Butyrate Mediates Longevity Of C.elegans By Regulating Acetylation Of Histone H4

Short-chain fatty acid(SCFAs)butyrate,produced by microbial fermentation of dietary fiber in the gut,is involved in various physiological processes.Treatment of exogenous butyrate inhibits insulin resistance and obesity in C57BL/6 mice fed a high-fat diet.In addition,exogenous butyrate addition improves the imbalance of intestinal microbiota in mice induced by high-fat diet,and also increases the abundance of beneficial bacteria,such as Christensenellaceae,Blautia and Lactobacilus.Butyrate improves the production of non-alcoholic steatohepatitis induced by a high-fat diet by up-regulating the expression of glucagon peptide GLP-1.These studies demonstrate that butyrate can improve pathogenesis caused by high-fat diet.In addition,butyrate can extend the lifespan of the nematode Caenorhabditis elegans.However,the mechanism underlying butyrate-mediated life extension in worms is not clear.In this study,we investigated the transcription profiles in worms treated with butyrate.Of these regulayed genes,GO analysis revealed that histone acetylation was significantly enriched,which was probably associated with the action of butyrate as an inhibitor of histone deacetylase.We found that the addition of butyrate exogenously significantly increased the acetylation levels of total histone H4 as well as histone H4K8 ac in worms.Through RNAi screening,we found that the histone deacetylase HDA-3 affected the levels of H4K8 ac.Meanwhile,we found that butyrate supplementation or had-3 RNAi could activate the transcription factor DAF-16 by promoting its nuclear translocation.Further study indicated that butyrate could upregulate the mRNA levels of sir-2.4.Co-IP showed that SIR-2.4 interacted with DAF-16 and reduced DAF-16 acetylation level,leading to its nucleation translocation.In summary,our current study reveal a novel mechanism by which butyrate extends lifespan of worms.Butyrate increases the acetylation level of histone H4K8 by inhibiting HDA-3,resulting in up-regulation of sir-2.4 expression.SIR-2.4 in turn activate DAF-16 by inhbiting DAF-16 acetylation.DAF-16 is involved in lifespan extension in worms.