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Protease-mediated suppression of DRG neuron excitability by commensal bacteria.

J Neurosci; 2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-29089436
Peripheral pain signaling reflects a balance of pro and anti-nociceptive influences; the contribution by the gastrointestinal (GI) 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 GI bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse dorsal root ganglion (DRG) neurons. MET-1 reduced the excitability of DRG neurons by significantly increasing rheobase, decreasing responses to capsaicin (2µM) 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 cocktail 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 (PAR)-4, but not PAR-2, blocked the effects of MET-1. Furthermore, recapitulated the effects of MET-1 on excitability of DRG neurons. We conclude that serine proteases derived from commensal bacteria can directly impact the excitability of DRG neurons, through PAR-4 activation. The ability of microbiota-neuronal interactions to modulate afferent signaling suggests that therapies that induce or correct microbial dysbiosis may impact visceral pain. Commercially available probiotics have the potential to modify visceral pain. Here we show that secretory products from GI microbiota derived from a human donor signal to DRG neurons. Their secretory products contain serine proteases that suppress excitability via activation of PAR Moreover, from this community of commensal microbes, strain 16-6-I 40 FAA had the greatest effect. Our study suggests that therapies that induce or correct microbial dysbiosis may affect the excitability of primary afferent neurons, many of which are nociceptive. Furthermore, identification of the bacterial strains capable of suppressing sensory neuron excitability, and their mechanisms of action, may allow therapeutic relief for patients with GI diseases associated with pain.