Exposure to the mycotoxin deoxynivalenol reduces the transport of conjugated bile acids by intestinal Caco-2 cells

Wang, Jingxuan; Bakker, Wouter; Zheng, Weijia; Haan, Laura de; Rietjens, Ivonne M.C.M.; Bouwmeester, Hans

doi:10.1007/s00204-022-03256-8

Cited by 4 publications

(12 citation statements)

References 48 publications

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“…DON-3/15-GlcA and DOM-1 are less abundant in the human intestine than free-DON, and they are less potent in inducing the pro-inflammatory response than free-DON . Moreover, these DON metabolites likely do not reduce bile acid transport because their molecular structure is larger than that of free-DON hampering their binding to ribosomes, which is the molecular initiating event of bile acid malabsorption . Thus, DON-3/15-GlcA and DOM-1 are not included in the current PBK modeling.…”

Section: Methodsmentioning

confidence: 99%

“…1 Moreover, these DON metabolites likely do not reduce bile acid transport because their molecular structure is larger than that of free-DON hampering their binding to ribosomes, which is the molecular initiating event of bile acid malabsorption. 25 Thus, DON-3/15-GlcA and DOM-1 are not included in the current PBK modeling.…”

Section: Development Of a Pbk Model For Don In Humansmentioning

confidence: 99%

“…The transport of GCDCA across Caco-2 cell layers was studied following 0−2.5 μM DON exposure as DON does not affect the Caco-2 barrier integrity at concentrations up to 2.5 μM. 14 DON-pre-exposed Caco-2 cells were apically exposed to GCDCA, and the transport of GCDCA from the apical to the basolateral compartment was determined. The k a-GCDCA dose-dependently decreased from 0.92 ± 0.01/h (without DON exposure) to 0.77 ± 0.07, 0.75 ± 0.05, 0.67 ± 0.01, and 0.51 ± 0.06/h following 0.125, 0.25, 1.0, and 2.5 μM DON pre-exposure (Figure 5A).…”

Section: Model Evaluation By Comparison Of Predictions Tomentioning

confidence: 99%

“…GCDCA in the transport medium was quantified using the LC/MS/MS Shimadzu 8045 System (Kyoto, Japan) as shown before. 14 Aliquots of samples and standards (1 μL) were separated using a Phenomenex 00B-4475-AN column ( phases consisting of Milli-Q water with 0.01% formic acid (A) and methanol with 50% acetonitrile (B) was set at 0.4 mL/min: the starting gradient contained 30% B, which linearly increased to 70% B over 10 min then increased to 98% B at 11.0−18.0 min and finally was reduced to 30% at 19−25 min. The mass spectrometer (MS) used electrospray ionization in the negative-ion mode with the optimal electrospray ionization source parameters as follows: a nebulizer gas flow of 3 L/min, a heating gas and drying gas flow of 10 L/min, the interface temperature at 300 °C, the desolvation line temperature at 250 °C, and the heat block temperature at 400 °C.…”

Section: In Vitro Pro-inflammatory Effect Of Don On Immune Thp-1 Cellsmentioning

confidence: 99%

“…In addition, intestinal inflammation is associated with bile acid malabsorption in humans . Recent studies have shown that DON disrupts bile acid transport across intestinal epithelium Caco-2 cell layers. , Bile acids are synthesized in the liver and secreted into the intestinal lumen via bile. Most bile acids are reabsorbed via the intestinal epithelium and are transported back to the liver .…”

Section: Introductionmentioning

confidence: 99%

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Use of Physiologically Based Kinetic Modeling to Predict Deoxynivalenol Metabolism and Its Role in Intestinal Inflammation and Bile Acid Kinetics in Humans

Wang,

de Bruijn,

Rietjens

et al. 2023

J. Agric. Food Chem.

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Current points of departure used to derive health-based guidance values for deoxynivalenol (DON) are based on studies in laboratory animals. Here, an animal-free testing approach was adopted in which a reverse dosimetry physiologically based kinetic (PBK) modeling is used to predict in vivo dose response curves for DON's effects on intestinal pro-inflammatory cytokine secretion and intestinal bile acid reabsorption in humans from concentration−effect relationships for DON in vitro. The calculated doses for inducing a 5% added effect above the background level (ED 5 ) of DON for increasing IL-1β secretion in intestinal tissue and for increasing the amounts in the colon lumen of glycochenodeoxycholic acid (GCDCA) were 246 and 36 μg/kg bw/day, respectively. These in vitro−in silico-derived ED 5 values were compared to human dietary DON exposure levels, indicating that the risk of DON's effects on these end points occurring in various human populations cannot be excluded. This in vitro−in silico approach provides a novel testing strategy for hazard and risk assessment without using laboratory animals.

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Section: Methodsmentioning

confidence: 99%

Section: Development Of a Pbk Model For Don In Humansmentioning

confidence: 99%

Section: Model Evaluation By Comparison Of Predictions Tomentioning

confidence: 99%

Section: In Vitro Pro-inflammatory Effect Of Don On Immune Thp-1 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Use of Physiologically Based Kinetic Modeling to Predict Deoxynivalenol Metabolism and Its Role in Intestinal Inflammation and Bile Acid Kinetics in Humans

Wang,

de Bruijn,

Rietjens

et al. 2023

J. Agric. Food Chem.

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Complementary transcriptomic and proteomic analyses elucidate the toxicological molecular mechanisms of deoxynivalenol-induced contractile dysfunction in enteric smooth muscle cells

Qiao,

Ji,

Guo

et al. 2024

Food and Chemical Toxicology

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New approach methodologies (NAMs) to understand and predict drug-induced effects on bile acid homeostasis and cholestasis

de Bruijn

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General introduction1.1 Bile acids as signaling molecules Bile acids are the major functional components of bile, and have been known to serve as emulsifiers of dietary lipids and lipid-soluble vitamins for a long time (Hofmann, 1961). Bile acids are found throughout the whole body, but mainly in the liver, gall bladder and intestine (Jantti et al., 2014; Monteiro-Cardoso et al., 2021). Besides their role as emulsifiers in the intestinal lumen, bile acids are increasingly recognized as important hormone-like signaling molecules regulating lipid, glucose and energy metabolism and innate and adaptive immune functions in the whole body (Jia et al., 2023;Hylemon et al., 2009). Bile acids exert these signaling functions via binding to numerous nuclear receptors, such as the farnesoid X receptor (FXR, NR1H4), the G protein-coupled bile acid receptor (TGR5, GPBAR1), vitamin D receptor (VDR, NR1I1) and pregnane X receptor (PXR, NR1I2) (Guo et al., 2003; Makishima et al., 2002; Anstee et al., 2013). Two major pathways include those regulated via FXR and TGR5 (Fiorucci et al., 2009). FXR is highly expressed in the gastrointestinal tract . FXR tightly controls bile acid homeostasis by regulation the expression of genes related to bile acid synthesis, secretion and absorption. FXR also acts as a metabolic sensor in glucose metabolism, lipid and energy metabolism (Chiang, 2017), and regulates cell proliferation and inflammation (Fiorucci et al., 2011). Furthermore, FXR-deficient mice were shown to have increased colon cell proliferation rates and subsequent tumorigenesis compared to wildtype mice, indicating that FXR has anti-tumorigenic properties (Maran et al., 2009). TGR5 is not only expressed throughout the intestinal epithelium, but also in monocytes and macrophages, liver sinusoidal endothelial cells and Kupffer cells, but not in hepatocytes . TGR5 regulates amongst others energy homeostasis, intestinal integrity, insulin secretion, cell proliferation and inflammation (Ticho et al., 2019; Guo et al., 2016).Bile acids are involved in the crosstalk between the host and the gut microbiome in the intestinal lumen. The gut microbiome is a dynamic ecosystem that plays a pivotal role in shaping various aspects of human physiology and heath (Visconti et al., 2019). Comprising more than 100 trillion microorganisms, the microbiome forms a symbiotic relationship with the host, influencing essential functions ranging from digestion to immune response modulation (Comess and Abad-Jorge, 2023). Several microbial species in the microbiome possess the ability to modify bile acid structures. These modifications result in different bile acid species with different kinetic and signaling properties.For example, the first bacterial modification step is deconjugation of bile acids. Deconjugation improves membrane-permeability and thereby intestinal reuptake of bile acids . Furthermore, the affinity for the nuclear receptors depends on the type of bile acid formed, since some types of bile acids are more potent ligands for nuclear recept...

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Exposure to the mycotoxin deoxynivalenol reduces the transport of conjugated bile acids by intestinal Caco-2 cells

Cited by 4 publications

References 48 publications

Use of Physiologically Based Kinetic Modeling to Predict Deoxynivalenol Metabolism and Its Role in Intestinal Inflammation and Bile Acid Kinetics in Humans

Use of Physiologically Based Kinetic Modeling to Predict Deoxynivalenol Metabolism and Its Role in Intestinal Inflammation and Bile Acid Kinetics in Humans

Complementary transcriptomic and proteomic analyses elucidate the toxicological molecular mechanisms of deoxynivalenol-induced contractile dysfunction in enteric smooth muscle cells

New approach methodologies (NAMs) to understand and predict drug-induced effects on bile acid homeostasis and cholestasis

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