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.