Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction
Luke 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
Luke 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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Research Article Gastroenterology Neuroscience

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

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.

Authors

Luke 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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Figure 1

Chronic oral administration of linaclotide reduces colonic nociception and reverses chronic visceral hypersensitivity.

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Chronic oral administration of linaclotide reduces colonic nociception a...
(A) Chronic visceral hypersensitivity (CVH) mice have enhanced visceromotor responses (VMRs) to colorectal distension (CRD) compared with those of control mice (**P < 0.01). (B) Control mice orally administered linaclotide (3 μg/kg once daily for 14 days) show no difference in their VMR to CRD relative to vehicle-treated control mice. (C) CVH mice treated with chronic linaclotide (starting 14 days after intracolonic TNBS) display reduced VMRs relative to vehicle-treated CVH mice (*P < 0.05, **P < 0.01). The dashed line indicates the mean responses from controls. (D) Electromyographic (EMG) recordings of VMRs (20–80 mmHg, 20-second duration, 4-minute intervals) in control and CVH mice orally administered vehicle or linaclotide (3 μg/kg) once daily for 14 days. (E) Ex vivo single-fiber recordings of colonic nociceptors from linaclotide-treated control mice show reduced firing in response to higher forces of mechanical stimuli compared with vehicle-treated control mice (**P < 0.01). (F) Ex vivo colonic nociceptor recording. Arrows indicate application/removal of von Frey hairs (vfh). (G) Colonic nociceptors from linaclotide-treated CVH mice display reduced firing in response to mechanical stimuli compared with vehicle-treated CVH mice (**P < 0.01, ***P < 0.001). (H) Ex vivo nociceptor recordings from CVH mice treated with either vehicle or linaclotide. Arrows indicate application/removal of von Frey hairs. Data represent mean ± SEM. P values were determined by generalized estimating equations, followed by least significant difference post hoc (A–C) or by 2-way ANOVA with post hoc Tukey’s test (E and G).