The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages

Immunity. 2019 Feb 19;50(2):432-445.e7. doi: 10.1016/j.immuni.2018.12.018. Epub 2019 Jan 23.


Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response. Butyrate drove this monocyte to macrophage differentiation program through histone deacetylase 3 (HDAC3) inhibition. Administration of butyrate induced antimicrobial activity in intestinal macrophages in vivo and increased resistance to enteropathogens. Our data suggest that (1) increased intestinal butyrate might represent a strategy to bolster host defense without tissue damaging inflammation and (2) that pharmacological HDAC3 inhibition might drive selective macrophage functions toward antimicrobial host defense.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / pharmacology*
  • Butyrates / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Colon / drug effects
  • Colon / metabolism
  • Colon / microbiology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dysbiosis / microbiology
  • Gene Expression Regulation / drug effects
  • Humans
  • Intestines / drug effects
  • Intestines / microbiology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice, Inbred C57BL
  • Microbiota / drug effects
  • Microbiota / physiology
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Monocytes / microbiology


  • Anti-Infective Agents
  • Butyrates
  • Cytokines