Therapeutic Effect of Kakkonto in a Mouse Model of Food Allergy with Gastrointestinal Symptoms

Abstract

Background: The number of patients with food allergy has increased dramatically over the last several decades. However, there is no effective drug for food allergies. In the present study, we evaluated the effects of kakkonto, a traditional Japanese herbal medicine, in a mouse model of food allergy with gastrointestinal symptoms. Methods: BALB/c mice were systemically sensitized twice with ovalbumin (OVA) and then were repeatedly given OVA by oral intubation (OVA mice). Kakkonto was administered orally before the OVA challenges. Results: The OVA mice developed allergic diarrhea (91.8 ± 3.8% after 6 OVA challenges), and myeloperoxidase (MPO) activity was dramatically elevated in the colons of the OVA mice. Kakkonto significantly suppressed the occurrence of allergic diarrhea and MPO activity in the OVA mice. Furthermore, the number of mucosal mast cells was greatly increased in the proximal colons of the OVA mice, and this was also suppressed by kakkonto. Interestingly, mRNA expression of helper T cell type 1 (Th1) cytokines (IFN-γ) and Th2 cytokines (IL-4, IL-5 and IL-10) were significantly upregulated in the proximal colons of the OVA mice, an effect which was also reduced by kakkonto. Transcriptome analysis detected increased mRNA expression of suppressor of cytokine signaling-3 in the proximal colons of OVA mice, which was decreased by kakkonto administration. Conclusion: Kakkonto has immunosuppressive effects and interferes with the infiltration of mucosal mast cells in the colons of mice with induced food allergy, leading to improvement of allergic symptoms. Kakkonto has potential as a therapeutic drug for treatment of allergic symptoms induced by the disruption of intestinal mucosal immunity.

Induction of Regulatory T Cells as a Novel Mechanism Underlying the Therapeutic Action of Kakkonto, a Traditional Japanese Herbal Medicine, in a Murine Food Allergy Model

“…Recently, it has been reported that intestinal mucosal immunity plays an important role in FA [1,6,7]. In our FA model, the enhancement of Th2-type immune responses in intestinal mucosal immunity is one of the most pivotal etiologies of FA [1], consistent with previous studies in another mouse FA model [6,7].…”

“…However, effective drug therapies for FA are not available. We have previously suggested that kakkonto is a potential therapeutic drug for FA, using our mouse FA model with gastrointestinal symptoms [1]. Kakkonto is a traditional Japanese herbal medicine that originated in China and is composed of the following 7 species of medicinal plants: Puerariae radix (23.5%), Cinnamomi cortex (18.8%), Zizyphi fructus (17.6%), Paeoniae radix (11.8%), Ephedrae herba (17.6%), Zingiberis rhizoma (5.9%) and Glycyrrhizae radix (11.8%).…”

Eppikajutsuto Protects against Food Allergy Induced by Ovalbumin in a Murine Model

“…In contrast, EJT treatment led to a decrease in plasma mMcpt1 levels in EJT-treated mice. mMcpt1 is one of the mast cell proteases found in mucosal mast cells, and previous studies showed that plasma mMcpt1 levels were significantly increased in mice with FA [9,30]. These findings raise the possibility that EJT might suppress plasma mMcpt1 levels without affecting mucosal mast cell numbers, thus controlling their function and suppressing degranulation.…”

“…We also found that the number of mucosal mast cells in the small intestine was higher in mice with FA than those in control mice. Both FAHF-2 [6] and kakkonto [9] were previously shown to reduce the number of mast cells in the intestines. Thus, we expected EJT-treated mice to be protected from infiltrating mast cells in the intestines; however, the number of mast cells in the intestines was not different between FA and EJT-treated mice.…”

“…Kakkonto, a traditional Japanese Kampo medicine (TJKM), suppressed the incidence of allergic diarrhea caused by ovalbumin (OVA) and induced Foxp3 + /CD4 + /CD25 - regulatory T cells in the colon in a FA model [8,9]. There are no TJKMs except kakkonto that were reported to alleviate FA, but we hypothesized that other TJKMs are promising therapeutic candidates for treating FA for the following reasons.…”