Abstract Background Dietary modulation and lipid-based nutritional supplementation have emerged as promising therapeutic strategies in inflammatory bowel disease (IBD). Medium-chain fatty acids (MCFAs), naturally present in coconut oil, palm kernel oil, and dairy products, are associated with antimicrobial and anti-inflammatory properties. We identified a marked elevation of decanoic acid (DA; C10:0), a saturated MCFA, in the plasma of patients with IBD. However, its functional role and underlying mechanisms in IBD remain unclear. Methods We employed DSS-induced murine colitis models to evaluate the therapeutic effect of DA in vivo. To investigate the immunomodulatory mechanism of DA, we conducted functional assays in bone marrow-derived macrophages (BMDMs). Transcriptomic profiling was performed to identify DA-responsive pathways. In addition, neutralizing antibodies, receptor agonists, and a bone marrow chimera model were applied to identify the molecular target of DA and its downstream signaling mechanisms. Results The untargeted metabolomics study revealed a significantly elevated plasma level of DA in IBD patients (n = 157) compared to the healthy controls (n = 53). Functionally, DA exerted potent anti-inflammatory effects in a dose-dependent manner both in vivo and in vitro, including attenuation of DSS-induced colitis and suppression of inflammatory response in LPS-stimulated BMDMs. Transcriptomics analysis revealed broad alterations in immune response pathways. Western blot analysis further validated that DA potently suppresses NFκB activation. Mechanistically, we found that DA directly binds to macrophage-inducible C-type lectin (Mincle) and acts as an inhibitor of Mincle, and disrupts the formation of Mincle/FcRγ/Syk complex, thereby suppressing the downstream activation of NF-κB signaling pathway and inflammatory cytokines production. Mutagenesis studies identified residue R203 in the C-type lectin domain as critical for DA–Mincle interaction. Using bone marrow transplantation, Mincle-neutralizing antibodies, and agonists, we further confirmed Mincle is indispensable for the immunomodulatory effects of DA. Conclusion Our results define decanoic acid as an endogenous antagonist of Mincle and uncover a metabolite-receptor axis that restrains intestinal inflammation. These findings elucidate a new mechanism of immune-metabolic crosstalk in IBD and highlight decanoic acid and the R203-binding interface on Mincle as a promising target for future therapeutic strategies. Conflict of interest: Dr. Tu, Hanxiao: No conflict of interest Huang, Lingjie: No conflict of interest Cao, Qian: No conflict of interest
Tu et al. (Thu,) studied this question.