Cyclosporine A ameliorates ulcerative colitis by inhibiting cellular senescence, modulating the JAK2-STAT3/NF-κB signaling pathway, and regulating the gut microbiota-metabolite axis.

CsA significantly alleviated DSS-induced acute colitis in mice as demonstrated using a dextran sulfate sodium (DSS)-induced UC model.

• The study used a DSS-induced UC mouse model to evaluate CsA therapeutic effects.
• CsA treatment reduced colitis-associated pathological changes in the colon.
• Disease activity index and histological scoring were used to assess colitis severity.
• CsA treatment showed significant improvement in macroscopic and microscopic colitis parameters compared to DSS-only controls.

CsA ameliorated senescence-associated pathological changes in DSS-induced colitis.

• Cellular senescence was identified as a significant contributor to UC pathogenesis in this model.
• Senescent cells promote inflammatory responses via sustained release of pro-inflammatory mediators including IL-6, IL-1β, and TNF-α.
• CsA treatment reduced markers of cellular senescence in colonic tissue.
• Persistent inflammation was found to drive further cellular senescence, establishing a self-amplifying cycle that CsA helped break.

CsA exerts therapeutic effects through inhibition of the JAK2-STAT3/NF-κB signaling pathway.

• Multi-omics analyses integrating network pharmacology, transcriptomics, metabolomics, and metagenomics identified JAK2-STAT3/NF-κB as the primary signaling pathway modulated by CsA.
• Inhibition of JAK2-STAT3/NF-κB led to reduced release of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α.
• Network pharmacology analysis was used to predict and confirm molecular targets of CsA in UC.
• Transcriptomic analysis confirmed downregulation of JAK2-STAT3/NF-κB pathway genes following CsA treatment.

CsA modulated intestinal microbiota composition, including effects on Akkermansia abundance.

• Gut microbiota dysbiosis characterized by reduced Akkermansia abundance was observed in DSS-induced colitis.
• Metagenomic analysis was used to assess gut microbiota composition changes.
• CsA treatment modulated intestinal microbiota composition compared to DSS controls.
• Changes in Akkermansia abundance were associated with compromised intestinal barrier integrity in the disease model.

CsA regulated metabolite profiles including bile acid metabolism in DSS-induced colitis mice.

• Metabolomic analysis identified disrupted bile acid metabolism as a feature of DSS-induced colitis.
• CsA treatment modulated metabolite profiles, including normalization of bile acid metabolic abnormalities.
• Disrupted bile acid metabolism was identified as a factor that may further compromise intestinal barrier integrity.
• The gut microbiota-metabolite axis was identified as a key mechanism through which CsA exerts therapeutic effects.

CsA enhanced intestinal barrier function in the DSS-induced colitis model.

• Compromised intestinal barrier integrity is a key characteristic of UC involving immune dysregulation and microbiota-metabolite axis disruption.
• CsA treatment led to enhanced intestinal barrier function as part of its multi-mechanistic therapeutic action.
• Intestinal barrier improvement was associated with both anti-inflammatory effects and microbiota-metabolic regulation.
• The study identified intestinal barrier enhancement as a downstream consequence of JAK2-STAT3/NF-κB pathway inhibition by CsA.

Multi-omics integration revealed new mechanisms by which CsA improves DSS-induced colitis through anti-senescence effects and microbiota-metabolic regulation.

• The study integrated network pharmacology, transcriptomics, metabolomics, and metagenomics analyses.
• Prior mechanisms of CsA in UC were described as unclear, particularly regarding senescence and microbiota-metabolite axis effects.
• The anti-senescence mechanism of CsA in UC represents a newly elucidated therapeutic pathway.
• These findings provide potential therapeutic targets for UC beyond the classical immunosuppressive mechanisms of CsA.