Anti-Inflammatory and Barrier-Protective Effects of Berberine

Abstract

The plant alkaloid berberine has been used in traditional Eastern medicine for the treatment of gastroenteritis and diarrhea. Berberine, recently established in the therapy of diabetes and hypercholesterinemia, presents defined barrier preserving effects via specific regulation of tight junction (TJ) proteins. Additionally, berberine has been shown to completely antagonize TNFα-mediated barrier defects in intestinal HT-29/B6 cell monolayers. Three signaling pathways that are involved in this regulation could be identified, namely tyrosine kinase p-src, pAkt, and NF-κB pathway. Beside its anti-inflammatory and barrier protecting function berberine represents a new laboratory tool for the inhibition of a combined set of intracellular signaling events which render berberine also suitable for screening studies on signaling pathways in the future.

Zusammenfassung

Das Pflanzenalkaloid Berberin wird schon seit Jahrhunderten in der traditionellen östlichen Medizin als Therapeutikum gegen Gastroenteritis und Diarrhö genutzt. Aktuell konnte gezeigt werden, dass Berberin, das seit kurzem auch in der Therapie von Diabetes und Hypercholesterinämie eingesetzt wird, definierte barriereerhaltende Effekte durch die spezifische Regulation von Tight Junction(TJ)- Proteinen aufweist. Zusätzlich verhindert Berberin TNFα-induzierte Barrieredefekte in intestinalen HT-29/B6 Zellmonolayern. Es konnten drei Signalwege, die bei dieser Regulierung beteiligt sind, identifiziert werden: der Tyrosinkinase p-src-, der pAkt- und der NF-κB-Signalweg. Daher stellt Berberin neben der Wirkung als Barriereprotektivum und antiinflammatorisches Präparat ein neues Präparat für Screening und Analyse von intrazellulären Signalereignissen dar.

Pharmacological effects of berberine in traditional medicine and today

Berberine is the major plant alkaloid in several plants like the goldenseal (Hydrastis canadensis) or the Chinese goldthread (Coptis chinensis), where it occurs in the roots, rhizomes, stems, and the bark. It is known that it has anti-bacterial, anti-inflammatory and anti-tumor properties. In recent years, berberine has been reported to have a much wider range of pharmacological effects, including immunological regulation, myocardial protection, inhibition of tumor cell proliferation, and invasion. New developments in the therapy of diabetes and hyperlipidemia shift berberine into the focus of interest [1–3]. In studies with type 2 diabetes patients berberine lowered blood glucose as well as the serum concentrations of several fatty acids [4,5], hence berberine is able to improve two major components of the metabolic dysregulation typical for type 2 diabetes, namely hyperglycemia and dyslipidemia, suggesting an important role of berberine in the treatment of this disease.

Barrier-protective effects of berberine

In the past decades there have been several investigations showing that berberine acts on the intestinal barrier. The prevention of ion secretion, which was induced by berberine in in vitro intestinal models of rats and rabbits [6–8], may be due to a blockade of K⁺ channels, which was found to be true in human colonic epithelia [9]. In rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis berberine reduced intestinal inflammation. Furthermore, the production of IL-8, a chemoattractant for neutrophils, was inhibited. Therefore, the authors suggested that the inhibition of IL-8 by berberine may contribute to the beneficial effects of berberine on mucosal healing, however this was not verified [10].

In a recent study [11] we analyzed the effect of berberine on epithelial barrier function in HT-29/B6 cell monolayers grown on permeable supports. Berberine increased the transepithelial resistance (R^t) of HT-29/B6 cell monolayers. This increase of R^t was more distinct after serosal application than after administration to the mucosal side (ctrl 98% ± 3%; berb_muc 110% ± 2%; berb_ser 119% ± 3%). When treated with TNFα, R^t of HT-29/B6 cells decreased. This decrease was largely inhibited by mucosal application of berberine (TNFα 69% ± 4%; berb_muc+TNFα 86% ± 4%), while serosal applicated berberine completely blocked the effect of TNFα (berb_ser +TNFα 100% ± 2%). These effects of berberine could be mimicked by genistein plus BAY11–7082, indicating that they were mediated via tyrosine kinase p-src and NF-κB pathways.

In the same study it was shown that berberine increased the expression of the TJ protein claudin-1 via tyrosine kinase inhibition, and decreased claudin-2 expression via inhibition of the downstream targets GSK3β/Akt. However, the inhibition of the NFκB-pathway had no effect on the expression of TJ proteins, therefore it is assumable that it is rather important for the arrangement and distribution of TJ proteins [11].

These novel findings do not only advance our understanding of the regulation of paracellular intestinal barrier function, but may also push forward the future design and refinement of therapeutic study strategies enhancing barrier function during intestinal inflammation e.g. in inflammatory bowel disease (IBD).

Fig. 8.1 Berberine action on R^t of HT-29/B6 cell monolayers. Berberine (berb; 50 µmol/l) was added to the mucosal (berb_mucosal) or serosal side (berb_serosal) of the monolayers treated with or without TNFα (500 U/ml) and incubated for 24 hours. Values are means ± SEM; * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control; # p < 0.05, ### p < 0.001 vs. TNFα; n = 5. Data are expressed as the percentage of the initial resistance.

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Correspondence
Dr. Maren Amasheh
[e-mail]