Protease-Mediated Suppression of DRG Neuron Excitability by Commensal Bacteria.

TitleProtease-Mediated Suppression of DRG Neuron Excitability by Commensal Bacteria.
Publication TypeJournal Article
Year of Publication2017
AuthorsSessenwein JL, Baker CC, Pradhananga S, Maitland ME, Petrof EO, Allen-Vercoe E, Noordhof C, Reed DE, Vanner SJ, Lomax AE
JournalJ Neurosci
Volume37
Issue48
Pagination11758-11768
Date Published2017 Nov 29
ISSN1529-2401
KeywordsAnimals, Ganglia, Spinal, Gastrointestinal Microbiome, Granzymes, Humans, Male, Mice, Mice, Inbred C57BL, Neurons, Peptide Hydrolases, Symbiosis
Abstract

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 μm) 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, 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 gastrointestinal microbiota derived from a human donor signal to DRG neurons. Their secretory products contain serine proteases that suppress excitability via activation of protease-activated receptor-4. Moreover, from this community of commensal microbes, strain 16-6-I 40 fastidious anaerobe agar 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 gastrointestinal diseases associated with pain.

DOI10.1523/JNEUROSCI.1672-17.2017
Alternate JournalJ. Neurosci.
PubMed ID29089436
PubMed Central IDPMC5707769
Grant ListR21 AI121575 / AI / NIAID NIH HHS / United States

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