Gut Microbiota Dysbiosis-driven Bile Acid Dysfunction Alters Keratinocyte Lipid Metabolism via FXR-NQO1 Signaling in Psoriasis

Emerging evidence has shown that microbiota dysbiosis and aberrant bile acid (BA) profiles correlates with disease progression. However, it’s role in psoriasis progression remains unclear. This study elucidates dysregulated BA metabolism in psoriasis patients and imiquimod-treated mice, coupled with increased expression of the farnesoid X receptor (FXR) in keratinocyte. FXR activation with glycochenodeoxycholic acid (GCDCA) ameliorates psoriatic symptoms by enhancing lipid metabolism, particularly fatty acid oxidation. Mechanistically, the FXR-mediated enhancement of antioxidant capacity by upregulating NAD(P)H quinone dehydrogenase 1 (NQO1) expression underlies its regulatory role in lipid metabolism, offering a new insight into FXR’s role in oxidation stress and lipid metabolism. Conversely, keratinocyte-specific FXR ablation exacerbates psoriasis severity. Gut microbiota dysbiosis is further identified as a pivotal contributor to perturbed the profile of BA in psoriasis. These findings establish the gut microbiota-BA-FXR axis as a critical pathway in psoriasis pathogenesis and suggest probiotics/prebiotics as viable therapeutic interventions.