Fusobacterium nucleatum plays a pathogenic role in a murine model of irritable bowel syndrome by modulating intestinal purine metabolism and promoting mast cell activation.

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.

• Both antibiotic-treated (ABX) mice and germ-free mice were used as models for monocolonization with F. nucleatum.
• IBS-like symptoms were accompanied by mast cell activation in colonized animals.
• The model replicated the key hallmarks of IBS including visceral hypersensitivity, stool consistency changes, and altered motility.

F. nucleatum-induced IBS-like symptoms were effectively prevented by treatment with metronidazole, the mast cell depleting agent imatinib, or the mast cell stabilizer sodium cromoglicate.

• Metronidazole, an antibiotic targeting anaerobic bacteria including F. nucleatum, prevented symptom development.
• Imatinib was used as a mast cell depleting agent and blocked IBS-like symptoms.
• Sodium cromoglicate, a mast cell stabilizer, also effectively prevented the F. nucleatum-induced symptoms.
• These interventions collectively implicate mast cell activation as a key downstream mediator of F. nucleatum pathogenesis.

F. nucleatum upregulated the expression of purine nucleoside phosphorylase (PNP) in intestinal epithelial cells (IECs), a key enzyme in the purine degradation pathway.

• PNP is described as 'a key enzyme in the purine degradation pathway.'
• The upregulation of PNP occurred specifically in intestinal epithelial cells (IECs).
• This represented a reprogramming of intestinal purine metabolism driven by F. nucleatum colonization.

Elevated PNP activity in IECs promoted purine degradation and uric acid production, which directly activated mast cells.

• Increased PNP activity led to enhanced purine degradation within intestinal epithelial cells.
• The downstream product of this enhanced purine catabolism was increased uric acid production in IECs.
• Uric acid produced by this pathway directly activated mast cells.
• Blocking uric acid synthesis abrogated the F. nucleatum-driven mast cell activation in ABX-treated mice.

F. nucleatum-driven mast cell activation mediated IBS-like symptoms in ABX-treated mice, and this was abrogated by blocking uric acid synthesis.

• Blocking uric acid synthesis was sufficient to prevent mast cell activation downstream of F. nucleatum colonization.
• The causal chain identified was: F. nucleatum → PNP upregulation → purine degradation → uric acid production → mast cell activation → IBS-like symptoms.
• This finding identifies uric acid synthesis as a potential therapeutic target in F. nucleatum-positive IBS patients.

The study implicates purine metabolism reprogramming and low-grade mucosal immune responses as crucial mechanisms in F. nucleatum-mediated IBS-like symptoms in mice.

• The authors describe the mechanism as involving 'purine metabolism reprogramming and low-grade mucosal immune responses.'
• The findings provide 'promising therapeutic perspectives for targeting F. nucleatum-positive IBS patients.'
• The study used both antibiotic-treated and germ-free mouse models to establish the pathogenic role of F. nucleatum.