Melatonin mitigates aflatoxin B1‐induced liver injury via modulation of gut microbiota/intestinal FXR/liver TLR4 signaling axis in mice

Abstract

Aflatoxin B1 (AFB1) is a widespread contaminant in foods and feedstuffs, and its target organ is the liver. Melatonin (MT) has been shown to alleviate inflammation in organs and remodel gut microbiota in animals and humans.

Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications

“…Recently, Mehrzad’s study found that AFB1 exposure (i.e., 10 ng/mL for 12 h) could significantly upregulate the expression of MyD88, NF-κB, tumor necrosis factor-alpha (TNF-α), TLR2, TLR4, cyclooxygenase 2 (COX-2), human leukocyte antigen–DR isotype (HLA-DR), CD209, CD16, C-C motif chemokine receptor 7 (CCR7), and lymphocyte function-associated antigen 3 (LFA3), and it could significantly downregulate the expression of CD11c and CD64, Aryl hydrocarbon receptor (AhR), and transforming growth factor-β (TGF-β) in human dendritic cells, indicating that AFB1 exposure could alter the transcription of key functional immune and inflammatory genes, phagocytosis, and survival of human dendritic cells [ 113 ]. Consistent findings were confirmed in the liver and ileum tissues of mice and liver tissues of chicken [ 34 , 49 ]. Furthermore, AFB1-induced activation of TLR4/NF-κB may be attributed to the production of LPS caused by AFB1-induced gut-microbiota-dysfunction-derived abundance of LPS-producing related bacteria [ 49 ].…”

“…Consistent findings were confirmed in the liver and ileum tissues of mice and liver tissues of chicken [ 34 , 49 ]. Furthermore, AFB1-induced activation of TLR4/NF-κB may be attributed to the production of LPS caused by AFB1-induced gut-microbiota-dysfunction-derived abundance of LPS-producing related bacteria [ 49 ]. An early study found that LPS could enhance AFB1-induced liver toxicity, and this was dependent on the production of TNF-α [ 125 ].…”

“…Additionally, AFB1 might greatly inhibit the immune response, raising the risk of cirrhosis and HCC in those with chronic hepatitis B virus infection [ 43 , 44 ]. Excess reactive oxygen species (ROS) production, DNA damage, oxidative stress, lipid peroxidation, apoptosis, mitochondrial dysfunction, autophagy, necrosis, and inflammatory response were all implicated in the pathways of AFB1-induced cytotoxicity or cell death [ 45 , 46 , 47 , 48 , 49 , 50 ]. A number of signaling pathways, such as those involving p53, p21, phosphatidylinositide 3-kinase (PI3K), protein kinase B (PKB, also known as Akt), mammalian target of rapamycin (mTOR), NF-E2-related factor 2 (Nrf2), antioxidant responsive element (ARE), nuclear factor kappa-B (NF-κB), Toll-like receptor 4 (TLR4), TLR2, NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/Caspase-1, mitogen-activated protein kinases (MAPKs), and Wnt/β-catenin pathways, were exemplified to participate in AFB1-induced toxic effects in in vitro and in vivo models [ 45 , 46 , 47 , 48 , 49 , 50 ].…”

Investigation of the Therapeutic Effect of Total Alkaloids of Corydalis saxicola Bunting on CCl4-Induced Liver Fibrosis in Rats by LC/MS-Based Metabolomics Analysis and Network Pharmacology

“…This may be the result of intestinal inflammation caused by liver fibrosis. In addition, increased intestinal permeability leads to liver toxic substances (such as LPS) entering into the liver [ 45 ] and promotes intestinal bacterial translocation [ 46 ], thereby activating the hepatic inflammatory pathway and aggravating hepatic fibrosis. Nevertheless, the downregulation of glutathione was reversed by TACS intervention, indicating that TACS could ameliorate the disturbed glutathione metabolism.…”

Environmental toxicants impact on liver physiology and function

“…AFB1 can induce mutations in genomic DNA, and it can lead to neoplastic transformations through the deregulation of epigenetic conditions. 11 The toxic effects of AFB1 on the liver are closely associated with its metabolic activation to the free radical AFB1-exo-8,9-epoxide (AFBO) through the involvement of the cytochrome P-450 enzymes. 12 It is further associated with the formation of ROS, especially the hydroxyl radical (HO.…”