Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by sustained mucosal inflammation, disrupted epithelial barrier function, microbial dysbiosis, and impaired intestinal homeostasis. If chronic uncontrolled inflammation persists, it may lead to the development of colorectal cancer or other severe clinical complications. Emerging evidence suggests that cellular senescence promotes inflammatory cascades, aggravating UC symptoms and implicating a pathophysiological link to disease progression. Our previous studies have demonstrated that the anti-senescence compound Valnemulin (VAL) can mitigate colonic senescence and alleviate UC symptoms. In this study, subsequent integrative metagenomic and metabolomic analyses revealed that VAL's pharmacological mechanism involves restructuring the gut microbial community composition, enhancing the colonization abundance of beneficial bacteria, and thereby promoting the production of their key metabolites, which collectively contribute to UC remission. In vitro and in vivo studies demonstrated that VAL's anti-senescence effects are mediated by Neobavaisoflavone (NBIF), a functional metabolite produced by beneficial gut bacteria. NBIF effectively activates the AMP-activated protein kinase (AMPK) pathway, significantly reducing the expression levels of senescence marker proteins p16, p53, and p21. Consequently, this mechanism ameliorates the senescent phenotype in intestinal epithelial cells and contributes to the overall improvement of colonic tissue senescence in UC pathology. Concomitantly, NBIF also reduces levels of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, thereby attenuating DSS-induced pathological damage in UC. This study not only proposes a novel anti-senescence strategy for UC treatment but also elucidates the pivotal role of the gut microbiota-metabolite-AMPK axis in regulating intestinal inflammation.
