Berberine-Cinnamic Acid Co-Crystal Effect in Ameliorating Ulcerative Colitis Might Be Regulated Through Modulation of Intestinal Barrier and Improved Intestinal Absorption

Background: Berberine (BBR) has therapeutic effects against ulcerative colitis (UC). However, the poor solubility and low bioavailability of BBR limit the clinical utility of the chemical. BBR-CA, a co-crystal formed by BBR and cinnamic acid (CA), displays markedly improved intestinal bioavailability.Methods: The characteristics of BBR-CA were determined to confirm the formation of the co-crystal via intermolecular forces. The Cmax values of BBR-CA and BBR were compared in rat blood. The apparent permeability coefficients (Papp) were measured and compared in an in vitro intestinal model. The restoration of intestinal barrier function and the regulation of cytokine levels (IL-6, IL-8, and TNF-α) were further examined in UC mouse models following BBR-CA treatment. In addition, this study evaluated the molecular pathways regulating UC-associated inflammation using transcriptomic analysis of lipopolysaccharide (LPS)-challenged Intestinal Epithelial Cells-6 (IEC6) cells treated with BBR-CA.Results: The morphology of BBR-CA significantly differed from that of BBR and CA. In vitro experiments showed that the Papp of BBR-CA was significantly higher than that of BBR; in vivo pharmacokinetic studies in rats indicated that the Cmax of BBR-CA was significantly higher than that of BBR. Moreover, BBR-CA exhibited enhanced anti-inflammatory activity and improved intestinal epithelial tight junction integrity in vivo. Consistent with these findings, BBR-CA exerted therapeutic effects against UC by enhancing anti-inflammatory activity and preserving intestinal epithelial tight junctions. Participation of the JAK2-STAT3 signaling pathway in the regulation of inflammation in UC was further confirmed.Conclusions: BBR-CA improves the intestinal absorption properties of BBR, at least in part, through regulation of the JAK2-STAT3 signaling pathway. This results in reduced inflammation and increased integrity of the intestinal epithelial tight junction, thereby alleviating UC.