Qizhiweitong granule alleviates diarrhea-predominant irritable bowel syndrome via inhibition of the IL-6/Src/STAT3 feedback loop

Qizhiweitong granule (QZWT) is commonly used in clinical practice to treat chronic gastritis and gastric ulcers, and to enhance gastric motility. However, the mechanisms by which QZWT exerts its therapeutic effects on diarrhea-predominant irritable bowel syndrome (IBS-D) remain unclear.

To explore whether QZWT exerts anti-IBS-D effect, and to determine the molecular mechanism of the action of QZWT.

A IBS-D rat model induced by chronic unpredictable mild stress (CUMS) was established to determine the in vivo efficacy of QZWT. In vitro, lipopolysaccharide (LPS)-induced RAW264.7 macrophage and NCM460 human colon epithelial cell models were used to examine the anti-inflammatory activity of QZWT and its ability to repair the intestinal barrier function. In addition, untargeted metabolomics was used to detect the profile changes in endogenous metabolites that caused by QZWT in the treatment of IBS-D. A STAT3 activator was used to evaluate the involvement of STAT3 signaling in the anti-IBS-D effect of QZWT.

QZWT significantly reduced the fecal water content and the diarrhea index, improved stool consistency in IBS-D rats, and alleviated visceral hypersensitivity. Additionally, QZWT suppressed intestinal inflammation, decreased intestinal permeability, and restored the brain-gut axis homeostasis. Meanwhile, QZWT also enhanced mucus secretion from goblet cells and improved intestinal barrier function. Metabolomics analysis revealed that QZWT regulated steroid biosynthesis, taurine and β-taurine metabolism, as well as arachidonic acid metabolism. KEGG pathway enrichment analysis indicated that the anti-IBS-D effect of QZWT is primarily related to the inflammatory process. In vitro studies demonstrated that QZWT inhibited the IL-6 release, reduced the protein levels of phospho-Src (Tyr416), and phospho-STAT3 (Tyr705), as well as inhibited STAT3 activation. Moreover, the addition of the recombinant protein IL-6 diminished the anti-inflammatory effect of QZWT.

This study for the first time suggest that QZWT alleviates IBS-D by suppressing the inflammation response, repairing the damage to the intestinal barrier, and inhibiting the IL-6/Src/STAT3 feedback loop. These findings facilitate the secondary development and clinical application of QZWT for the treatment of patients with IBS-D.