Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3

Abstract

Gastrointestinal dysfunction in Cystic Fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a Guanylate Cyclase C (GCC) receptor agonist, is an FDA-approved drug prescribed for chronic constipation, but has not been widely utilized in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders utilizing CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity was assessed in wildtype and CF mouse models in response to linaclotide. CFTR and Sodium/Hydrogen Exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl- secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced similar improvements in gastrointestinal transit as linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3 mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations.

Animal Models in the Pathophysiology of Cystic Fibrosis

“…Linaclotide is a drug that has been approved by FDA to treat chronic idiopathic constipation. This study demonstrated that this drug elevates the amount of fluid in the intestinal lumen and improves intestinal transit, thus prompting the authors to recommend linaclotide as a therapeutic option to treat CF intestinal manifestations (Than et al, 2016; McHugh et al, 2018a).…”

“…In a recent study, McHugh et al (2018a) generated a G542X CF mouse model with CRISPR/Cas9 gene editing method. 40.9% of founder mice expressed the G542X mutation and this new clone was generated in approximately 3 months, whereas traditional methods using embryonic stem cells, would necessitate 1–2 years to obtain the desired mouse colony.…”

The therapeutic importance of acid-base balance

“…The CFTR corrector ivacaftor improves intestinal HCO 3 – secretion and nutrient absorption in individuals with CF [250] . The mode of action of the anti-constipation drug linaclotide (LINZESS®: a guanylate cyclase C receptor agonist) encompasses both paradigms by the cGMP-mediated reduction of NHE3 [251] and activation of CFTR activities [252] .…”

Inhibition of Na+/H+ exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator‐deficient and F508del mutant mice

“…All three agents result in low systemic exposure and have been approved for the treatment of constipation‐prone irritable bowel (IBS‐C) syndrome. Despite an interest to apply these agents in the fight against CF‐associated intestinal disease (De Lisle, Mueller, & Roach, 2010; McHugh et al, 2018; O'Brien, Anderson, & Stowe, 2011), the efficacy of these agents to increase gut fluidity and alkalinity in vivo is currently unknown. Therefore, small and large intestinal fluid movements and bicarbonate output were assessed in cftr −/− , F508del mut/mut and WT mice in vivo .…”