The role of short-chain fatty acids in health and disease

Adv Immunol. 2014:121:91-119. doi: 10.1016/B978-0-12-800100-4.00003-9.


There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.

Keywords: Fiber; G-protein-coupled receptor; Histone deacetylases; Microbiota; Short-chain fatty acids.

Publication types

  • Review

MeSH terms

  • Animals
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Cytokines / physiology
  • Fatty Acids, Volatile / biosynthesis
  • Fatty Acids, Volatile / physiology*
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / prevention & control
  • Microbiota / immunology
  • Microbiota / physiology
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Nicotinic / metabolism
  • Signal Transduction / immunology
  • Substrate Specificity / immunology


  • Cytokines
  • FFAR3 protein, human
  • Fatty Acids, Volatile
  • HCAR2 protein, human
  • Histone Deacetylase Inhibitors
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic