Microbial 10-oxostearic acid protects mice against colitis via the nuclear receptor PPARα

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 (PPARα). Biochemical and structural analyses reveal that 10-oxoSA binds PPARα with higher affinity than previously identified endogenous ligands. In a mouse model of colitis, 10-oxoSA confers protection in a PPARα-dependent manner. Multi-tissue transcriptomics show that 10-oxoSA upregulates beneficial PPARα 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.