Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids

• Published in: Scientific reports Vol. 13; no. 1; p. 2819
• Main Authors: Caetano-Silva, Maria Elisa, Rund, Laurie, Hutchinson, Noah T., Woods, Jeffrey A., Steelman, Andrew J., Johnson, Rodney W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/256/2515; 631/250/371; 631/337/176; Acetic acid; Animals; Anti-Inflammatory Agents; Cecum; Dietary fiber; Dietary Fiber - pharmacology; Digestive system; Epigenetics; Fatty acids; Fatty Acids, Volatile - metabolism; Gastrointestinal tract; Histone deacetylase; Homeostasis; Humanities and Social Sciences; Inflammation; Intestinal microflora; Intestine; Inulin; Inulin - metabolism; Inulin - pharmacology; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Membrane Transport Proteins; Mice; Microbiota; Microglia; Microglia - metabolism; multidisciplinary; Nuclear transport; Portal vein; Science; Science (multidisciplinary); Sequence analysis; Translocation; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• DOI: 10.1038/s41598-022-27086-x
• ISSN: 2045-2322

Microglia play a vital role maintaining brain homeostasis but can also cause persistent neuroinflammation. Short-chain fatty acids (SCFAs) produced by the intestinal microbiota have been suggested to regulate microglia inflammation indirectly by signaling through the gut-brain axis or directly by reaching the brain. The present work evaluated the anti-inflammatory effects of SCFAs on lipopolysaccharide (LPS)-stimulated microglia from mice fed inulin, a soluble fiber that is fermented by intestinal microbiota to produce SCFAs in vivo, and SCFAs applied to primary microglia in vitro. Feeding mice inulin increased SCFAs in the cecum and in plasma collected from the hepatic portal vein. Microglia isolated from mice fed inulin and stimulated with LPS in vitro secreted less tumor necrosis factor α (TNF-α) compared to microglia from mice not given inulin. Additionally, when mice were fed inulin and injected i.p with LPS, the ex vivo secretion of TNF-α by isolated microglia was lower than that secreted by microglia from mice not fed inulin and injected with LPS. Similarly, in vitro treatment of primary microglia with acetate and butyrate either alone or in combination downregulated microglia cytokine production with the effects being additive. SCFAs reduced histone deacetylase activity and nuclear factor-κB nuclear translocation after LPS treatment in vitro. Whereas microglia expression of SCFA receptors Ffar2 or Ffar3 was not detected by single-cell RNA sequencing analysis, the SCFA transporters Mct1 and Mct4 were. Nevertheless, inhibiting monocarboxylate transporters on primary microglia did not interfere with the anti-inflammatory effects of SCFAs, suggesting that if SCFAs produced in the gut regulate microglia directly it is likely through an epigenetic mechanism following diffusion.