Abstact

Interactions between the host, diet and intestinal microbiota are critical for metabolic and immune homeostasis, but the intersecting metabolites and receptors remain poorly defined. Here we identify 10-oxostearic acid (10-oxoSA), a microbial metabolite derived from oleic acid, the most abundant fatty acid in nature, as a potent and selective agonist of the lipid-sensing nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Biochemical and structural analyses reveal that 10-oxoSA binds PPARalpha with higher affinity than previously identified endogenous ligands. In a mouse model of colitis, 10-oxoSA confers protection in a PPARalpha-dependent manner. Multi-tissue transcriptomics show that 10-oxoSA upregulates beneficial PPARalpha target genes in the ileum and colon, many in previously unrecognized pathways, while also circumventing deleterious hepatic responses. Multi-omics analyses also show that prolonged oral 10-oxoSA administration is well tolerated in the gut and liver with minimal impact on gut microbiota composition. These findings establish a natural diet-microbiota-host axis with potential for anti-inflammatory interventions.