Gut bacteria enriched in obese mice produce leucic acid to counter obesity through HCAR2

Gut microbiota modulates a wide range of physiological processes in the host. However, whether host genes shape microbial communities to affect host physiology remains poorly explored. Using Aida ^-/- mice that develop obesity due to increased intestinal fat absorption, we identify two Clostridium strains enriched in their fat-depleted gut environment. We demonstrate that the growth of these strains is suppressed by oleate both in vivo and in vitro , mirroring their selective expansion. Paradoxically, these strains protect against diet-induced obesity. Integrated metabolomics and ¹³ C-tracing reveal that these strains biosynthesise leucic acid, whose administration reduces adiposity and enhances lean mass and exercise capacity by suppressing lipid synthesis and promoting catabolism. By combining computational prediction with transcriptomic and human genetic evidence, we identify HCAR2 as a candidate receptor for leucic acid and confirm this by demonstrating direct binding and showing that HCAR2 is required for metabolic effects of leucic acid in vitro and in adipose tissue in vivo . We thus establish a homeostatic host-microbiome feedback loop wherein a host gene-defined metabolic niche selects for microbes that produce a signalling metabolite, which in turn activates a physiologically relevant receptor to suppress obesity.