PPARγ/β/δ Agonists Can Ameliorate Dextran Sodium Sulfate–Induced Colitis and Modulate Gut Microbiota

ABSTRACT Background and Aim Peroxisome proliferator–activated receptors (PPARs), as nuclear receptors, modulate both lipid metabolism and inflammatory/immune processes. This study examines the impact of modulating the activities of the PPAR subtypes PPARβ/ð and PPARγ on the gut microbiota in inflammatory bowel disease (IBD). Methods Mice with dextran sulfate sodium (DSS)–induced acute colitis were treated with the PPARγ agonist pioglitazone, PPARβ/δ agonist GW0742, or their respective antagonists (GW9662, GSK3787). Weight loss, diarrhea severity, hematochezia, and disease activity index were assessed daily. Upon study completion, colon length, histopathology, and mRNA levels of the intestinal barrier and inflammatory markers were measured. Occludin and E‐cadherin levels were assessed via immunofluorescence analysis, and cecal samples underwent 16S rRNA sequencing for gut microbiota analysis. Results Our findings revealed that the agonists pioglitazone and GW0742 effectively suppressed DSS‐induced colitis, improved clinical symptoms, reversed colon shortening, and mitigated histological damage. Conversely, their antagonists, GW9662 and GSK3787, failed to alleviate inflammation and sometimes exacerbated disease indicators. Both agonists modulated DSS‐induced dysbiosis by reducing the abundance of proinflammatory cytokine–associated microbiota, including Bacteroides , Enterococcus , and Escherichia‐Shigella , while enhancing both α‐diversity and β‐diversity of the gut microbiome, to restore equilibrium. Conclusion Our findings reveal that activation of PPARγ and PPARβ/δ can balance the gut microbiota in mice and ameliorate experimental colitis in mice. Thus, PPARγ and PPARβ/δ have protective effects against IBD and could serve as novel therapeutic targets for its treatment.