Cannabidiol-Decorated Berberine-Loaded Microemulsions Improve IBS-D Therapy Through Ketogenic Diet-Induced Cannabidiol Receptors Overexpression

Int J Nanomedicine. 2023 May 30:18:2839-2853. doi: 10.2147/IJN.S402871. eCollection 2023.

Abstract

Background: Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.

Methods: The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.

Results: The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.

Conclusion: Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.

Keywords: CB1 receptors; berberine; irritable bowel syndrome-diarrhea; ketogenic diet; microemulsion.

MeSH terms

  • Animals
  • Berberine* / pharmacology
  • Berberine* / therapeutic use
  • Brain-Derived Neurotrophic Factor
  • Cannabidiol* / pharmacology
  • Cannabidiol* / therapeutic use
  • Diarrhea / drug therapy
  • Diet, Ketogenic*
  • Irritable Bowel Syndrome* / drug therapy
  • Irritable Bowel Syndrome* / metabolism
  • Rats

Substances

  • Berberine
  • Cannabidiol
  • Brain-Derived Neurotrophic Factor

Grants and funding

This work was also supported by Graduate Research and Practice Innovation Project of Jiangsu Province (SJCX22-0841).