Invariant NKT Cells Functionally Link Microbiota-Induced Butyrate Production and Joint Inflammation

Abstract

Key Points A high-fiber diet attenuates arthritis in a microbiota-dependent manner. Butyrate attenuates arthritis in an iNKT cell–dependent manner. Butyrate inhibits cytokine production of iNKT cells in an HDAC-dependent manner. Emerging evidence indicates that the gut microbiota contributes to the regulation of joint inflammation by modulating the function of immune cells. However, the mechanism by which the microbiota regulates joint inflammation is unclear. To address this, we investigated the effect of the gut microbiota on Ab-induced arthritis (AIA). Feeding mice a high-fiber diet attenuated AIA in a microbiota-dependent manner. Among the short-chain fatty acids produced by the microbiota, butyrate suppressed cytokine production by invariant NKT (iNKT) cells by inhibiting class I histone deacetylases. Furthermore, butyrate alleviated AIA in wild-type, but not iNKT cell–deficient Jα18 knockout (KO), mice. Adoptive transfer of butyrate-pretreated iNKT cells had no effect on AIA in Jα18 KO mice, whereas transfer of untreated iNKT cells into Jα18 KO mice restored AIA. In conclusion, our data indicate that gut microbiota–induced butyrate production attenuates AIA by inhibiting cytokine production by iNKT cells. Thus, the microbiota/butyrate/iNKT cell axis may be a therapeutic target for joint inflammation.