AUTHOR=Ando Miki , Nagata Kazuki , Takeshita Ryuki , Ito Naoto , Noguchi Sakura , Minamikawa Natsuki , Kodama Naoki , Yamamoto Asuka , Yashiro Takuya , Hachisu Masakazu , Ichihara Gaku , Kishino Shigenobu , Yamamoto Masayuki , Ogawa Jun , Nishiyama Chiharu 

TITLE=The gut lactic acid bacteria metabolite, 10-oxo-cis-6,trans-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1374425

DOI=10.3389/fimmu.2024.1374425

ISSN=1664-3224

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-11octadecadienoic acid (KetoC), a -linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with KetoC significantly suppressed proliferation of CD4 + T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c + cells isolated from the spleen. KetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further in vitro experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of KetoC on DCs. We also found that KetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of KetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in Nrf2 -/-BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of KetoC in a dextran sodium sulfate-induced colitis model. The oral administration of KetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and Nrf2 +/-mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2 -/-mice even with the administration of KetoC.  Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in KetoC-mediated anti-inflammatory responses.