Abstract
BackgroundButyrate is known as histone deacetylase inhibitor, inducing histone hyperacetylation in vitro and playing a predominant role in the epigenetic regulation of gene expression and cell function. We hypothesized that butyrate, endogenously produced by intestinal microbial fermentation or applied as a nutritional supplement, might cause similar in vivo modifications in the chromatin structure of the hepatocytes, influencing the expression of certain genes and therefore modifying the activity of hepatic microsomal drug-metabolizing cytochrome P450 (CYP) enzymes.MethodsAn animal study was carried out in chicken as a model to investigate the molecular mechanisms of butyrate’s epigenetic actions in the liver. Broiler chicks in the early post-hatch period were treated once daily with orally administered bolus of butyrate following overnight starvation with two different doses (0.25 or 1.25 g/kg body weight per day) for five days. After slaughtering, cell nucleus and microsomal fractions were separated by differential centrifugation from the livers. Histones were isolated from cell nuclei and acetylation of hepatic core histones was screened by western blotting. The activity of CYP2H and CYP3A37, enzymes involved in biotransformation in chicken, was detected by aminopyrine N-demethylation and aniline-hydroxylation assays from the microsomal suspensions.ResultsOrally added butyrate, applied in bolus, had a remarkable impact on nucleosome structure of hepatocytes: independently of the dose, butyrate caused hyperacetylation of histone H2A, but no changes were monitored in the acetylation state of H2B. Intensive hyperacetylation of H3 was induced by the higher administered dose, while the lower dose tended to increase acetylation ratio of H4. In spite of the observed modification in histone acetylation, no significant changes were observed in the hepatic microsomal CYP2H and CYP3A37 activity.ConclusionOrally added butyrate in bolus could cause in vivo hyperacetylation of the hepatic core histones, providing modifications in the epigenetic regulation of cell function. However, these changes did not result in alteration of drug-metabolizing hepatic CYP2H and CYP3A37 enzymes, so there might be no relevant pharmacoepigenetic influences of oral application of butyrate under physiological conditions.
Highlights
Butyrate is known as histone deacetylase inhibitor, inducing histone hyperacetylation in vitro and playing a predominant role in the epigenetic regulation of gene expression and cell function
Acetylation of hepatic core histones Screening of the important acetylation sites of core histones showed that butyrate treatment in bolus at the lower dose (0.25 g/kg body weight (BW)) tended to increase acetylation of histone H2A at lysine 5 (P=0.063), and the higher applied dose (1.25 g/kg BW) caused significant, approximately twofold increase in acetylation (P=0.048) compared to the control group at the same acetylation site of H2A (Figure 1A and Figure 2)
Among the many acetylation sites, in agreement with our results, it was recently described that butyrate induced H3 hyperacetylation first of all at lysine 9, an acetylation site that plays a critical role in the epigenetic regulation of cell function [39]
Summary
Butyrate is known as histone deacetylase inhibitor, inducing histone hyperacetylation in vitro and playing a predominant role in the epigenetic regulation of gene expression and cell function. Endogenously produced by intestinal microbial fermentation or applied as a nutritional supplement, might cause similar in vivo modifications in the chromatin structure of the hepatocytes, influencing the expression of certain genes and modifying the activity of hepatic microsomal drug-metabolizing cytochrome P450 (CYP) enzymes. Due to its numerous beneficial properties improving health and the growth performance of pigs [12] and chickens [13], butyrate is of special interest as a nutritional supplement, especially after the banning of the traditional antibiotical growth promoters in the European Union [14]
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