A Cardiolipin from Muribaculum intestinale Induces Antigen-Specific Cytokine Responses

• DOI: 10.1021/jacs.3c09734
• Publication Date: 2023-10-23T18:35:16Z
• Authors: Sunghee Bang; Yern-Hyerk Shin; Xiao Ma; Sung-Moo Park; Daniel B. Graham; Ramnik J. Xavier; Jon Clardy
• Keywords: Mammals; Mice; Toll-Like Receptor 6; Cardiolipins; Bacteroidetes; Animals; Cytokines

An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect identified Muribaculum intestinale as one of only two members with an oversized effect on T-cell populations. Here we report the identification and characterization of a lipid, MiCL-1, as the responsible metabolite. MiCL-1 is an 18:1-16:0 cardiolipin, whose close relatives are found on concave lipid surfaces of both mammals and bacteria. MiCL-1 was synthesized to confirm the structural analysis and functionally characterized in cell-based assays. It has a highly restrictive structure-activity profile, as its chain-switched analog fails to induce responses in any of our assays. MiCL-1 robustly induces the production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-23, but has no detectable effect on the anti-inflammatory cytokine IL-10. As is the case with other recently discovered immunomodulatory lipids, MiCL-1 requires functional TLR2 and TLR1 but not TLR6 in cell-based assays.