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 8

Chronic oral administration of linaclotide reverses CVH-induced bladder DRG neuronal hyperexcitability.

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Chronic oral administration of linaclotide reverses CVH-induced bladder ...
(A) Whole-cell current-clamp recordings of retrogradely traced lumbosacral (LS) bladder-innervating DRG neurons, showing reduced rheobase of neurons from CVH (n = 18, **P < 0.01) and vehicle-treated CVH (n = 26, *P < 0.05) versus control (n = 20) mice. Bladder-innervating DRG neurons from mice chronically administered linaclotide (n = 27) showed normalized rheobase, which are significantly different compared to CVH neurons (*P < 0.05). (B) Action potential firing at 2× rheobase is increased in vehicle-treated CVH mice (*P < 0.05), while CVH mice receiving chronic linaclotide show normalized firing at 2× rheobase (*P < 0.05). (C) Whole-cell current-clamp traces at rheobase and 2× rheobase in bladder-innervating neurons from control, CVH, vehicle-treated CVH, and linaclotide-treated CVH mice. (D) Sections of colon and bladder at increasing magnifications showing in situ hybridization. GC-C is observed in colonic mucosa of GC-C (gucy2c+/+) wild-type, but not gucy2c-null (gucy2c–/–) mutant mice. GC-C expression is absent in bladder samples from both gucy2c+/+ and gucy2c–/– mice. Results were repeated in N = 3 mice/group. Scale bars: 200 μm (top); 50 μm (middle); 25 μm (bottom). (E) Quantitative RT-PCR confirming expression of gucy2c in primary colonic epithelium and absence in primary bladder urothelium. In comparison, trpv4 is highly expressed in bladder urothelium (N = 4–6 mice/group). (F) Ex vivo bladder afferent mechanosensitivity to ramp distension is increased in CVH (N = 7) compared with control (N = 6) mice. Bladder afferent responses from control or CVH mice are unaltered following ex vivo intravesical infusion of linaclotide (1,000 nM), showing linaclotide does not directly inhibit bladder afferents. (G) Action potential firing and intravesical pressure from control mice during bladder distension (0–30 mmHg) with intravesical saline and linaclotide (1,000 nM). Data represent mean ± SEM. P values are based on 1-way ANOVA (A and B) or 2-way ANOVA (F) with Bonferroni post hoc tests.