Parabacteroides distasonis-derived extracellular vesicles alleviate ulcerative colitis by regulating tryptophan metabolism to activates AhR

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by impaired intestinal barrier function. Previous studies have indicated that Parabacteroides distasonis ( P. distasonis ) exerts a protective effect in experimental models of colitis. However, the therapeutic application of live bacteria is often hampered by inconsistent efficacy and potential safety issues. In this study, we isolated extracellular vesicles from P. distasonis (PDEV) and investigated their therapeutic potential. We provide the first demonstration that PDEV administration ameliorates disease severity in DSS-induced colitis models. Mechanistically, PDEV modulates the gut microbiota composition and host tryptophan metabolism, resulting in the accumulation of specific indole derivatives within the intestine lumen. Notably, these accumulated indole derivatives, such as indole-3-carboxaldehyde (I3A) and indole-3-propionic acid (IPA), are potent aryl hydrocarbon receptor (AhR) ligands. PDEV-induced activation of AhR was found to be crucial for the protection of the intestinal barrier against DSS-induced damage. Collectively, our results demonstrate that PDEV attenuates colitis progression primarily by enhancing AhR activation. In conclusion, our findings establish PDEV as a novel and promising biotherapeutic strategy for the management of ulcerative colitis. • PDEV alleviates inflammation, restores intestinal barrier integrity, and reverses DSS-induced ulcerative colitis (UC). • PDEV regulates the gut microbiota composition and associated metabolic profile. • PDEV upregulates aryl hydrocarbon receptor (AhR) signaling via increased tryptophan metabolites indole-3-aldehyde (I3A) and indole-3-propionic acid (IPA). • AhR activation mediates PDEV-induced restoration of the intestinal barrier, revealing a key protective mechanism.