Bojan Jevtić, Milica Lazarević, Goran Stegnjaić, Suzana Stanisavljević, Ivan Pilipović, Neda Nikolovski, Zorana Milosavljević, Miljana Momčilović, Ivan Koprivica, Natalija Jonić, Dragica Mićanović, Nataša Radulović, Maša Marković, Ksenija Mirković, Danijela Mišić, Uroš Gašić, Filip Nikolić, Nikola Veselinović, Henrike Körner, Lukas Grimm, Dmitri Lodygin, Alexander Flügel, Graeme Fraser, Tamara Saksida, Mirjana Dimitrijević, Ivana Stojanović, Đorđe Miljković
Short-chain fatty acids (SCFA) protect against central nervous system (CNS) autoimmunity, but the receptor-mediated mechanisms underlying these effects remain poorly understood, limiting their therapeutic exploitation. Here, we show that selective oral activation of free fatty acid receptor 2 (FFAR2) with the synthetic agonist Cpd1 effectively ameliorates established experimental autoimmune encephalomyelitis (EAE), demonstrating therapeutic efficacy after the onset of the autoimmune response. Cpd1 treatment promoted regulatory T cells and type 3 innate lymphoid cells in the intestine while reducing inflammatory infiltration in the CNS, indicating that modulation of intestinal immunity is sufficient to restrain neuroinflammation. Transcriptomic analysis of intestinal CD4⁺ T cells revealed broad suppression of pathways controlling T-cell activation and proliferation. Mechanistically, the therapeutic effects of Cpd1 required interleukin-22 (IL-22), as antibody-mediated IL-22 neutralization abolished disease protection, identifying IL-22 as a key downstream effector of FFAR2 signaling. Together, these findings establish selective FFAR2 agonism as a tractable strategy to therapeutically modulate the gut-CNS immune axis and identify FFAR2 as a promising target for the treatment of multiple sclerosis and other autoimmune diseases.