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Here we show that nucleocytosolic acetyl-CoA deficiency in colon epithelial cells, caused by\n                  <jats:italic>Acly<\/jats:italic>\n                  ablation and bacterial depletion, triggers age-independent, p53-dependent colonic senescence leading to severe systemic inflammation. Acetate supplementation, acetate-producing bacterial transplantation, targeted depletion of senescent cells or treatment with lysine deacetylase inhibitors blocks colonic senescence and inflammatory injury. Spontaneous colonic senescence develops following simultaneous deletion of epithelial\n                  <jats:italic>Acly<\/jats:italic>\n                  and\n                  <jats:italic>Acss2<\/jats:italic>\n                  , confirming that microbe-derived acetate maintains the epithelial acetyl-CoA pool via ACSS2 to avert colonic senescence. Mechanistically, acetyl-CoA deficiency deprives a cohort of mitochondrial and nuclear proteins of acetylation, leading to increased oxidative stress and DNA repair stress that trigger cellular senescence. Among these proteins, ATP5F1A-K161 acetylation and H4-K5\/8 acetylation are required to protect colonic epithelial cells from developing senescence. These observations unveil a previously unknown mechanism that governs colonic senescence.\n                <\/jats:p>","DOI":"10.64898\/2026.05.15.725523","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T18:00:21Z","timestamp":1779213621000},"source":"Crossref","is-referenced-by-count":1,"title":["Gut Microbiota-derived Acetate Safeguards the Colonic Epithelial Acetyl-CoA Reserve to Avert Colonic Senescence"],"prefix":"10.64898","author":[{"given":"Jie","family":"Du","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois, 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