Butyrate produced by commensal bacteria potentiates phorbol esters induced AP-1 response in human intestinal epithelial cells

PLoS One. 2012;7(12):e52869. doi: 10.1371/journal.pone.0052869. Epub 2012 Dec 27.


The human intestine is a balanced ecosystem well suited for bacterial survival, colonization and growth, which has evolved to be beneficial both for the host and the commensal bacteria. Here, we investigated the effect of bacterial metabolites produced by commensal bacteria on AP-1 signaling pathway, which has a plethora of effects on host physiology. Using intestinal epithelial cell lines, HT-29 and Caco-2, stably transfected with AP-1-dependent luciferase reporter gene, we tested the effect of culture supernatant from 49 commensal strains. We observed that several bacteria were able to activate the AP-1 pathway and this was correlated to the amount of short chain fatty acids (SCFAs) produced. Besides being a major source of energy for epithelial cells, SCFAs have been shown to regulate several signaling pathways in these cells. We show that propionate and butyrate are potent activators of the AP-1 pathway, butyrate being the more efficient of the two. We also observed a strong synergistic activation of AP-1 pathway when using butyrate with PMA, a PKC activator. Moreover, butyrate enhanced the PMA-induced expression of c-fos and ERK1/2 phosphorylation, but not p38 and JNK. In conclusion, we showed that SCFAs especially butyrate regulate the AP-1 signaling pathway, a feature that may contribute to the physiological impact of the gut microbiota on the host. Our results provide support for the involvement of butyrate in modulating the action of PKC in colon cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation / metabolism
  • Butyrates / metabolism*
  • Butyrates / pharmacology
  • Caco-2 Cells
  • Cell Differentiation
  • Cell Proliferation
  • Culture Media, Conditioned
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fatty Acids / metabolism
  • Fatty Acids / pharmacology
  • Gene Expression
  • Gene Expression Regulation
  • Genes, Reporter
  • HT29 Cells
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Hydroxamic Acids / pharmacology
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / microbiology
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • MAP Kinase Signaling System
  • Metagenome
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factor AP-1 / physiology
  • Transcriptional Activation


  • Antigens, Differentiation
  • Butyrates
  • CCND1 protein, human
  • Culture Media, Conditioned
  • Fatty Acids
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Proto-Oncogene Proteins c-fos
  • Transcription Factor AP-1
  • Cyclin D1
  • trichostatin A
  • Luciferases
  • Extracellular Signal-Regulated MAP Kinases
  • Tetradecanoylphorbol Acetate

Grant support

This work was financed by grants from the European Community's Seventh Framework Programme (FP7/2007–2013), MetaHIT, grant agreement HEALTH-F4-2007-201052. M.N. has been supported by the European Marie-Curie Initial Training Network Cross-Talk (grant agreement # 215553). J.D., V.A., and H.B. are partners of the European Marie-Curie Initial Training Network Cross-Talk. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.