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Cited by 58Pain Mechanisms and TreatmentsGastrointestinal motility and disordersIon Channels and Receptors

Protease-Mediated Suppression of DRG Neuron Excitability by Commensal Bacteria

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Sessenwein, Jessica L., Baker, Corey C., Pradhananga, Sabindra, Maitland, Megan E., Petrof, Elaine O., Allen-Vercoe, Emma, Noordhof, Curtis, Reed, David E. +2 more·2017·The Journal of Neuroscience
DOI 10.1523/jneurosci.1672-17.2017PMC PMC5707769
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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 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 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. SIGNIFICANCE STATEMENT 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, Faecalibacterium prausnitzii 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.

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  • Serine proteases from a consortium of gut bacteria modulate the excitability of nociceptors via activation of protease-activated receptor 4.

    “serine proteases from a consortium of gut bacteria modulate the excitability of nociceptors via activation of protease-activated receptor 4 (PAR-4).19”

    From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [19]

  • The suppression of DRG neuron excitability by F. prausnitzii supernatant was the result of a cathepsin G-like serine protease that activated neuronal PAR-4.

    “This was the result of a cathepsin G-like serine protease that activated neuronal PAR-4.”

    From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [19]

  • Media supernatant from cultures of F. prausnitzii acted directly on DRG neurons to suppress their excitability due to an increase in voltage-gated K+ conductance.

    “Media supernatant from cultures of F. prausnitzii acted directly on DRG neurons to suppress their excitability due to an increase in voltage-gated K+ conductance.”

    From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [19]

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Authors
Sessenwein, J. L., Baker, C. C., Pradhananga, S., Maitland, M. E., Petrof, E. O., Allen-Vercoe, E., Noordhof, C., Reed, D. E., Vanner, S. J., & Lomax, A. E.
Affiliations
Queen's University (CA)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2017-10-31
Volume
37
Issue
48
Pages
11758-11768
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1672-17.2017
PMC
PMC5707769
OpenAlex
W2766697751
Cited by
58
References
64
Citations by year
2026: 4 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 8 · 2018: 2 · 2016: 1
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R21AI121575, R33AI121575)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
gut microbiota, commensal bacteria, dorsal root ganglion neurons, neuronal excitability, serine protease, cathepsin G, PAR4, Faecalibacterium prausnitzii, visceral pain, capsaicin response, voltage-gated potassium currents, dysbiosis, probiotics
MeSH terms
Gastrointestinal Microbiome, Animals, Ganglia, Spinal, Humans, Male, Mice, Inbred C57BL, Neurons, Peptide Hydrolases, Symbiosis, Mice, Granzymes

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