Icariside II ameliorates slow transit constipation by inhibiting macrophage polarization and suppressing the cGAS-STING pathway

Background

Slow transit constipation (STC) is a functional disorder characterized by slowed colonic peristalsis and delayed emptying. Its pathogenesis involves enteric nervous system damage and immune dysregulation, among other factors. Icariside II (ICS II) is a natural flavonoid glycoside from Herba Epimedii and is known for its anti-inflammatory, antioxidant, and neuroprotective effects. However, the effect of ICS II on STC and the underlying mechanisms remains unclear.

Methods

In this study, the effects of ICS II on STC were assessed in a loperamide-induced STC animal model. Drug efficacy was evaluated by observing the general phenotype using hematoxylin and eosin staining, immunofluorescence, Western blotting, and flow cytometry. Additionally, the roles of intestinal macrophages and the cyclic guanosine monophosphate-adenosine synthase/stimulator of interferon genes (cGAS-STING) signaling pathway in STC were studied using clodronate liposomes and STING inhibitor.

Results

ICS II treatment significantly increased fecal count, fecal moisture content, and intestinal propulsion rate, shortened first dark fecal defecation time, and improved colonic histopathology in the STC animal model. Notably, ICS II reduced intestinal M1-type macrophage proportion, downregulated proteins in the cGAS-STING signaling pathway, and lowered the release of inflammatory factors interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. ICS II also decreased intestinal neuronal damage and increased nerve fiber density in STC disease, demonstrating its anti-inflammatory and neuroprotective effects.

Conclusion

This study provides evidence that ICS II exerts significant anti-inflammatory and neuroprotective effects. This is achieved by inhibiting the cGAS-STING pathway and suppressing macrophage M1 polarization, suggesting its potential as a therapeutic agent for STC.