Abstract
Gut microbiota dysbiosis has been implicated in the pathogenesis of irritable bowel syndrome (IBS), a globally prevalent functional gastrointestinal disorder; however, mechanistic insights remain limited. We determined that the bacterium Fusobacterium nucleatum (F. nucleatum) played a pathogenic role in a murine model of IBS. Monocolonization of antibiotic-treated or germ-free mice with F. nucleatum induced IBS-like symptoms, including visceral hypersensitivity, increased fecal water content, and accelerated gastrointestinal transit, accompanied by mast cell activation. These effects were effectively prevented by treatment with the antibiotic metronidazole, as well as by the mast cell depleting agent imatinib or the mast cell stabilizer sodium cromoglicate. Mechanistically, F. nucleatum upregulated the expression of purine nucleoside phosphorylase (PNP) in intestinal epithelial cells (IECs), a key enzyme in the purine degradation pathway. The elevated PNP activity promoted purine degradation and uric acid production in IECs, which in turn directly activated mast cells. This F. nucleatum-driven mast cell activation mediated IBS-like symptoms in ABX treated mice but was abrogated by blocking uric acid synthesis. In summary, our findings highlight the crucial role of purine metabolism reprogramming and low-grade mucosal immune responses in F. nucleatum-mediated IBS-like symptoms in mice, providing promising therapeutic perspectives for targeting F. nucleatum-positive IBS patients.