Oral administration of an ethanolic extract of Hypericum gentianoides attenuates spontaneous colitis in mdr1a-/- mice

Abstract

Background: Nutraceuticals (i.e., complementary and alternative medicines) are gaining ground as therapeutic modalities for inflammatory and autoimmune disorders due to their low toxicity and high patient compliance. Several species of Hypericum have been shown to possess immunomodulatory capabilities in many disease models; however, the therapeutic potential of the chemically unique Hypericum gentianoides (HG) is largely untested. We investigated the efficacy of an orally administered ethanolic extract of HG (HGEE) to prophylactically inhibit/ameliorate the spontaneous colitis that develops in mdr1a deficient (mdr1a-/-) mice.Methods: Beginning at six weeks of age, vehicle (5% ethanol), HGEE (4.8 mg/day) or metronidazole (0.75 mg/mL) were orally administered daily to mdr1a-/- or FVBWT mice until they reached 20 weeks of age or had lost ≥ 15 % of their body weight. Macroscopic disease assessment included measurement of weight loss, colon shortening, and combined colonic/cecal macroscopic lesion scores. Colonic/cecal inflammation was also scored histologically. Inflammatory responses were assessed using myeloperoxidase (MPO) assay and analysis of serum cytokines/chemokines.Results: Daily administration of HGEE significantly (p < 0.05) delayed the onset of clinical signs of disease, reduced the associated morbidity and attenuated macroscopic and microscopic disease/inflammatory scores in mdr1a-/- mice. After 14 weeks of treatment, there were no adverse macroscopic or microscopic effects observed following the daily administration of HGEE to wild type FVB mice. Histological evaluation of colonic tissue revealed a decrease in neutrophil infiltration in HGEE treated mdr1a-/- mice, which was substantiated by a significant decrease (p ≤ 0.05) in colonic MPO activity. Compared to vehicle treated mdr1a-/- mice, levels of G-CSF, KC, and TNFα were significantly lower in the serum of mdr1a-/- mice treated with HGEE.Conclusions: Oral administration of HGEE was shown to be safe and effectively ameliorated  mucosal inflammation and disease severity in mdr1a-/- mice. The attenuation of mucosal inflammation correlated with a reduction in the production of pro-inflammatory cytokines and the recruitment of inflammatory granulocytes to the intestinal mucosa and suggests that extracts of H. gentianoides has potential to be used as a CAM product for mucosal inflammation.Keywords: Hypericum gentianoides, colitis, IBD, mdr1a deficient mice, botanical