Unravelling the Gut‐Skin Axis in Chronic Urticaria: Dysbiosis, Metabolites and Immunological Mechanisms

Although the core pathophysiological pathways of chronic urticaria (CU) are increasingly understood, the upstream triggers and factors contributing to disease chronicity remain poorly understood. Emerging evidence suggests that gut microbiota dysbiosis represents a potentially modifiable upstream factor, which has been predominantly investigated in patients with chronic spontaneous urticaria (CSU). Multi-omics and Mendelian randomization studies have provided convergent evidence linking gut dysbiosis to systemic inflammation and mast cell instability. This is characterized primarily by the depletion of short-chain fatty acid (SCFA)-producing taxa (e.g., Faecalibacterium, Roseburia and Bifidobacterium) and the relative enrichment of pro-inflammatory Proteobacteria (particularly Enterobacteriaceae). Mechanistically, these alterations may lower the mast cell activation threshold and promote systemic immune dysregulation through specific metabolic shifts, such as the depletion of SCFAs and unsaturated fatty acids, and the translocation of endotoxins (e.g., lipopolysaccharide) due to compromised intestinal barrier function. In this review, we discuss how the use of Mendelian randomization (MR) and germ-free mouse models can advance the gut-urticaria axis (with a primary focus on CSU) from mere correlation to causation, while highlighting the crucial need to account for clinical confounders. Finally, we evaluate the clinical translational potential and associated challenges of microbiome-targeted interventions (e.g., probiotics, faecal microbiota transplantation) as novel adjuvant therapies.