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

Specific gut microbiota is critically involved in the development of metabolic diseases, particularly obesity. Through studies in diabetic patients and animal models, we identified a novel gut microbe, Romboutsia ilealis, which alleviates obesity and associated metabolic disorders by modulating intestinal lipid absorption, rather than energy expenditure. Notably, 2-oxindole-3-acetic acid (OAA), a key metabolite of R. ilealis, was identified as a crucial regulator for mediating this effect. Mechanistically, biotin-labeled OAA combined with proteomic analysis revealed a direct interaction between OAA and the 26S proteasome subunit PSMD3, which leads to destabilization of the m⁶A-binding protein YTHDF2. Further investigations showed that YTHDF2 suppresses CD36 and FABP2 expression through m⁶A modified Rxrb mRNA, thereby reducing intestinal lipid absorption. In conclusion, our findings reveal a novel mechanism by which R. ilealis and its metabolite OAA modulate obesity-related lipid accumulation through PSMD3-mediated degradation of YTHDF2, highlighting their potential as innovative prebiotic or probiotic therapies for obesity.