Aflatoxin B1 Induces Intestinal Barrier Dysfunction by Regulating the FXR-Mediated MLCK Signaling Pathway in Mice and in IPEC-J2 Cells

Abstract

Aflatoxin B1 (AFB1) is a widespread mycotoxin in food and feed. Although the liver is the main target organ of AFB1, the intestine is the first exposure organ to AFB1. However, the mechanism by which AFB1 induced intestinal barrier dysfunction via regulating the farnesoid X receptor (FXR)-mediated myosin light chain kinase (MLCK) signaling pathway has rarely been studied. In vivo, AFB1 exposure significantly decreased the small intestine length and increased the intestinal permeability. Meanwhile, AFB1 exposure markedly suppressed the protein expressions of FXR, ZO-1, occludin, and claudin-1 and enhanced the protein expression of MLCK. In vitro, AFB1 exposure induced intestinal barrier dysfunction by the elevation in the FITC-Dextran 4 kDa flux and inhibition in the transepithelial electrical resistance in a dose-dependent manner. In addition, AFB1 exposure downregulated the mRNA and protein expressions of FXR, ZO-1, occludin, and claudin-1, redistributed the ZO-1 protein, and enhanced the protein expressions of MLCK and p-MLC. However, fexaramine (Fex, FXR agonist) pretreatment markedly reversed the AFB1-induced FXR activity reduction, MLCK protein activation, and intestinal barrier impairment in vitro and in vivo. Moreover, pretreatment with the inhibition of MLCK with ML-7 significantly alleviated the AFB1-induced intestinal barrier dysfunction and tight junction disruption in vitro. In conclusion, AFB1 induced intestinal barrier impairment via regulating the FXR-mediated MLCK signaling pathway in vitro and in vivo and provided novel insights to prevent mycotoxin poisoning in the intestine.

Astaxanthin Alleviates Aflatoxin B1-Induced Oxidative Stress and Apoptosis in IPEC-J2 Cells via the Nrf2 Signaling Pathway

“…The first organ to be exposed to AFB1 is the intestine, which weakens the intestinal cell viability and disorders the expression of tight junction proteins, weakening the intestinal barrier [ 23 ]. In this study, we obtained the same results.…”

Farnesoid X Receptor Plays a Key Role in Ochratoxin A-Induced Nephrotoxicity by Targeting Ferroptosis In Vivo and In Vitro

“…In the current study, OTA treatment decreased FXR mRNA and protein expressions in kidney and HK-2 cells, consistent with the recently published paper that AFB1 suppressed FXR protein expressions in the liver of mice and IPEC-J2 cells. 39,40 Besides, this work used the FXR activator GW4064 to boost FXR expression. GW4064 reversed the increase in BUN, CRE, and UA levels, Ntn-1, Kim-1, TNF-α, IL-1β, and IL-6 mRNA levels, decrease in IL-10 mRNA level, and lessened pathological injury of the kidney induced by OTA.…”

Aflatoxin B1-Induced Testosterone Biosynthesis Disorder via the ROS/AMPK Signaling Pathway in Male Mice

“…Mycotoxins cause a major health hazard to both animals and humans, and a recent increase in the male reproductive disorder has been related to the increased occurrence of mycotoxins in food and the environment . AFB 1 is a mycotoxin that can contaminate agricultural products and accumulate in livestock and poultry through the enrichment in the food chain, causing serious food safety problems . Our previous study found that AFB 1 decreased testis coefficients, and damaged testicular morphology of mice. , One of the main functions of the testis is to synthesize T. Reduced T biosynthesis caused by AFB 1 is the main factor that induces reproductive dysfunction and male infertility; , however, the precise mechanism is still unclear.…”