Akkermansia muciniphila</i> (<i>AKK</i>) as a key mediator of this response. <i>AKK</i> was enriched in fasted mice and its antibiotic depletion abrogated radioprotection, whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with <i>AKK</i>'s metabolic output. <i>AKK</i>-conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced <i>AKK</i>-dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of primed persister cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including <i>Clu</i>, <i>Olfm4</i>, <i>Lgr5, Ascl2, Lrig1, Sox9, Rnf43, and Axin2.</i> These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister cells for rapid regeneration of the intestinal epithelium following radiation-induced injury.