FFAR2 activation induces IL-22-dependent intestinal immune responses to suppress CNS autoimmunity.

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.