Azelaic Acid Mediates the Protective Effect of Lactiplantibacillus plantarum F1m against Colitis via PPARγ Activation

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a high recurrence risk. Although probiotics show promise for UC treatment, the underlying mechanisms remain incompletely understood. Herein, we found that Lactiplantibacillus plantarum F1m, isolated from yak yogurt, alleviated dextran sulfate sodium (DSS)-induced colitis in mice, improving symptoms, restoring intestinal barrier function, and alleviating gut microbiota dysbiosis. F1m reversed DSS-induced phylum-level changes by increasing Bacteroidota and decreasing Bacillota, and enriched Faecalibaculum and Akkermansia at the genus level. Mechanistically, F1m suppressed the NF-κB and ERK/MAPK pathways while activating PPARγ signaling. Metabolomics revealed elevated azelaic acid (AzA) levels in F1m-treated mice, positively correlated with the abundances of Bifidobacterium bifidum, Bifidobacterium pluvialisilvae, and Methanobrevibacter smithii. Furthermore, AzA was identified as a microbiota-derived PPARγ ligand, and exogenous AzA alleviated colitis in a PPARγ-dependent manner. Collectively, these findings indicate that F1m enhances AzA production by modulating gut microbiota, thereby protecting against colitis via PPARγ activation.