**Background:** Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting 2–3% of the population worldwide, with plaque-type psoriasis accounting for over 80% of cases. Its pathogenesis involves genetic predisposition, external triggers (stress, infections, medications, microbiota alterations), and immune dysregulation driven by Th17 and Th1 pathways. Emerging evidence indicates that psoriasis is a systemic disease with compromised skin and gut barriers, leading to increased intestinal permeability, microbial translocation, and systemic inflammation. The gut–skin axis, mediated by microbiota and immune cells, is critical in psoriasis pathogenesis. Biologic therapies targeting TNFα and IL-17 are effective for moderate-to-severe psoriasis but can cause paradoxical adverse events, including new-onset or exacerbation of inflammatory bowel disease (IBD) and psoriasiform skin lesions. This review examines the role of skin and gut microbiota in these paradoxical reactions.
**Methods:** This is a narrative review synthesizing published literature on psoriasis pathogenesis, gut–skin axis, microbiota composition, biologic therapies (anti-TNFα and anti-IL-17), and paradoxical adverse events. The authors discuss findings from human studies, animal models, and clinical trials, focusing on barrier dysfunction, microbiota dysbiosis, immune responses, and treatment outcomes. Key studies cited include those measuring serum markers of intestinal barrier damage (claudin-3, zonulin, I-FABP), microbiota composition analyses (16S rRNA sequencing), and clinical observations of paradoxical reactions.
**Key Results:** Psoriasis patients exhibit impaired skin barrier (lower stratum corneum hydration, higher transepidermal water loss) and gut barrier (elevated serum claudin-3, zonulin, I-FABP). Serum zonulin levels are three times higher in psoriasis patients versus healthy controls, positively correlating with lipopolysaccharide levels, indicating bacterial translocation. Gut microbiota dysbiosis in psoriasis includes increased Actinobacteria, Blautia, Coprococcus, Ruminococcus, Dorea, and decreased Akkermansia muciniphila. Skin microbiota shows altered composition with Proteobacteria dominance in unaffected skin and Actinobacteria/Firmicutes in lesions. Biologic treatment affects microbiota: IL-17 inhibitors (secukinumab) shift gut microbiota toward an IBD-like profile (increased Proteobacteria, decreased Bacteroidota and Firmicutes), while IL-12/23 inhibitors (ustekinumab) increase Coprococcus. Paradoxical skin reactions occur in up to 30% of anti-TNFα-treated patients, with 34% severe enough to discontinue therapy. IBD prevalence in psoriasis is 1–2% (four times higher than general population), and anti-IL-17 therapy can worsen or trigger IBD in <1% of patients. Probiotic interventions show promise: a mixture of Bifidobacterium longum, B. lactis, and Lactobacillus rhamnosus reduced PASI score in 66.7% of patients versus 41.9% placebo, with lower relapse risk at 6 months.
**Clinical Implications:** The gut–skin axis and microbiota are central to psoriasis pathogenesis and treatment outcomes. Biologic therapies, while effective, can induce paradoxical reactions through cytokine imbalance (e.g., increased IFN-α after TNFα inhibition) and microbiota shifts. Personalized medicine is needed, as current approaches lack predictive biomarkers for efficacy or adverse events. Screening for latent IBD (e.g., anti-Saccharomyces cerevisiae antibodies) and avoiding IL-17 inhibitors in patients with active or past IBD is recommended. Probiotics and fecal microbiota transplantation may offer adjunctive benefits, but more research is required. Understanding microbiota–immune interactions could yield biomarkers to predict paradoxical reactions and guide safer, more effective therapy.