Berberine Improves Irinotecan-Induced Intestinal Mucositis Without Impairing the Anti-colorectal Cancer Efficacy of Irinotecan by Inhibiting Bacterial β-glucuronidase

Abstract

Irinotecan (CPT11), a broad-spectrum cytotoxic anticancer agent, induces a series of toxic side-effects. The most conspicuous side-effect is gastrointestinal mucositis, including nausea, vomiting, and diarrhea. A growing body of evidence indicates that bacteria β-glucuronidase (GUS), an enzyme expressed by intestinal microbiota, converts the inactive CPT11 metabolite SN38G to the active metabolite SN38 to ultimately induce intestinal mucositis. We sought to explore the potential efficacy and underlying mechanisms of berberine on CPT11-induced mucositis. Our study showed that berberine (50 mg/kg; i. g.) mitigated the CPT11-induced loss of mucosal architecture, ulceration, and neutrophil infiltration. Meanwhile, berberine improved mucosal barrier function by increasing the number of globlet cells, protecting trans-endothelial electrical resistance (TEER), reducing permeability and increasing tight junction proteins expression. LC-MS analysis showed that berberine decreased the content of SN38 in feces, which correlated with decreases in both GUS activity and GUS-producing bacteria. Further molecular docking and Lineweaver-Burk plots analyses suggested that berberine functions as a potential non-competitive inhibitor against GUS enzyme. Of note, berberine maintained the anti-tumor efficacy of CPT11 in a tumor xenograft model while abrogating the intestinal toxicity of CPT11. Overall, we identified for the first time the remission effects of berberine on intestinal mucositis induced by CPT11 without impairing the anti-colorectal cancer efficacy of CPT11 partially via inhibiting bacterial GUS enzyme.

Therapeutic effects and mechanisms of plant-derived natural compounds against intestinal mucositis

“…Significantly, fecal transplantation from berberine-treated rats could relieve intestinal mucosal injury. Yue et al (2021 )also found that berberine conspicuously ameliorated gut mucositis in irinotecan-treated mucositis murines and SN38-stimulated NCM460 or Caco-2 cells. The underlying mechanism might be closely associated with the suppression of pro-inflammatory mediators (including COX-2, iNOS, TNF-α, IL-8, and IL-1β), bacterial GUS activity and the improvement of mucosal barrier integrality by elevating the protein expression of ZO-1, occludin, and claudin-1 and decreasing the levels of LPS, DAO, and FITC-dextran fluorescence.…”

The semi-synthetic flavonoid 2′,3′,4′-trihydroxyflavone (2-D08) inhibits both SN-38- and cytokine-evoked increases in epithelial barrier permeability in anin vitrointestinal mucositis model

“…Treatment with SN-38 alone resulted in a significant decrease in TEER over 48 hours, an effect which echoes previous studies. 45 SN-38 has been shown to disrupt tight junction (TJ) formation and significantly downregulate the expression of occludin, which may explain this reduction in TEER. 45 Previous studies have indicated that quercetin can increase TEER via upregulation of TJ proteins such as occludin and claudin-1.…”

“…85,86 Moreover, treatment with both irinotecan and SN-38 have been linked to the downregulation of several TJ proteins, resulting in reduced barrier function. 45,87 Numerous flavonoids possess the ability to maintain and even increase TJ protein expression, highlighting their therapeutic potential in this regard. 88,89 Future studies exploring the protective efficacy of 2-D08 and transilitin in maintaining intestinal barrier integrity should therefore investigate the effect of these novel flavonoids on TJ expression.…”

“…45 has been shown to disrupt tight junction (TJ) formation and significantly downregulate the expression of occludin, which may explain this reduction in TEER. 45 Previous studies have indicated that quercetin can increase TEER via upregulation of TJ proteins such as occludin and claudin-1. 46,47 However, these studies have also used significantly higher concentrations of quercetin, which may account for the lack of efficacy observed in the present study.…”

Pharmacomicrobiomics in Pediatric Oncology: The Complex Interplay between Commonly Used Drugs and Gut Microbiome

“…3D X-ray crystallographic data are also under investigation in order to rationally design a β-glucuronidase inhibitor [ 102 ]. More recent pharmacological compounds have been tested with positive results [ 109 ], but their application in clinical practice has not been yet validated.…”