Betulinic Acid Ameliorates the T-2 Toxin-Triggered Intestinal Impairment in Mice by Inhibiting Inflammation and Mucosal Barrier Dysfunction through the NF-κB Signaling Pathway

Abstract

T-2 toxin, a trichothecene mycotoxin produced by Fusarium, is widely distributed in crops and animal feed and frequently induces intestinal damage. Betulinic acid (BA), a plant-derived pentacyclic lupane-type triterpene, possesses potential immunomodulatory, antioxidant and anti-inflammatory biological properties. The current study aimed to explore the protective effect and molecular mechanisms of BA on intestinal mucosal impairment provoked by acute exposure to T-2 toxin. Mice were intragastrically administered BA (0.25, 0.5, or 1 mg/kg) daily for 2 weeks and then injected intraperitoneally with T-2 toxin (4 mg/kg) once to induce an intestinal impairment. BA pretreatment inhibited the loss of antioxidant capacity in the intestine of T-2 toxin-treated mice by elevating the levels of CAT, GSH-PX and GSH and reducing the accumulation of MDA. In addition, BA pretreatment alleviated the T-2 toxin-triggered intestinal immune barrier dysregulation by increasing the SIgA level in the intestine at dosages of 0.5 and 1 mg/kg, increasing IgG and IgM levels in serum at dosages of 0.5 and 1 mg/kg and restoring the intestinal C3 and C4 levels at a dosage of 1 mg/kg. BA administration at a dosage of 1 mg/kg also improved the intestinal chemical barrier by decreasing the serum level of DAO. Moreover, BA pretreatment improved the intestinal physical barrier via boosting the expression of ZO-1 and Occludin mRNAs and restoring the morphology of intestinal villi that was altered by T-2 toxin. Furthermore, treatment with 1 mg/kg BA downregulated the expression of p-NF-κB and p-IκB-α proteins in the intestine, while all doses of BA suppressed the pro-inflammatory cytokines expression of IL-1β, IL-6 and TNF-α mRNAs and increased the anti-inflammatory cytokine expression of IL-10 mRNA in the intestine of T-2 toxin-exposed mice. BA was proposed to exert a protective effect on intestinal mucosal disruption in T-2 toxin-stimulated mice by enhancing the intestinal antioxidant capacity, inhibiting the secretion of inflammatory cytokines and repairing intestinal mucosal barrier functions, which may be associated with BA-mediated inhibition of the NF-κB signaling pathway activation.

Damage to intestinal barrier integrity in piglets caused by porcine reproductive and respiratory syndrome virus infection

“…The NF-κB pathway is the main signalling pathway involved in secondary immune responses to various stimuli and the main pathway involved in intestinal inflammation [ 12 , 13 ]. These proinflammatory factors contribute to the stimulation of protective immune responses, leading to the development of excessive systemic inflammatory reactions and causing inflammatory lesions [ 14 – 16 ].…”

Acankoreagenin and acankoreosides, a family of lupane triterpenoids with anti‐inflammatory properties: an overview

“…BA has been found to interfere with N‐linked glycan modifications of intercellular adhesion molecule‐1 in human lung carcinoma cells 49 . An effect on secretion is also expected, as has been observed with both BA and ACK 50–52 . In RAW264.7 macrophages, the anti‐inflammatory action of acankoreosides (Ack‐A and ‐B, essentially) involves three major aspects, as summarized in Figure 5: (1) inhibition of NF‐κB expression and activation, (2) inhibition of the proinflammatory cytokines IL‐1β and TNF‐α at the transcriptional level (leading also to reduced secretion levels), and (3) inhibition of the secretion of HMGB1 52,53 …”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

“…Since the ingestion of contaminated products is the main entry for T-2 toxin in the organism, intestinal dysfunctions are frequently associated with T-2 toxicity. Luo et al found that pretreatment with BA ameliorated the intestinal inflammation in mice through the inhibition of the NF-κB signaling pathway, which increased the anti-inflammatory/ pro-inflammatory cytokine ratio [ 88 ]. BA pretreatment also diminished intestinal injury produced by cyclophosphamide through the same NF-κB pathway inhibition [ 89 ], suggesting that this pathway could represent a valuable target for the development of new molecules able to treat intestinal dysfunctions.…”