A Common Mechanism Links Activities of Butyrate in the Colon

Abstract

Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of the activity of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation), demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

Class I histone deacetylases (HDAC1–3) are histone lysine delactylases

“…This epigenetic mechanism has also been attributed to L- and D-lactate ( 66 ) and to β-hydroxybutyrate ( 67 ). However, the concentrations necessary for achieving HDAC inhibition by these hydroxylated species are in the high millimolar range (~100-fold higher than that of n -butyrate) and often lead to minor changes in acetylation ( 66 , 68 , 69 ). Alternatively, dynamic covalent modification of histones by L-lactyl–CoA and other activated acyl groups may explain their regulatory effects at physiological concentration.…”

The Anti-colitis Effect of Schisandra chinensis Polysaccharide Is Associated With the Regulation of the Composition and Metabolism of Gut Microbiota

“…It was found that butyric acid can also activate GPR to affect the activation of inflammatory factors such as IL-1 and IL-6, inhibit the expression of other inflammatory factors, and promote the secretion of intestinal antimicrobial peptides and the apoptosis of T cells (Aguilar et al, 2014;Ran et al, 2018). Two biological activities of butyric acid in the colon (inhibition of proliferation of colonic epithelial stem cells and inflammation) are related to the inhibition of histone deacetylase activity (Verma et al, 2018). In addition, butyric acid, as a histone deacetylase inhibitor, enhances the intestinal mucosal immune response in the proliferation and differentiation of T and B lymphocytes (Park et al, 2015;Kim et al, 2016), which may be related to butyric acid driving the differentiation and function of macrophages, increasing the expression of antimicrobial peptides and enhancing the bacteriostatic ability after bacteriostatic ability after inhibiting histone deacetylase-3 (Schulthess et al, 2019).…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…55 Second, butyrate is well recognized as a histone deacetylase (HDAC) inhibitor, and the suppressive effect of butyrate on HDAC occurs in part by tightly binding to Zn 2+ in the active site of HDAC. 56 Butyrate increases the acetylation of histone H3 at the Foxp3 promoter and at the enhancer conserved noncoding sequence 1 (CNS1), ultimately eliciting robust gene expression and functional maturation. 57,58 Butyrate derived from commensal bacteria Clostridium exerts epigenetic control over transforming growth factor β (TGF-β) in intestinal epithelial cells (IECs), a process mediated by its HDAC-inhibitory activity and through transcription factor specific protein binding on the core promoter, which drives TGF-β1 expression in IECs and the subsequent convergence of Treg cells in the intestine.…”