Methyl indole-3-acetate contributes to strain-specific anti-inflammatory effects of Lactiplantibacillus plantarum

Lactiplantibacillus plantarum is a widely recognized probiotic with anti-inflammatory potential, yet its efficacy varies among strains and the underlying determinants remain poorly defined. Here, we identify methyl indole-3-acetate (MIA), a previously uncharacterized microbial metabolite, as a contributor to the strain-specific anti-inflammatory effects of L. plantarum . Strains with higher MIA production show stronger protection against colitis in mice, whereas deletion of the key biosynthetic enzyme eliminates this protective effect. Mechanistically, MIA epigenetically activates the transcription of lncRNA Snhg9 by promoting histone H4K8 acetylation at its promoter, an effect mediated through direct inhibition of HDAC1. In turn, Snhg9 suppresses NF-κB signaling by enhancing the deacetylase activity of SIRT1, thereby attenuating inflammatory responses. Together, our findings support a role for MIA in shaping strain-dependent host responses to L. plantarum , uncover a lncRNA-mediated host–microbe regulatory pathway, and provide a framework for further investigation of strain-specific probiotic function in inflammatory disorders.