Inorganic Polyphosphate Relieves Ulcerative Colitis by Modulating the Gut Microbiota and Metabolites

Ulcerative colitis (UC) poses a significant therapeutic challenge due to its complex pathogenesis and limited treatment efficacy. Restoring gut microbiota homeostasis is a critical strategy, given its profound influence on immunity and metabolic dysregulation in UC. This study demonstrates the therapeutic potential of inorganic polyphosphate (polyP) in ameliorating UC by modulating gut microbiota and metabolites. In vivo experiments demonstrate that polyP administration alleviates colitis pathology, reduces proinflammatory cytokines (IL-1β, TNF-α), and reinforces intestinal barrier integrity. PolyP restructures microbial communities by enriching probiotics (Ruminococcaceae, Butyricicoccus, Harryflintia) while depleting Parasutterella. Concurrently, it reprograms metabolomic profiles, elevating barrier-repairing metabolites─notably indoleacetaldehyde (IAAld). These findings establish polyP as a microbiota-modulating therapeutic agent for UC, highlighting its role in modeling host-microbiota-metabolite interactions for gut homeostasis.