Protease-Mediated Suppression of DRG Neuron Excitability by Commensal Bacteria

作者：Jessica Sessenwein, Corey C. Baker, Sabindra Pradhananga, Megan E. Maitland, Elaine O. Petrof, Emma Allen‐Vercoe, Curtis Noordhof, David E. Reed, Stephen Vanner, Alan Lomax · 发表于：Journal of Neuroscience · 年份：2017 · DOI：10.1523/jneurosci.1672-17.2017 · 被引用次数：57 · 研究领域：Gastrointestinal motility and disorders、Gut microbiota and health、Pediatric Pain Management Techniques

Peripheral pain signaling reflects a balance of pronociceptive and antinociceptive influences; the contribution by the gastrointestinal microbiota to this balance has received little attention. Disorders, such as inflammatory bowel disease and irritable bowel syndrome, are associated with exaggerated visceral nociceptive actions that may involve altered microbial signaling, particularly given the evidence for bacterial dysbiosis. Thus, we tested whether a community of commensal gastrointestinal bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse DRG neurons. MET-1 reduced the excitability of DRG neurons by significantly increasing rheobase, decreasing responses to capsaicin (2 μ m ) and reducing action potential discharge from colonic afferent nerves. The increase in rheobase was accompanied by an increase in the amplitude of voltage-gated K + currents. A mixture of bacterial protease inhibitors abrogated the effect of MET-1 effects on DRG neuron rheobase. A serine protease inhibitor but not inhibitors of cysteine proteases, acid proteases, metalloproteases, or aminopeptidases abolished the effects of MET-1. The serine protease cathepsin G recapitulated the effects of MET-1 on DRG neurons. Inhibition of protease-activated receptor-4 (PAR-4), but not PAR-2, blocked the effects of MET-1. Furthermore, Faecalibacterium prausnitzii recapitulated the effects of MET-1 on excitability of DRG neurons. We concl...