Cardiotonic Steroids as a Potential Novel Approach for Immunomodulation in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a chronic condition that significantly impairs the quality of life of millions of individuals. The pathogenesis of IBD is closely linked to dysbiosis of microbiota and the activation of various inflammatory pathways, which are characterized by elevated levels of activated immune cells, such as neutrophils and lymphocytes. While several therapeutic options, including corticosteroids and biologic agents, are available for the treatment of IBD, their efficacy remains limited. Consequently, the development of novel therapies is essential. In this context, cardiotonic steroids, a class of drugs traditionally known for their effects on the cardiovascular system, have gained attention due to their potential immunomodulatory properties. Thus, this review aims to explore the emerging therapeutic potential of cardiotonic steroids in the treatment of IBD.

Keywords: T cells; anti-inflammatory; digoxin; neutrophils; ouabain.

Figure 1

Inflammatory bowel disease (IBD) includes several factors and the interplay between them.

Figure 2

Several mechanisms contribute to the pathogenesis of inflammatory bowel disease (IBD), including disruption of the mucus layer, dysbiosis, and increased epithelial permeability, facilitating bacterial translocation (1). This process triggers immune system activation, characterized by intense cellular infiltration, particularly of neutrophils and monocytes (2), accompanied by the release of various inflammatory mediators and neutrophil extracellular traps (NETs) (3). The presence of T cells with Th1 and Th17 profiles is a hallmark of IBD (4), contributing to the dysregulation of gut homeostasis (5). The inflammatory cycle is perpetuated by continuous cell migration and sustained release of cytokines and chemokines (6). Based on the mechanisms described in the literature, cardiotonic steroids may interfere at multiple points in this inflammatory cascade, including by reducing cytokine production (7), modulating T cell activity (8), dampening Th17 responses (9), preserving epithelial barrier integrity (10), and inhibiting immune cell migration (11). ↑ indicates increase, ↓ indicates decrease, and ⊣ indicates inhibition.