Zerumbone Suppresses Enterotoxigenic Bacteroides fragilis Infection-Induced Colonic Inflammation through Inhibition of NF-κΒ

Abstract

Enterotoxigenic Bacteroides fragilis (ETBF) is human intestinal commensal bacterium and a potent initiator of colitis through secretion of the metalloprotease Bacteroides fragilis toxin (BFT). BFT induces cleavage of E-cadherin in colon cells, which subsequently leads to NF-κB activation. Zerumbone is a key component of the Zingiber zerumbet (L.) Smith plant and can exhibit anti-bacterial and anti-inflammatory effects. However, whether zerumbone has anti-inflammatory effects in ETBF-induced colitis remains unknown. The aim of this study was to determine the anti-inflammatory effect of orally administered zerumbone in a murine model of ETBF infection. Wild-type C57BL/6 mice were infected with ETBF and orally administered zerumbone (30 or 60 mg/kg) once a day for 7 days. Treatment of ETBF-infected mice with zerumbone prevented weight loss and splenomegaly and reduced colonic inflammation with decreased macrophage infiltration. Zerumbone treatment significantly decreased expression of IL-17A, TNF-α, KC, and inducible nitric oxide synthase (iNOS) in colonic tissues of ETBF-infected mice. In addition, serum levels of KC and nitrite was also diminished. Zerumbone-treated ETBF-infected mice also showed decreased NF-κB signaling in the colon. HT29/C1 colonic epithelial cells treated with zerumbone suppressed BFT-induced NF-κB signaling and IL-8 secretion. However, BFT-mediated E-cadherin cleavage was unaffected. Furthermore, zerumbone did not affect ETBF colonization in mice. In conclusion, zerumbone decreased ETBF-induced colitis through inhibition of NF-κB signaling.

Protective Effects of Zerumbone on Colonic Tumorigenesis in Enterotoxigenic Bacteroides fragilis (ETBF)-Colonized AOM/DSS BALB/c Mice

“…In the current study, zerumbone treatment induced no alterations in ETBF number in the stool of ETBF-colonized AOM/DSS model, but suppressed ETBF-mediated tumorigenesis. This result is consistent with our previous findings and showing that ETBF infected mice given zerumbone show no change in ETBF colonization [9]. The addition of AOM/DSS in the current study also did not affect ETBF colonization density.…”

“…ETBF is a molecular subset of Bacteroides fragilis distinguished based on the secretion of a sole virulence factor, the Bacteroides fragilis toxin (BFT) [3,4]. The epithelial response to BFT shows E-cadherin cleavage resulting in NF-κB signaling in colonic epithelial cells [5][6][7][8][9].…”

“…Zerumbone has been reported to have anti-bacterial, anti-inflammatory and anti-cancer activities [19][20][21][22][23]. Zerumbone decreases ETBF infection-induced colon inflammation in mice via suppression of NF-κB signaling irrespective of ETBF colonization [9]. Inhibition of NF-κB signaling observed in colon of ETBF-infected mice administered zerumbone is directly BFT-dependent, since in vitro, zerumbone treatment diminishes NF-κB activation in BFT-exposed HT29/C1 human colon carcinoma cells [9].…”

“…Zerumbone decreases ETBF infection-induced colon inflammation in mice via suppression of NF-κB signaling irrespective of ETBF colonization [9]. Inhibition of NF-κB signaling observed in colon of ETBF-infected mice administered zerumbone is directly BFT-dependent, since in vitro, zerumbone treatment diminishes NF-κB activation in BFT-exposed HT29/C1 human colon carcinoma cells [9]. As our initial findings demonstrated the suppression of colonic inflammation to ETBF infection by zerumbone, we hypothesized that zerumbone decreases ETBF-mediated tumorigenesis in mice.…”

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

“…There is no doubt that this will be the focus of our future studies. In this study, we selected the dose of 25 mg/kg orally in mice based on previous animal studies with zerumbone [94,95]. According to the guide for dose conversion between mice and human, the daily human oral dose would be 2.75 mg/kg, which can be reasonable [96].…”