Effects of Aluminum on the Integrity of the Intestinal Epithelium: An in Vitro and in Vivo Study

Abstract

BACKGROUND: Aluminum (Al) is the most abundant and ubiquitous metal in the environment. The main route of human exposure to Al is through food and water intake. Although human exposure to Al is common, the influence of Al on the gastrointestinal tract remains poorly understood. OBJECTIVES: We aimed to further understand the toxic effect of Al and to elucidate the underlying cellular mechanisms in the intestinal barrier. METHODS: The human intestinal epithelial cell line HT-29 and C57BL6 mice were exposed to AlCl 3 at 0-16 mM (1-24 h) and 5-50 mg=kg body weight (13 weeks), respectively. In cell culture experiments, intracellular oxidative stress, inflammatory protein and gene expression, and intestinal epithelial permeability were measured. In animal studies, histological examination, gene expression, and myeloperoxidase (MPO) activity assays were conducted. RESULTS: Cellular oxidative stress level (superoxide production) in AlCl 3-treated cells (4 mM, 3 h) was approximately 38-fold higher than that of the control. Both protein and mRNA expression of tight junction (TJ) components (occludin and claudin-1) in AlCl 3-treated cells (1-4 mM, 24 h) was significantly lower than that of the control. Transepithelial electrical resistance (TEER) decreased up to 67% in AlCl 3-treated cells (2 mM, 24 h) compared with that of the control, which decreased approximately 7%. Al activated extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B (NF-jB), resulting in mRNA expression of matrix metalloproteinase-9, myosin light-chain kinase, and inflammatory cytokines [tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b), and IL-6] in HT-29 cells. Moreover, oral administration of AlCl 3 to mice induced pathological alteration, MPO activation, and inflammatory cytokine (TNF-a, IL-1b, and IL-6) production in the colon. CONCLUSION: Al induced epithelial barrier dysfunction and inflammation via generation of oxidative stress, down-regulation of the TJ proteins, and production of inflammatory cytokines in HT-29 cells. In addition, Al induced toxicity in the colon by increasing the levels of inflammatory cytokines and MPO activity and induced histological damage in a mouse model. Our data suggest that Al may be a potential risk factor for human intestinal diseases.

Verapamil administration alleviates microcytosis and tissue accumulation after chronic aluminum exposure in rats

“…The most important finding, that MCV and MCHC values were significantly reversed after verapamil administration may be explained by the hypothesis that AlCl3 changes erythrocyte membrane permeability for ions, interrupting the function of the cation pumps [17], phenomenon that, based on presented findings, may be alleviated by calcium channels blockage.…”

“…In recent years, there has been abundant data on Al systemic toxicity, in order to clarify its role in the pathophysiology of many disorders: reproductive and breast diseases [2], bone impairment [3], lung disorders [4], impacts on the immune system [5], as well as neurological diseases [6], whereas inhibition of Ca 2+ channels may represent potential therapeutic strategy for addressing Al-induced toxicity.…”

Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation

“…Earlier studies have shown that Helicobacter pylori induced activation of NF-κB, leading to MMP-9 gene transcription in gastric epithelial cells [ 65 ]. More recent studies have shown that aluminum caused an increase in HT-29 intestinal epithelial TJ permeability that was mediated by NF-κB induced up-regulation of MMP-9 [ 66 ]. In addition to their roles in increasing intestinal permeability, the current study showed the sequential relationship of MMP-9 activating the downstream effector NF-κB to regulate the intestinal epithelial TJ barrier function.…”

Assessment of Pb(II), Cd(II), and Al(III) Removal Capacity of Bacteria from Food and Gut Ecological Niches: Insights into Biodiversity to Limit Intestinal Biodisponibility of Toxic Metals

“…It has also been suggested that Al is involved in neurological disorders, such as Alzheimer’s disease, autism spectrum disorders, and multiple sclerosis [ 20 ]. With regard to the digestive tract, Al induces epithelial barrier dysfunction, abdominal pain, and inflammation [ 21 , 22 ], and the metal’s involvement in inflammatory bowel disease is strongly suspected [ 23 , 24 , 25 ]. Al adversely affects reproduction [ 25 ], and in utero exposure has a negative impact even at low concentrations [ 26 ].…”