Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction.

Luke Alexander Grundy, Andrea M. Harrington, Joel Castro, Sonia Garcia-Caraballo, Annemie Deiteren, Jessica Maddern, Grigori Y. Rychkov, Pei Ge, Stefanie Peters, Robert Feil, Paul Miller, Andre Ghetti, Gerhard Hannig, Caroline B. Kurtz, Inmaculada Silos-Santiago, Stuart M. Brierley

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Abstract

Irritable bowel syndrome (IBS) patients suffer from chronic abdominal pain and extraintestinal comorbidities, including overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome (IC-PBS). Mechanistic understanding of the cause and time course of these comorbid symptoms is lacking, as are clinical treatments. Here, we report that colitis triggers hypersensitivity of colonic afferents, neuroplasticity of spinal cord circuits, and chronic abdominal pain, which persists after inflammation. Subsequently, and in the absence of bladder pathology, colonic hypersensitivity induces persistent hypersensitivity of bladder afferent pathways, resulting in bladder-voiding dysfunction, indicative of OAB/IC-PBS. Daily administration of linaclotide, a guanylate cyclase-C (GC-C) agonist that is restricted to and acts within the gastrointestinal tract, reverses colonic afferent hypersensitivity, reverses neuroplasticity-induced alterations in spinal circuitry, and alleviates chronic abdominal pain in mice. Intriguingly, daily linaclotide administration also reverses persistent bladder afferent hypersensitivity to mechanical and chemical stimuli and restores normal bladder voiding. Linaclotide itself does not inhibit bladder afferents, rather normalization of bladder function by daily linaclotide treatment occurs via indirect inhibition of bladder afferents via reduced nociceptive signaling from the colon. These data support the concepts that cross-organ sensitization underlies the development and maintenance of visceral comorbidities, while pharmaceutical treatments that inhibit colonic afferents may also improve urological symptoms through common sensory pathways.

Original languageEnglish
Article numbere121841
Pages (from-to)1-20
Number of pages21
JournalJCI insight
Volume3
Issue number19
DOIs
Publication statusPublished - 4 Oct 2018

Bibliographical note

Authors associated with a submission are sent an e-mail requesting assignment of copyright to the American Society for Clinical Investigation (ASCI) prior to publication. A CC-BY license can be provided upon request for authors with funding sources that mandate its use (e.g., Wellcome Trust and HHMI), and the ASCI will ensure that these articles are published according to the funding agency’s policy.

All articles published in JCI Insight are freely available from the moment of publication on insight.jci.org.

Keywords

  • Bladder function
  • linaclotide
  • colitis

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    Grundy, L. A., Harrington, A. M., Castro, J., Garcia-Caraballo, S., Deiteren, A., Maddern, J., Rychkov, G. Y., Ge, P., Peters, S., Feil, R., Miller, P., Ghetti, A., Hannig, G., Kurtz, C. B., Silos-Santiago, I., & Brierley, S. M. (2018). Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction. JCI insight, 3(19), 1-20. [e121841]. https://doi.org/10.1172/jci.insight.121841