The trichothecenes, produced by Fusarium, contaminate animal feed and human food in all stages of production and lead to a large spectrum of adverse effects for animal and human health. An hallmark ...of trichothecenes toxicity is the onset of emesis followed by anorexia and food intake reduction in different animal species (mink, mice and pig). The modulation of emesis and anorexia can result from a direct action of trichothecenes in the brain or from an indirect action in the gastrointestinal tract. The direct action of trichothecenes involved specific brain areas such as nucleate tractus solitarius in the brainstem and the arcuate nuclei in the hypothalamus. Activation of these areas in the brain leads to the activation of specific neuronal populations containing anorexigenic factors (POMC and CART). The indirect action of trichothecenes in the gastrointestinal tract involved, by enteroendocrine cells, the secretion of several gut hormones such as cholecystokinin (CCK) and peptide YY (PYY) but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP) and 5-hydroxytryptamine (5-HT), which transmitted signals to the brain via the gut-brain axis. This review summarizes current knowledge on the effects of trichothecenes, especially deoxynivalenol, on emesis and anorexia and discusses the mechanisms underlying trichothecenes-induced food reduction.
•Trichothecenes are a family of mycotoxins, produced by fungi.•Trichothecenes have adverse effects including emesis, anorexia, growth retardation.•The central nervous system is involved in emesis/anorexia induced by trichothecenes.•Trichothecenes modulate the release of gut hormones (CCK, PYY, GIP, 5-HT, GLP-1).
Intestinal barrier defects lead to "leaky gut syndrome", defined as an increase in intestinal permeability that allows the passage of luminal content into intestinal tissue and the bloodstream. Such ...a compromised intestinal barrier is the main factor underlying the pathogenesis of inflammatory bowel disease, but also commonly occurs in various systemic diseases such as viral infections and metabolic syndrome. The non-pathogenic yeast
CNCM I-745 has demonstrated its effectiveness as a probiotic in the prevention and treatment of antibiotic-associated, infectious and functional diarrhea. Via multiple mechanisms of action implicated in intestinal barrier function,
has beneficial effects on altered intestinal microbiota and epithelial barrier defects in different pathologies. The well-studied probiotic yeast
plays a crucial role in the preservation and/or restoration of intestinal barrier function in multiple disorders. This could be of major interest in diseases characterized by alterations in intestinal barrier function.
The intestinal epithelium is a functional and physical barrier formed by a cell monolayer that constantly differentiates from a stem cell in the crypt. This is the first target for food contaminants, ...especially mycotoxins. Deoxynivalenol (DON) is one of the most prevalent mycotoxins. This study compared the effects of DON (0–100 μM) on proliferative and differentiated intestinal epithelial cells. Three cell viability assays (LDH release, ATP content and neutral red uptake) indicated that proliferative Caco-2 cells are more sensitive to DON than differentiated ones. The establishment of transepithelial electrical resistance (TEER), as a read out of the differentiation process, was delayed in proliferative cells after exposure to 1 μM DON. Transcriptome analysis of proliferative and differentiated exposure to 0–3 μM DON for 24 h revealed 4862 differentially expressed genes (DEG) and indicated an effect of both the differentiation status and the DON treatment. KEGG enrichment analysis indicated involvement of metabolism, ECM receptors and tight junctions in the differentiation process, while ribosome biogenesis, mRNA surveillance, and the MAPK pathway were involved in the response to DON. The number of differentially expressed genes and the amplitude of the effect were higher in proliferative cells exposed to DON than that in differentiated cells. In conclusion, our study shows that proliferative cells are more susceptible than differentiated ones to DON and that the mycotoxin delays the differentiation process.
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•Intestinal proliferative cells are more sensitive to deoxynivalenol (DON) than differentiated cells.•DON delays the establishment of TEER in proliferative cells.•DON up-regulated genes involved in ribosome biogenesis, mRNA surveillance and MAPk.•DON down-regulated genes involved in protein digestion and absorption, metabolic pathway and cholesterol metabolism.•Upon DON exposure more genes are differentially expressed in proliferative cells than in differentiated ones.
Proliferative intestinal epithelial cells are more susceptible than differentiated ones, to DON.
NX is a type A trichothecene produced by
Fusarium graminearum
with limited information on its toxicity. NX is structurally similar to deoxynivalenol (DON), only differing by the lacking keto group at ...C8. Because of the structural similarity of the two toxins as well as their potential co-occurrence in food and feed, it is of interest to determine the toxicity of this new compound. In this study, we compared the protein composition of the extracellular media of pig intestinal explants (secretome) exposed to 10 µM of DON or NX for 4 h compared with controls. The combination of two complementary quantitative proteomic approaches (a gel-based and a gel-free approach) identified 18 and 23 differentially abundant proteins (DAPs) for DON and NX, respectively, compared to controls. Functional analysis suggested that, whereas DON toxicity was associated with decreased cell viability and cell destruction, NX toxicity was associated with an enrichment of mitochondrial proteins in the secretome. The presence of these proteins may be associated with the already known ability of NX to induce an intestinal inflammation. Overall, our results indicated that DON- and NX-induced changes in the extracellular proteome of intestinal explants are different. The increased leakage/secretion of mitochondrial proteins by NX may be a feature of NX toxicity.
Deoxynivalenol (DON), one of the most widespread mycotoxins in Europe, and cadmium (Cd), a widespread environmental pollutant, are common food contaminants. They exert adverse effects on different ...organs including kidney, liver, and intestine. The intestine is a common target of DON and Cd when they are ingested. Most studies have focused on their individual effects whereas their combined toxicity has rarely been studied. The aim of this study was thus to evaluate their individual and combined effects on the intestinal barrier function in vitro and in vivo. In vitro, Caco-2 cells were treated with increasing concentrations of DON and Cd (1–30 μM). In vivo, Wistar rats were used as controls or exposed to DON contaminated feed (8.2 mg/kg feed), Cd-contaminated water (5 mg/l) or both for four weeks. In Caco-2 cells, DON, Cd and the DON+Cd mixture reduced transepithelial electrical resistance (TEER) and increased paracellular permeability in a dose-dependent manner. Impairment of the barrier function was associated with a decrease in the amount of E-cadherin and occludin after exposure to the two contaminants alone or combined. A decrease in E-cadherin expression was observed in rats exposed to the two contaminants alone or combined, whereas occludin expression only decreased in animals exposed to DON and DON+Cd. Jejunal crypt depth was reduced in rats exposed to DON or Cd, whereas villi height was not affected. In vitro and in vivo results showed that the effects of exposure to combined DON and Cd on the intestinal barrier function in the jejunum of Wistar rats and in the colorectal cancer cell line (Caco-2) was similar to the effects of each individual contaminant. This suggests that regulations for each individual contaminant are sufficiently protective for consumers.
•Both DON and Cd alter the intestinal epithelial barrier function.•Both DON and Cd disrupt the intercellular junctions (tight and adherens junctions).•Both DON and Cd reduce the depth of jejunal crypts.•Combined, DON and Cd have the same effects as each individual contaminant.
Alteration in intestinal permeability is the main factor underlying the pathogenesis of many diseases affecting the gut, such as inflammatory bowel disease IBD. Characterization of molecules ...targeting the restoration of intestinal barrier integrity is therefore vital for the development of alternative therapies. The yeast Saccharomyces boulardii CNCM I-745 Sb, used to prevent and treat antibiotic-associated infectious and functional diarrhea, may have a beneficial effect in the treatment of IBD.
We analyzed the impact of Sb supernatant on tissue integrity and components of adherens junctions using cultured explants of colon from both IBD and healthy patients. To evaluate the pathways by which Sb regulates the expression of E-cadherin at the cell surface, we developed in vitro assays using human colonic cell lines, including cell aggregation, a calcium switch assay, real-time measurement of transepithelial electrical resistance TEER and pulse-chase experiments.
We showed that Sb supernatant treatment of colonic explants protects the epithelial morphology and maintains E-cadherin expression at the cell surface. In vitro experiments revealed that Sb supernatant enhances E-cadherin delivery to the cell surface by re-routing endocytosed E-cadherin back to the plasma membrane. This process, involving Rab11A-dependent recycling endosome, leads to restoration of enterocyte adherens junctions, in addition to the overall restoration and strengthening of intestinal barrier function.
These findings open new possibilities of discovering novel options for prevention and therapy of diseases that affect intestinal permeability.
Intestinal epithelial cell damage is frequently seen in the mucosal lesions of infectious or inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. Complete remission of these ...diseases requires both the disappearance of inflammation and the repair of damaged epithelium. Saccharomyces boulardii (Sb, Biocodex) is a non-pathogenic yeast widely used as a preventive and therapeutic probiotic for the prevention and treatment of diarrhea and other gastrointestinal disorders. We recently showed that it enhances the repair of intestinal epithelium through activation of α2β1 integrin collagen receptors. In the present study, we demonstrated that α2β1 integrin is not the sole cell-extracellular matrix receptor involved during Sb-mediated intestinal restitution. Indeed, by using cell adhesion assays, we showed that Sb supernatant contains heat sensitive molecule(s), with a molecular weight higher than 9 kDa, which decreased αvβ5 integrin-mediated adhesion to vitronectin by competing with the integrin. Moreover, Sb-mediated changes in cell adhesion to vitronectin resulted in a reduction of the αvβ5signaling pathway. We used a monolayer wounding assay that mimics in vivo cell restitution to demonstrate that down-modulation of the αvβ5 integrin-vitronectin interaction is related to Sb-induced cell migration. We therefore postulated that Sb supernatant contains motogenic factors that enhance cell restitution through multiple pathways, including the dynamic fine regulation of αvβ5 integrin binding activity. This could be of major importance in diseases characterized by severe mucosal injury, such as inflammatory and infectious bowel diseases.
Most patients affected with colorectal cancers (CRC) are treated with 5-fluorouracil (5-FU)-based chemotherapy but its efficacy is often hampered by resistance mechanisms linked to tumor ...heterogeneity. A better understanding of the molecular determinants involved in chemoresistance is critical for precision medicine and therapeutic progress. Caudal type homeobox 2 (CDX2) is a master regulator of intestinal identity and acts as tumor suppressor in the colon. Here, using a translational approach, we examined the role of CDX2 in CRC chemoresistance. Unexpectedly, we discovered that the prognosis value of CDX2 for disease-free survival of patients affected with CRC is lost upon chemotherapy and that CDX2 expression enhances resistance of colon cancer cells towards 5-FU. At the molecular level, we found that CDX2 expression correlates with higher levels of genes regulating the bioavailability of 5-FU through efflux (ABCC11) and catabolism (DPYD) in patients affected with CRC and CRC cell lines. We further showed that CDX2 directly regulates the expression of ABCC11 and that the inhibition of ABCC11 improves 5-FU-sensitivity of CDX2-expressing colon cancer cells. Thus, this study illustrates how biological functions are hijacked in CRC cells and reveals the therapeutic interest of CDX2/ABCC11/DPYD to improve systemic chemotherapy in CRC.
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•Chemotherapy has reduced efficacy in the presence of CDX2.•CDX2 increases the expression of several genes involved in chemoresistance.•The 5-FU transporter ABCC11 is a direct target gene of CDX2.•ABCC11 contributes to CDX2-associated chemoresistance.
Fumonisins (FBs) are mycotoxins produced by
species that can contaminate human food and animal feed. Due to the harmful effects of FBs on animals, the European Union (EU) defined a recommendation of ...a maximum of 5 mg FBs (B1 + B2)/kg for complete feed for swine and 1 µg FBs/kg body weight per day as the tolerable daily intake for humans. The aim of this study was to evaluate the toxicity of dietary exposure to low doses of FBs, including a dose below the EU regulatory limits. Four groups of 24 weaned castrated male piglets were exposed to feed containing 0, 3.7, 8.1, and 12.2 mg/kg of FBs for 28 days; the impact was measured by biochemical analysis and histopathological observations. Dietary exposure to FBs at a low dose (3.7 mg/kg of feed) significantly increased the plasma sphinganine-to-sphingosine ratio. FBs-contaminated diets led to histological modifications in the intestine, heart, lung, lymphoid organs, kidney, and liver. The histological alterations in the heart and the intestine appeared at the lowest dose of FBs-contaminated diet (3.7 mg/kg feed) and in the kidney at the intermediate dose (8.1 mg/kg feed). At the highest dose tested (12.2 mg/kg feed), all the organs displayed histological alterations. This dose also induced biochemical modifications indicative of kidney and liver alterations. In conclusion, our data indicate that FBs-contaminated diets at doses below the EU regulatory limit cause histological lesions in several organs. This study suggests that EU recommendations for the concentration of FBs in animal feed, especially for swine, are not sufficiently protective and that regulatory doses should be modified for better protection of animal health.
Intestinal epithelial cell damage is frequently seen in the mucosal lesions of infectious or inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. Complete remission of these ...diseases requires both the disappearance of inflammation and the repair of damaged epithelium. Saccharomyces boulardii (Sb, Biocodex) is a non-pathogenic yeast widely used as a preventive and therapeutic probiotic for the prevention and treatment of diarrhea and other gastrointestinal disorders. We recently showed that it enhances the repair of intestinal epithelium through activation of alpha2beta1 integrin collagen receptors. In the present study, we demonstrated that alpha2beta1 integrin is not the sole cell-extracellular matrix receptor involved during Sb-mediated intestinal restitution. Indeed, by using cell adhesion assays, we showed that Sb supernatant contains heat sensitive molecule(s), with a molecular weight higher than 9 kDa, which decreased alphavbeta5 integrin-mediated adhesion to vitronectin by competing with the integrin. Moreover, Sb-mediated changes in cell adhesion to vitronectin resulted in a reduction of the alphavbeta5signaling pathway. We used a monolayer wounding assay that mimics in vivo cell restitution to demonstrate that down-modulation of the alphavbeta5 integrin-vitronectin interaction is related to Sb-induced cell migration. We therefore postulated that Sb supernatant contains motogenic factors that enhance cell restitution through multiple pathways, including the dynamic fine regulation of alphavbeta5 integrin binding activity. This could be of major importance in diseases characterized by severe mucosal injury, such as inflammatory and infectious bowel diseases.
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