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Background Acyl-homoserine lactones (AHLs) are quorum sensing molecules involved in bacterial communication network and can also have an impact on host’s cells. We recently showed the presence of AHLs in the gut ecosystem and identified one that has never been described: 3-oxo-C12:2. This molecule was decreased in faecal samples of inflammatory bowel disease (IBD) patients, especially during flare, and its absence was correlated to dysbiosis. 3-Oxo-C12:2 is structurally close to an AHL well described and synthesised by P. aeruginosa, 3-oxo-C12. We intent to describe 3-oxo-C12:2 effects on gut inflammation and to identify which signalling pathways are involved. Given its analogous structure to 3-oxo-C12, we hypothesised that 3-oxo-C12:2 can interact with the same cellular partners, in particular a bitter taste receptor, called T2R138, which is a GPCR expressed by immune and epithelial gut cells. Methods To test our hypothesis, we used murine macrophages cell line RAW264.7, stimulated by interferon-γ (IFN-γ; 20 U/ml) and lipopolysaccharide (LPS; 10 ng/ml). Inflammatory response was monitored by measuring cytokine secretion (TFNα, IL-6 and IL-10) via ELISA. Protein expression was assessed by Western blot. Probenecid, a known allosteric inhibitor for T2R138, was used to study T2R138 role in AHL signalling. Cytotoxicity was checked by measuring LDH release. Results In steady state, challenged by 3-oxo-C12:2, RAW264.7 macrophages showed no change in cytokine expression (TNFα, IL-6 and IL-10). After LPS/IFN-γ activation, we observed a decrease in the ratio of secreted TNFα/IL-10 when cells are exposed to 3-oxo-C12:2, in a dose-dependent manner: 15 μM (−30%, p &amp;lt; 0.05), 25 μM (−50%, p &amp;lt; 0.001) and 50 μM (−65%, p &amp;lt; 0.0001). This reflects an anti-inflammatory effect, without increasing cytotoxicity. Those immune-modulatory effects were lost in presence of Probenecid. Moreover, the amount of T2R138 protein was not changed in the presence of Probenecid and/or 3-oxo-C12:2. Therefore, the loss of anti-inflammatory effects with the inhibitor was not due to a decrease of the receptor expression in our experimental conditions. Conclusion 3-Oxo-C12:2 exerts a dose-dependent anti-inflammatory effect on murine immune cells. This response is partly mediated by the bitter taste receptor T2R138. This receptor is a potential target of our AHL. We are currently studying via a multiplex assay the cytokine response after exposing cells to 3-oxo-C12:2. Studying the signalling between the receptor and the anti-inflammatory response would allow us to understand better the inter-kingdom dialogue between microbiota and the host and to what extend AHLs are involved. We are grateful for the FRM for the financial support (ECO201806006843)

P053 3-Oxo-C12:2, a quorum sensing molecule from the human gut, exerts anti-inflammatory effects through a bitter taste receptor