Abstract Various gut bacteria, including Lactobacillus plantarum , possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo- cis -6, trans -11-octadecadienoic acid (γKetoC), a γ-linolenic acid-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and the LPS-induced production of inflammatory cytokines. The treatment with γKetoC markedly increased the protein level of NRF2, a master transcription factor for antioxidant responses, and the mRNA level of Hmox1 , a target gene of NRF2, in bone marrow-derived dendritic cells (BMDCs). Although γKetoC significantly suppressed the LPS-induced activation of control BMDCs, particularly the secretion of IL-12/23p40, the suppressive effects of γKetoC were reduced in Nrf2 -/- BMDCs. GW9508, an agonist of GPR40/GPR120, inhibited the release of cytokines from LPS-stimulated BMDCs without activating the NRF2 pathway. We evaluated the role of NRF2 in the anti-inflammatory effects of γKetoC in a dextran sodium sulfate-induced colitis model. The oral administration of γKetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6J and Nrf2 +/- (C57BL/6N) mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2 -/- mice even with the administration of γKetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway in γKetoC-mediated anti-inflammatory responses.