Spironolactone and Colitis: Increased Mortality in Rodents and in Humans

Abstract

Background and Methods Crohn’s disease causes intestinal inflammation leading to intestinal fibrosis. Spironolactone is an anti-fibrotic medication commonly used in heart failure to reduce mortality. We examined whether spironolactone is anti-fibrotic in the context of intestinal inflammation. In vitro, spironolactone repressed fibrogenesis in TGFβ-stimulated human colonic myofibroblasts. However, spironolactone therapy significantly increased mortality in two rodent models of inflammation-induced intestinal fibrosis, suggesting spironolactone could be harmful during intestinal inflammation. Since IBD patients rarely receive spironolactone therapy, we examined whether spironolactone use was associated with mortality in a common cause of inflammatory colitis, Clostridium difficile infection (CDI). Results Spironolactone use during CDI infection was associated with increased mortality in a retrospective cohort of 4008 inpatients (15.9% vs. 9.1%, n=390 deaths, p<0.0001). In patients without liver disease, the adjusted OR for inpatient mortality associated with 80 mg spironolactone was 1.99 (95% CI: 1.51 – 2.63) In contrast to the main effect of spironolactone mortality, multivariable modeling revealed a protective interaction between liver disease and spironolactone dose. The adjusted odds ratio for mortality after CDI was 1.96 (95% CI: 1.50 – 2.55) for patients without liver disease on spironolactone vs. 1.28 (95% CI: 0.82 – 2.00) for patients with liver disease on spironolactone, when compared to a reference group without liver disease or spironolactone use. Conclusions We propose that discontinuation of spironolactone in patients without liver disease during CDI could reduce hospital mortality by 2-fold, potentially reducing mortality from CDI by 35,000 patients annually across Europe and the US.

The Aldosterone-Mineralocorticoid Receptor Pathway Exerts Anti-Inflammatory Effects in Endotoxin-Induced Uveitis

“…In dog sepsis, specific MR agonists increased survival when given preventively [35] . It was also observed that mortality was enhanced by spironolactone during infectious colitis in two rodents model and in humans [36] . In neutrophils, functional MR was reported to mediate anti-inflammatory effects via inactivation of nuclear factor-kappa B (NF-κB); indeed aldosterone strongly diminished NF-κB dependant TNF-α production in IL-8 stimulated neutrophils, resulting in reduced neutrophil adhesion to endothelial cells [37] .…”

Intestinal organoids: A model of intestinal fibrosis for evaluating anti-fibrotic drugs

“…Spironolactone is a competitive aldosterone receptor antagonist that is commonly used as an anti-fibrotic medication in heart patients, and has proven protective in several rodent models of fibrosis (Ersoy et al, 2007; Gullulu et al, 2006; Nishimura et al, 2008; Rajagopalan and Pitt, 2003). Previously, our group determined that spironolactone was anti-fibrotic in isolated human colonic myofibroblasts and repressed TGFβ-mediated induction of pro-fibrotic genes and proteins (Johnson et al, 2012a). To determine whether spironolactone could prevent TGFβ-induced fibrogenic gene and protein expression in HIOs, we analyzed the expression of fibrogenic genes and proteins in HIOs by qPCR and Western blot after 96 hours of co-treatment of various concentrations of spironolactone with 2 ng/mL TGFβ.…”

Novel Rho/MRTF/SRF Inhibitors Block Matrix-stiffness and TGF-β–Induced Fibrogenesis in Human Colonic Myofibroblasts

“…Cells were serum-starved overnight before stimulation with 1 ng/mL of TGF-β as previously described. 18,38 To determine the effect of Rho/ ROCK or Rho/MRTF/SRF inhibitors, cells were cotreated with 1 ng/mL TGF-β and 1, 3, 10, 17.5, or 25 μM of inhibitors and incubated for 48 hours before harvest for molecular analysis. The media was replaced at 24 hours with fresh media containing TGF-β or TGF-β and inhibitors.…”