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

Abstract

Irritable bowel syndrome (IBS) patients suffer from chronic abdominal pain and extraintestinalcomorbidities, including overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome(IC-PBS). Mechanistic understanding of the cause and time course of these comorbid symptoms islacking, as are clinical treatments. Here, we report that colitis triggers hypersensitivity of colonicafferents, neuroplasticity of spinal cord circuits, and chronic abdominal pain, which persists afterinflammation. Subsequently, and in the absence of bladder pathology, colonic hypersensitivityinduces persistent hypersensitivity of bladder afferent pathways, resulting in bladder-voidingdysfunction, 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 colonicafferent hypersensitivity, reverses neuroplasticity-induced alterations in spinal circuitry, andalleviates chronic abdominal pain in mice. Intriguingly, daily linaclotide administration also reversespersistent bladder afferent hypersensitivity to mechanical and chemical stimuli and restoresnormal bladder voiding. Linaclotide itself does not inhibit bladder afferents, rather normalizationof bladder function by daily linaclotide treatment occurs via indirect inhibition of bladder afferentsvia reduced nociceptive signaling from the colon. These data support the concepts that crossorgan sensitization underlies the development and maintenance of visceral comorbidities, whilepharmaceutical treatments that inhibit colonic afferents may also improve urological symptomsthrough common sensory pathways.