Romboutsia ilealis related metabolite OAA controls obesity and lipid metabolism through PSMD3-mediated degradation of YTHDF2.

Specific gut microbes are critically involved in the development of metabolic diseases, particularly obesity. Here, through analyses of diabetic patients and animal models, we identified Romboutsia ilealis as a novel gut bacterium that alleviates obesity and associated metabolic disorders by suppressing intestinal lipid absorption rather than altering energy expenditure. Metabolomic profiling revealed 2-oxoindole-3-acetate (OAA) as a key mediator of this effect, which was validated both in vitro and in vivo. Mechanistically, biotin-labeled OAA pull-down coupled with proteomics in the intestinal IPEC-J2 cells identified a direct interaction between OAA and the 26S proteasome subunit PSMD3, leading to destabilization of the m6A-binding protein YTHDF2. Loss of YTHDF2 derepressed Rxrb mRNA, increasing CD36 and FABP2 expression and thereby promoting intestinal lipid absorption. Together, our findings uncover a previously unrecognized R. ilealis-OAA-PSMD3-YTHDF2-Rxrb signaling axis that links the gut microbiota to host metabolism, and highlight R. ilealis and OAA as potent next-generation probiotic or metabolite-based therapies for obesity.