Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex

Abstract

Butyrate, a short-chain fatty acid produced by the colonic bacterial fermentation is able to induce cell growth inhibition and differentiation in colon cancer cells at least partially through its capacity to inhibit histone deacetylases. Since butyrate is expected to impact cellular metabolic pathways in colon cancer cells, we hypothesize that it could exert its antiproliferative properties by altering cellular metabolism. We show that although Caco2 colon cancer cells oxidized both butyrate and glucose into CO 2 , they displayed a higher oxidation rate with butyrate as substrate than with glucose. Furthermore, butyrate pretreatment led to an increase cell capacity to oxidize butyrate and a decreased capacity to oxidize glucose, suggesting that colon cancer cells, which are initially highly glycolytic, can switch to a butyrate utilizing phenotype, and preferentially oxidize butyrate instead of glucose as energy source to produce acetyl coA. Butyrate pretreated cells displayed a modulation of glutamine metabolism characterized by an increased incorporation of carbons derived from glutamine into lipids and a reduced lactate production. The butyrate-stimulated glutamine utilization is linked to pyruvate dehydrogenase complex since dichloroacetate reverses this effect. Furthermore, butyrate positively regulates gene expression of pyruvate dehydrogenase kinases and this effect involves a hyperacetylation of histones at PDK4 gene promoter level. Our data suggest that butyrate exerts two distinct effects to ensure the regulation of glutamine metabolism: it provides acetyl coA needed for fatty acid synthesis, and it also plays a role in the control of the expression of genes involved in glucose utilization leading to the inactivation of PDC.Epidemiologic studies suggest that environmental factors including nutrients strongly influence the incidence of colon cancer. Dietary fibers found in cereals, vegetables and fruits undergo bacterial fermentation leading to the production of short-chain fatty acids (SCFAs) in the colon lumen. Butyrate is one of the most abundant SCFA and plays a key role in colonic epithelium homeostasis. It is oxidized to acetyl coA in mitochondria and represents the main fuel for normal colonocytes 1,2 as well as for colon cancer cells. 3 In human colon cancer cells, butyrate inhibits cell growth 3-5 and promotes differentiation. 6 Although the underlying mechanisms by which butyrate regulates cell proliferation and/or differentiation are not fully understood, it has been shown that butyrate action could involve various effects on gene expression, which are often attributed to its capacity to act as an inhibitor of histone deacetylases (HDACs). This effect leads to a hyperacetylation of histones and increased accessibility of transcription factors to promoters in the DNA. 7 Moreover, butyrate influences post-traductional modifications including DNA methylation, 8 histone methylation, 9 histone phosphorylation 10 and hyperacetylation of nonhistone proteins. 11 Those diverse effects may explain the i...

The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism

“…In the last few decades, it became apparent that SCFAs might play a key role in the prevention and treatment of the metabolic syndrome, bowel disorders, and certain types of cancer (16)(17)(18)(19)(20)(21)(22). In clinical studies SCFA administration positively infl uenced the treatment of ulcerative colitis, Crohn's disease, and antibiotic-associated diarrhea ( 10,(23)(24)(25)(26)(27).…”

Oxygen metabolism and barrier regulation in the intestinal mucosa

“…In contrast to other SCFAs, very little butyrate is released into portal circulation (78). Butyrate-derived acetyl-CoA is made available for oxidative phosphorylation and becomes a prominent fuel for colonic epithelial cells (80). It was recently revealed by Kelly et al that butyrate increases epithelial O 2 consumption to the extent that cells sense metabolic hypoxia and HIF is stabilized (81).…”

Gut microbiota, the pharmabiotics they produce and host health

“…Indeed, SCFA play a key role in the prevention and treatment of metabolic and bowel disorders and certain types of cancer (124)(125)(126)(127)(128) . The positive influence of SCFA treatment on ulcerative colitis and Crohn's disease have been demonstrated in various clinical studies (129)(130)(131)(132)(133) .…”