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

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dc.contributor.authorGrundy, L.
dc.contributor.authorHarrington, A.M.
dc.contributor.authorCastro, J.
dc.contributor.authorGarcia-Caraballo, S.
dc.contributor.authorDeiteren, A.
dc.contributor.authorMaddern, J.
dc.contributor.authorRychkov, G.Y.
dc.contributor.authorGe, P.
dc.contributor.authorPeters, S.
dc.contributor.authorFeil, R.
dc.contributor.authorMiller, P.
dc.contributor.authorGhetti, A.
dc.contributor.authorHannig, G.
dc.contributor.authorKurtz, C.B.
dc.contributor.authorSilos-Santiago, I.
dc.contributor.authorBrierley, S.M.
dc.date.issued2018
dc.description.abstractIrritable 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.
dc.description.statementofresponsibilityLuke Grundy, Andrea M. Harrington, Joel Castro, Sonia Garcia-Caraballo, Annemie Deiteren ... Grigori Y. Rychkov ... at al.
dc.identifier.citationJCI Insight, 2018; 3(19):e121841-1-e121841-20
dc.identifier.doi10.1172/jci.insight.121841
dc.identifier.issn2379-3708
dc.identifier.issn2379-3708
dc.identifier.orcidGrundy, L. [0000-0002-3900-7141]
dc.identifier.orcidHarrington, A.M. [0000-0002-1562-4137]
dc.identifier.orcidCastro, J. [0000-0002-5781-2224]
dc.identifier.orcidRychkov, G.Y. [0000-0002-2788-2977]
dc.identifier.orcidBrierley, S.M. [0000-0002-2527-2905]
dc.identifier.urihttp://hdl.handle.net/2440/117888
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigation
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1126378
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1083480
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1139366
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1140297
dc.relation.granthttp://purl.org/au-research/grants/arc/DE130100223
dc.relation.granthttp://purl.org/au-research/grants/arc/DP180101395
dc.rightsJCI Insight is an open access journal. All research content is freely available immediately upon publication, and all articles published in JCI Insight are deposited in PubMed Central (PMC). Users are allowed to read, download, print, search, or link to the full texts of the articles under the "fair use" limitations of US copyright law.
dc.source.urihttps://doi.org/10.1172/jci.insight.121841
dc.subjectGastroenterology
dc.subjectGuanylate cyclase
dc.subjectNeuroscience
dc.subjectPain
dc.subjectUrology
dc.titleChronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction
dc.typeJournal article
pubs.publication-statusPublished

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