Isolation, Identification, and Characterization of a Serine Protease with Anti-nociceptive Activity from the Gut Bacterium, Faecalibacterium prausnitzii

Inflammatory bowel disease (IBD) induces hyperexcitability in dorsal root ganglion (DRG) nociceptors, which contributes to abdominal pain. Proteases modulate the excitability of nociceptive neurons via activation of cell-surface protease-activated receptors. Recent findings indicate that serine proteases from Faecalibacterium prausnitzii, a bacterial strain found in the colonic microbiota of healthy individuals, can directly signal to the DRG neurons and reduce excitability, which may suppress abdominal pain. Herein we identify an anti-nociceptive serine protease from F. prausnitzii by heterologous expression and purification of multiple putative anti-nociceptive serine proteases followed by clamp electrophysiology experiments. A single serine protease, Clp-fp, from F. prausnitzii reduced DRG neuronal excitability via activation of protease-activated receptor-4, thereby recapitulating the effect of F. prausnitzii culture supernatants. The identification and characterization of a potentially analgesic serine protease from a commensal gut bacterium makes possible the further exploration of new treatments for IBD-related abdominal pain.