Chlorella pyrenoidosa-derived extracellular vesicles ameliorate ulcerative colitis through microbiota-mediated AKT/mTOR/ferroptosis pathway

Background: Ulcerative Colitis (UC) is a chronic inflammatory disease characterized by frequent relapses and slow recovery, with a current deficiency in safe and effective therapeutic options. Chlorella pyrenoidosa (CP), a natural green microalga, is abundant in bioactive compounds possessing anti-inflammatory and antioxidant properties. Microalga-derived extracellular vesicles, characterized by their non-destructive isolation process and potential for recyclability, exhibit distinct advantages over those from other plant sources.

Purpose: To investigate the protective effects and underlying mechanisms of CP-derived extracellular vesicles (CPEVs) in dextran sulfate sodium (DSS)-induced UC.

Methods: In this study, CPEVs were successfully isolated and characterized, and their effect on the mitigation of UC was evaluated in the DSS-induced mice model. Furthermore, the core targets associated with gut microbiota metabolites modulated by CPEVs during Ferroptosis and UC pathogenesis were predicted, and the potential signaling pathways were experimentally validated and comprehensively analyzed.

Results: CPEVs were successfully isolated and demonstrated superior gastrointestinal stability, efficient cellular uptake capability, and excellent biocompatibility. In in vivo experiments, oral administration of CPEVs significantly alleviated a series of DSS-induced UC symptoms and restored the disrupted intestinal microecology. Mechanistically, CPEVs may exert protective effects on UC by targeting the Akt/mTOR/Ferroptosis pathway through the gut microbiota affected by CPEVs (CPEVMs).

Conclusion: We demonstrated that CPEVs effectively ameliorate UC, and the modulation of gut microbiota to mediate the Akt/mTOR signaling pathway, thereby enhancing the inhibition of Ferroptosis caused by UC.