Microbiota-Derived Metabolites Mediate Immune Regulatory Networks in the Gut-Skin Axis of Psoriasis

Psoriasis is a chronic immune-mediated inflammatory disease affecting 2–3% people globally. Current biologic therapies targeting interleukin-23 and interleukin-17 pathways achieve only partial responses in most patients, highlighting the need for understanding upstream triggers. Emerging evidence implicates gut microbiome dysbiosis as a notable contributor to psoriasis pathogenesis through metabolite-mediated immune regulation. Psoriasis patients exhibit characteristic gut microbial alterations, including depletion of beneficial commensals such as Faecalibacterium prausnitzii and expansion of proinflammatory taxa. These compositional changes are associated with altered profiles of immunomodulatory metabolites, including short-chain fatty acids, tryptophan-derived indole compounds, and secondary bile acids, which promote regulatory T-cell differentiation, enhance immune tolerance through aryl hydrocarbon receptor activation, and modulate metabolic-immunological pathways. Such metabolic alterations may impair regulatory T cell function, promote T helper 17 (Th17) differentiation, compromise intestinal barrier integrity, and influence tissue-resident memory T cells that perpetuate disease chronicity. This process facilitates bacterial product translocation that amplifies inflammation, thereby amplifing relationship is bidirectional; psoriatic skin inflammation reciprocally affects gut homeostasis through circulating inflammatory mediators, systemic immune cell activation, and neuroendocrine stress pathways. Recent clinical evidence demonstrates that biologic therapies normalize gut microbiome composition and reduce trimethylamine N-oxide levels, supporting bidirectional gut-skin communication. These interactions create self-perpetuating cycles, suggesting that therapeutic strategies interrupting this feedback loop may offer novel treatment approaches. This review synthesizes current evidence on metabolite-mediated immune regulatory networks linking gut microbiome dysbiosis to psoriatic inflammation, evaluates clinical trials of microbiome-targeted interventions, and discusses methodological challenges, regulatory considerations, and future research directions for clinical translation. Understanding these mechanisms may inform the development of microbiome-targeted therapeutic approaches.