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

Area of Science:

• Gastroenterology and Urology
• Neuroscience
• Pharmacology

Background:

• Irritable bowel syndrome (IBS) frequently co-occurs with bladder conditions like overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome (IC-PBS).
• The underlying mechanisms and treatment options for these visceral comorbidities remain poorly understood.
• Colitis can lead to chronic abdominal pain and subsequent bladder dysfunction.

Purpose of the Study:

• To investigate the mechanistic link between colonic inflammation and bladder dysfunction.
• To explore the therapeutic potential of linaclotide in mitigating these comorbid symptoms.
• To understand the role of cross-organ sensitization in visceral pain and dysfunction.

Main Methods:

• Induction of colitis in mice to model IBS-associated pain.
• Assessment of colonic and bladder afferent nerve sensitivity.
• Evaluation of spinal cord circuit plasticity.
• Pharmacological intervention using linaclotide, a guanylate cyclase-C agonist.
• Analysis of bladder voiding function.

Main Results:

• Colitis induced persistent hypersensitivity in colonic afferents, spinal circuits, and led to chronic abdominal pain.
• Colonic hypersensitivity subsequently caused bladder afferent hypersensitivity and voiding dysfunction, mimicking OAB/IC-PBS.
• Daily linaclotide treatment reversed colonic hypersensitivity, spinal neuroplasticity, and abdominal pain.
• Linaclotide also restored normal bladder function by indirectly inhibiting bladder afferents via reduced colonic nociception.

Conclusions:

• Cross-organ sensitization contributes to the development and maintenance of visceral comorbidities.
• Linaclotide's therapeutic effects extend beyond the gut, improving urological symptoms.
• Targeting colonic afferent pathways may offer a novel strategy for treating IBS-related bladder dysfunction.