Short-, medium-, versus long-chain fatty acids: mechanisms of immunomodulation and disease pathogenesis

Fatty acids, such as short-chain fatty acids, medium-chain fatty acids and long-chain fatty acids, exist in different chain lengths and with various modifications, which determine their physical, metabolic and biological properties. They serve as important nutrients in energy production via mitochondrial beta-oxidation in various cell types including immune cells. At optimal levels in the body, fatty acids support normal differentiation and function of immune cells. However, at excessive levels, they can cause dysregulation of immune cells and inflammation. The three types of fatty acids regulate cells, in part, via the activation of G protein-coupled receptors, such as GPR41, GPR43, GPR109A, and Olfr78 for short-chain, GPR40 and GPR120 for both medium- and long-chain fatty acids, and GPR84 for medium-chain fatty acids. Activation of these receptors by fatty acids regulates cell proliferation and cell-specific functions. Importantly, fatty acids induce the production of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide through activation of G-protein coupled receptors. Short-chain fatty acids additionally control epigenetic regulators such as histone deacetylases and histone acetyltransferases. Saturated long-chain fatty acids and omega-6 polyunsaturated fatty acids are implicated in metabolic diseases and inflammatory conditions, whereas short-chain fatty acids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids are generally associated with functional immunity with anti-inflammatory effects. This article explores how fatty acids regulate the immune system, focusing on their common and unique roles, as well as their opposing functions.