Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by immune dysregulation, compromised intestinal barrier integrity, and disruptions in the microbiota-metabolite axis. Current clinical management of UC remains limited, underscoring the need for novel therapeutic approaches. Cellular senescence is increasingly recognized as a significant contributor to the pathogenesis of this disease. Senescent cells promote inflammatory responses via the sustained release of pro-inflammatory mediators such as IL-6, IL-1β, and TNF-α. Conversely, persistent inflammation drives further cellular senescence, establishing a self-amplifying cycle that exacerbates disease progression. Additionally, gut microbiota dysbiosis (reduced Akkermansia abundance) and metabolic abnormalities (disrupted bile acid metabolism) may further compromise intestinal barrier integrity. Cyclosporine A (CsA), a classical immunosuppressant, has unclear mechanisms in UC, particularly regarding its potential effects on senescence and the microbiota-metabolite axis. In this investigation, using a dextran sulfate sodium (DSS)-induced UC model, we demonstrated that CsA significantly alleviated DSS-induced acute colitis in mice and senescence-associated pathological changes. Multi-omics analyses integrating network pharmacology, transcriptomics, metabolomics, and metagenomics demonstrated that CsA likely exerts its therapeutic effects through inhibition of the JAK2-STAT3/NF-κB signaling pathway. This leads to reduced release of pro-inflammatory cytokines, modulation of intestinal microbiota composition and metabolite profiles, and enhanced intestinal barrier function.These findings elucidate new mechanisms by which CsA improves DSS-induced colitis in mice through anti-senescence effects and microbiota-metabolic regulation, providing potential therapeutic targets for UC. • Cyclosporine A (CsA) alleviates ulcerative colitis through anti-senescence effects and regulation of the microbiota-metabolite axis. • CsA can modulate the gut microbiota and inhibit the JAK2-STAT3/NF-κB signaling pathway in dextran sulfate sodium (DSS)-induced colitis. • CsA reduces the levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and senescence-associated pathological changes.
Zhao et al. (Wed,) studied this question.