Deoxynivalenol as a New Factor in the Persistence of Intestinal Inflammatory Diseases: An Emerging Hypothesis through Possible Modulation of Th17-Mediated Response

Cano, Patricia; Seeboth, Julie; Meurens, François; Cognié, Juliette; Abrami, Roberta; Oswald, Isabelle P.; Guzylack‐Piriou, Laurence

doi:10.1371/journal.pone.0053647

Cited by 96 publications

(92 citation statements)

References 67 publications

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“…Cytokines and chemokines are sensitive biomarkers for DON exposure (Pestka 2010;Wu et al 2014a). Indeed, pro-inflammatory response upon DON exposure has been described both in vitro in cell lines from murine, human and porcine origins and in vivo in several organs (Cano et al 2013;Pestka 2010). In contrast to DON, D3G did not induce any histological damage and was largely incapable of evoking ribotoxin-induced cytokine production on pig jejunum confirming data obtained in vivo in mouse spleens (Wu et al 2014a).…”

Section: Discussionsupporting

confidence: 66%

“…Pig can be regarded as a good model of extrapolation to humans (Helke and Swindle 2013). DON induces morphological injury (Osselaere et al 2013) and inflammation on porcine jejunum explants (Cano et al 2013). Cytokines and chemokines are sensitive biomarkers for DON exposure (Pestka 2010;Wu et al 2014a).…”

Section: Discussionmentioning

confidence: 99%

“…DON alters the integrity of the intestine, resulting in a loss of mucosal integrity and a translocation of commensal and pathogenic bacteria across the epithelium (Maresca 2013;Pinton and Oswald 2014). DON also disturbs the intestinal immune responses: The toxin induces the local production of pro-inflammatory cytokines and potentiates existing intestinal inflammatory processes (Cano et al 2013;Van De Walle et al 2010;Vandenbroucke et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside

et al. 2015

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Natural food contaminants such as mycotoxins are an important problem for human health. Deoxynivalenol (DON) is one of the most common mycotoxins detected in cereals and grains. Its toxicological effects mainly concern the immune system and the gastrointestinal tract. This toxin is a potent ribotoxic stressor leading to MAP kinase activation and inflammatory response. DON frequently co-occurs with its glucosylated form, the masked mycotoxin deoxynivalenol-3-β-D-glucoside (D3G). The toxicity of this later compound remains unknown in mammals. This study aimed to assess the ability of D3G to elicit a ribotoxic stress and to induce intestinal toxicity. The toxicity of D3G and DON (0-10 µM) was studied in vitro, on the human intestinal Caco-2 cell line, and ex vivo, on porcine jejunal explants. First, an in silico analysis revealed that D3G, contrary to DON, was unable to bind to the A-site of the ribosome peptidyl transferase center, the main targets for DON toxicity. Accordingly, D3G did not activate JNK and P38 MAPKs in treated Caco-2 cells and did not alter viability and barrier function on cells, as measured by the trans-epithelial electrical resistance. Treatment of intestinal explants for 4 h with 10 µM DON induced morphological lesions and up-regulated the expression of pro-inflammatory cytokines as measured by qPCR and pan-genomic microarray analysis. By contrast, expression profile of D3G-treated explants was similar to that of controls, and these explants did not show histomorphology alteration. In conclusion, our data demonstrated that glucosylation of DON suppresses its ability to bind to the ribosome and decreases its intestinal toxicity.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside

et al. 2015

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“…For example, vomitoxin (deoxynivalenol or DON) provokes intestinal inflammation in vivo [267], and its presence drives the immune system in the intestine toward a Th17 bias involving the presence of the pathogenic group of activated Th17 cells [268,269]. Ingestion of this toxin induces significant increases in the levels of proinflammatory cytokines and chemokines, e.g., IL-8, IL-1β, TNFα, and IL-6 [270,271].…”

Section: Chronic Mold and Mycotoxin Exposurementioning

confidence: 99%

“…DON activates ERK1/2 thereby activating MAPK signaling cascades that consequently upregulate COX-2, NF-κB, and PGE-2 which are major drivers of the inflammatory response [241,268,272]. DON also significantly induces the expression of several genes that play a role in driving the differentiation of Th17 cells including signal transducer and activator of transcription 3 (STAT3), IL-17A, and suppresses the production of T regulatory cells and the transcription of FoxP3 [269]. Furthermore, this trichothecene stimulates IL-23A, IL-22, and IL-21 production at the expense of IL-10 producing Th17 lymphocytes [269].…”

Section: Chronic Mold and Mycotoxin Exposurementioning

confidence: 99%

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

Morris¹,

Berk

Walder

et al. 2015

Mol Neurobiol

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Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

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Impacts of the feed contaminant deoxynivalenol on the intestine of monogastric animals: poultry and swine

Ghareeb

Awad

Böhm

et al. 2014

J of Applied Toxicology

142

111

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Deoxynivalenol (DON) is one of the most prevalent cereal contaminants with major public health concerns owing to its high toxigenic potentials. Once ingested, DON first and foremost targets epithelial cells of the gastrointestinal tract, whose proper functioning, as the first line of defence, is of paramount importance for the host's health. Emerging evidences, summarized in this article, suggest that DON produces its toxicity primarily via activation of the mitogen-activated protein kinases (MAPKs) signalling pathway and alteration in the expression of genes responsible for key physiological and immunological functions of the intestinal tissue of chickens and pigs. The activation of MAPKs signalling cascade results in disruption of the gut barrier function and an increase in the permeability by reducing expression of the tight junction proteins. Exposure to DON also down-regulates the expression of multiple transporter systems in the enterocytes with subsequent impairment of the absorption of key nutrients. Other major intestinal cytotoxic effects of DON described herein are modulation of mucosal immune responses, leading to immunosupression or stimulation of local immune cells and cytokine release, and also facilitation of the persistence of intestinal pathogens in the gut. Both of the last events potentiate enteric infections and local inflammation in pigs and poultry, rendering enterocytes and the host more vulnerable to luminal toxic compounds. This review highlights the cytotoxic risks associated with the intake of even low levels of DON and also identifies gaps of knowledge that need to be addressed by future research.

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Deoxynivalenol as a New Factor in the Persistence of Intestinal Inflammatory Diseases: An Emerging Hypothesis through Possible Modulation of Th17-Mediated Response

Cited by 96 publications

References 67 publications

Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside

Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

Impacts of the feed contaminant deoxynivalenol on the intestine of monogastric animals: poultry and swine

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