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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\u207a 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.<\/jats:p>","DOI":"10.1038\/s44321-026-00517-2","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T16:15:13Z","timestamp":1788452113000},"page":"4090-4116","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FFAR2 activation induces IL-22-dependent intestinal immune responses to suppress CNS 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The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}