Acute Colchicine Poisoning Causes Endotoxemia via the Destruction of Intestinal Barrier Function: The Curative Effect of Endotoxin Prevention in a Murine Model

Abstract

Background: Colchicine binds to intracellular tubulin and prevents mitosis. Colchicine is also used as an anti-inflammatory drug. Meanwhile, excess administration of medication or accidental ingestion of colchicine-containing plants can cause acute colchicine poisoning, which initially results in gastrointestinal effects that may be followed by multiorgan dysfunction. However, the mechanism of colchicine poisoning remains unclear, and there are no standard therapeutic strategies.

Aims: We focused on intestinal barrier function and attempted to reveal the underlying mechanism of colchicine poisoning using an animal model.

Methods: Colchicine was orally administered to C57Bl/6 mice. Then, we performed histopathological analysis, serum endotoxin assays, and intestinal permeability testing. Additionally, the LPS-TLR4 signaling inhibitor TAK-242 was intraperitoneally injected after colchicine administration to analyze the therapeutic effect.

Results: We observed villus height reduction and increased numbers of apoptotic cells in the gastrointestinal epithelium of colchicine-treated mice. Both intestinal permeability and serum endotoxin levels were higher in colchicine-treated mice than in control mice. Although colchicine-poisoned mice died within 25 h, those that also received TAK-242 treatment survived for more than 48 h.

Conclusion: Colchicine disrupted intestinal barrier function and caused endotoxin shock. Therapeutic inhibition of LPS-TLR4 signaling might be beneficial for treating acute colchicine poisoning.

Keywords: Colchicine; Endotoxin; Intestinal barrier.

Fig. 1

Morphological observations in colchicine-poisoned mice. a H&E staining in control and colchicine-poisoned mice. b The average villus length (n = 5, *P < 0.05). The error bar indicates the SD. c The contents of colchicine in the whole blood of mice (n = 5, *P < 0.05). d Scanning electron microscopy of the surface of intestinal villi. These analyses were performed using samples obtained 18 h after colchicine administration

Fig. 2

Immunohistochemical analysis in colchicine-poisoned mice. a Immunohistochemical staining of cleaved caspase-3 as an apoptosis marker (left: control, right: 18 h after colchicine administration). b Immunohistochemical staining of ZO-1 as a marker of intestinal barrier (left: control, right: 18 h after colchicine administration). c Time sequence of changes in the frequency of cleaved caspase-3-positive epithelial cells (n = 3 for each time point, *P < 0.05, N.S.: no significance). d Time sequence of changes in the frequency of ZO-1-absent villi (n = 3 for each time point, *P < 0.05, N.S.: no significance)

Fig. 3

Time sequence of changes in serum endotoxin and tumor necrosis alpha (TNF)-α levels. a The levels of endotoxin in mice (n = 3 for each time point, *P < 0.05, N.S.: no significance). b The serum TNF-α levels in mice (n = 3 for each time point, *P < 0.05, N.S.: no significance). c The levels of H³ radioactivity that leaked from inside the intestines (n = 5, *P < 0.05). The error bar indicates the SD

Fig. 4

The effect of endotoxin inhibition in colchicine-treated mice. a Survival curve of colchicine-poisoned mice that received TAK-242 (n = 10). b The levels of endotoxin in mice that received TAK-242 (n = 10, *P < 0.05, N.S.: no significance). c The levels of H³ radioactivity that leaked from inside the intestines of mice that received TAK-242 (n = 5, *P < 0.05). d The levels of serum TNF-α in mice that received TAK-242 (n = 10, *P < 0.05)

Fig. 5

The schema of colchicine-induced endotoxin shock