A Common Mechanism Links Activities of Butyrate in the Colon

Abstract

Two\nbiological activities of butyrate in the colon (suppression\nof proliferation of colonic epithelial stem cells and inflammation)\ncorrelate with inhibition of the activity of histone deacetylases.\nCellular and biochemical studies of molecules similar in structure\nto butyrate, but different in molecular details (functional groups,\nchain-length, deuteration, oxidation level, fluorination, or degree\nof unsaturation), demonstrated that these activities were sensitive\nto molecular structure, and were compatible with the hypothesis that\nbutyrate acts by binding to the Zn<sup>2+</sup> in the catalytic site\nof histone deacetylases. Structure–activity relationships drawn\nfrom a set of 36 compounds offer a starting point for the design of\nnew compounds targeting the inhibition of histone deacetylases. The\nobservation that butyrate was more potent than other short-chain fatty\nacids is compatible with the hypothesis that crypts evolved (at least\nin part), to separate stem cells at the base of crypts from butyrate\nproduced by commensal bacteria.