Irisin prevents visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome

Abstract

Visceral hypersensitivity and impaired gut barrier function, accompanied by minor inflammation, are crucial components of the pathophysiology of irritable bowel syndrome (IBS). Research has demonstrated that corticotropin-releasing factor (CRF) and toll-like receptor 4 (TLR4) signaling mutually activate to produce proinflammatory cytokines, which modulate these gastrointestinal changes. Irisin, a myokine, has been shown to inhibit TLR4-proinflammatory cytokine signaling, thereby improving inflammation driven by obesity and metabolic syndrome. Based on this, we hypothesized that irisin could improve visceral hypersensitivity and impaired gut barrier function induced by lipopolysaccharide (LPS) or CRF (IBS rat models), and tested this hypothesis. The visceral pain threshold, triggered by colonic balloon distention, was assessed by electrophysiologically monitoring abdominal muscle contractions in male Sprague-Dawley rats. Colonic permeability was evaluated by measuring the amount of Evans blue dye absorbed within the colonic tissue. Intraperitoneal irisin prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Irisin also prevented CRF-induced gastrointestinal alterations. The beneficial effects of irisin in the LPS model were reversed by compound C, an AMP-activated protein kinase (AMPK) inhibitor; N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor; sulpiride or domperidone, a dopamine D₂ receptor antagonist; atropine and intracisternal injection of SB-334867, a selective orexin 1 receptor antagonist. Overall, these findings suggest that irisin improves visceral sensation and colonic barrier function through AMPK, NO and dopamine D₂, cholinergic and brain orexin signaling in IBS model. Thus, irisin may be a promising therapeutic agent for treating IBS.