Potential role played by mycotoxins in human intestinal inflammatory diseases.

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Potential role played by mycotoxins in human intestinal inflammatory diseases.

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Dr Marc Maresca

Université Cézanne

Published on 25 October 2010

http://www.scitopics.com/Potential_role_played_by_mycotoxins_in_human_intestinal\

_inflammatory_diseases.html

Human intestinal inflammatory diseases or inflammatory bowel diseases (IBD) are

caracterized by chronic inflammation of the gut, leading to pain, malabsorption,

malnutrition, diarrhea and eventually to lethal complications such as cancers.

Among IBD, Crohn's and celiac diseases are the best know and caracterized. In

both cases, exacerbated immunity and auto-immunity reactions lead to persistent

intestinal inflammation. Although IBD depend primary on genetic predispositions

(associated with mutations in various genes involved in the intestinal immunity

and epithelial integrity) such genetic back-ground is not suffisant. Like in

many other diseases, the induction and the progression of IBD also critically

depend on environmental factors, such as food allergen (i.e. gluten) or bacteria

in celiac and Crohn's diseases, respectively.

Although many publications reported that some mycotoxins, described as

enterotoxic, are able to affect gut integrity and to cause intestinal

inflammation, a link between chronic exposure to mycotoxins and the induction

and/or persistance of IBD in predisposed patients was not proposed until

recently.

Mycotoxins are secondary metabolites produced by different fungal species,

mainly Penicillium, Aspergillus and Fusarium. Due to their antibiotic

activities, it is admitted that molds produce mycotoxins in their natural

environment (i.e. crops and plants) to kill others micro-organisms (bacteria,

others fungi) colonizing the same niche.

In addition to possess antibiotic activities, mycotoxins are known to affect the

cell functions in animals, including humans. Thus, mycotoxins are able to affect

the functions of numerious tissus and systems, including: i) renal, hepatic,

respiratory and intestinal epithelia and ii) the immune, reproductive and

nervous systems. In addition, exposure to certain mycotoxins have been related

to cancerigenic and teratogenic effects in humans and animals.

The impact of some mycotoxins on the intestinal physiology is well known. In

addition to animal experiments, the recent use of cell lines mimicking human

intestinal epithelial cells (hIEC), demonstrated that many food-associated

mycotoxins (mainly aflatoxins, ochratoxins, patulin, fumonisin, trichothecenes,

zearalenone) are able to perturbate key intestinal functions such as: the

barrier function, the absorption of nutriments or the intestinal immunity. Based

on these publications, we recently critically analysed the potential role of

certain mycotoxins as etiologic agents in patients predisposed to IBD [Maresca

and Fantini, 2010].

Based on scientific publications reporting the action of single mycotoxin on

human intestinal epithelial cells and/or animals, we found that many mycotoxins

could be considered as at risk for this particular population based on: i) the

similarity existing between the pathophysiological process involved in the

on-set / the progression of IBD and in mycotoxicosis and ii) on the low security

factor existing in many cases between the doses of mycotoxin causing the

intestinal perturbations and the tolerable daily intact doses (TDI) fixed by

health and agricultural administrations.

Situtation could be even more dramatic if we consider that humans are not

exposed to single mycotoxin but rather to cocktail of mycotoxins and to mixture

of mycotoxins with others toxicans (such as phytotoxins, pesticides, heavy

metals) also able to perturbate the gut function [Mattsson, 2007]. In vitro

experiments on hIEC have already demonstrated that mixture of mycotoxins results

in addive and/or synergistic toxicity eventually leading to a decrease in the

efficient toxic dose of each compound of the mixture [Creppy et al., 2004;

Kouadio et al., 2007]. If such potentiation due to mixture of contaminants also

happens in vivo, it will have major consequence on the safety values of the the

tolerable daily intact doses (TDI).

Although epidemiologic studies are required to confirm our hypothesis, it seems

that certain food-associated mycotoxins have to be added to the list of

molecules and environmental factors potentially involved in the etiology of IBD

in predisposed patients. Effort must be made to limit further the exposure of

this particular population to mycotoxin-contaminated food.

We hope our hypothesis will stimulate discussions and will leads to an

epidemiologic evaluation of a link between food-associated mycotoxins and IBD.

Human intestinal inflammatory diseases or inflammatory bowel diseases (IBD) are

caracterized by chronic inflammation of the gut, leading to pain, malabsorption,

malnutrition, diarrhea and eventually to lethal complications such as cancers.

Among IBD, Crohn's and celiac diseases are the best know and caracterized. In

both cases, exacerbated immunity and auto-immunity reactions lead to persistent

intestinal inflammation. Although IBD depend primary on genetic predispositions

(associated with mutations in various genes involved in the intestinal immunity

and epithelial integrity) such genetic back-ground is not suffisant. Like in

many other diseases, the induction and the progression of IBD also critically

depend on environmental factors, such as food allergen (i.e. gluten) or bacteria

in celiac and Crohn's diseases, respectively.

Although many publications reported that some mycotoxins, described as

enterotoxic, are able to affect gut integrity and to cause intestinal

inflammation, a link between chronic exposure to mycotoxins and the induction

and/or persistance of IBD in predisposed patients was not proposed until

recently.

Mycotoxins are secondary metabolites produced by different fungal species,

mainly Penicillium, Aspergillus and Fusarium. Due to their antibiotic

activities, it is admitted that molds produce mycotoxins in their natural

environment (i.e. crops and plants) to kill others micro-organisms (bacteria,

others fungi) colonizing the same niche.

In addition to possess antibiotic activities, mycotoxins are known to affect the

cell functions in animals, including humans. Thus, mycotoxins are able to affect

the functions of numerious tissus and systems, including: i) renal, hepatic,

respiratory and intestinal epithelia and ii) the immune, reproductive and

nervous systems. In addition, exposure to certain mycotoxins have been related

to cancerigenic and teratogenic effects in humans and animals.

The impact of some mycotoxins on the intestinal physiology is well known. In

addition to animal experiments, the recent use of cell lines mimicking human

intestinal epithelial cells (hIEC), demonstrated that many food-associated

mycotoxins (mainly aflatoxins, ochratoxins, patulin, fumonisin, trichothecenes,

zearalenone) are able to perturbate key intestinal functions such as: the

barrier function, the absorption of nutriments or the intestinal immunity. Based

on these publications, we recently critically analysed the potential role of

certain mycotoxins as etiologic agents in patients predisposed to IBD [Maresca

and Fantini, 2010].

Based on scientific publications reporting the action of single mycotoxin on

human intestinal epithelial cells and/or animals, we found that many mycotoxins

could be considered as at risk for this particular population based on: i) the

similarity existing between the pathophysiological process involved in the

on-set / the progression of IBD and in mycotoxicosis and ii) on the low security

factor existing in many cases between the doses of mycotoxin causing the

intestinal perturbations and the tolerable daily intact doses (TDI) fixed by

health and agricultural administrations.

Situtation could be even more dramatic if we consider that humans are not

exposed to single mycotoxin but rather to cocktail of mycotoxins and to mixture

of mycotoxins with others toxicans (such as phytotoxins, pesticides, heavy

metals) also able to perturbate the gut function [Mattsson, 2007]. In vitro

experiments on hIEC have already demonstrated that mixture of mycotoxins results

in addive and/or synergistic toxicity eventually leading to a decrease in the

efficient toxic dose of each compound of the mixture [Creppy et al., 2004;

Kouadio et al., 2007]. If such potentiation due to mixture of contaminants also

happens in vivo, it will have major consequence on the safety values of the the

tolerable daily intact doses (TDI).

Although epidemiologic studies are required to confirm our hypothesis, it seems

that certain food-associated mycotoxins have to be added to the list of

molecules and environmental factors potentially involved in the etiology of IBD

in predisposed patients. Effort must be made to limit further the exposure of

this particular population to mycotoxin-contaminated food.

We hope our hypothesis will stimulate discussions and will leads to an

epidemiologic evaluation of a link between food-associated mycotoxins and IBD.

continue reading

Further reading

Abid-Essefi et al., (2009). Comparative study of toxic effects of zearalenone

and its two major metabolites alpha- zearalenol and beta-zearalenol on cultured

human Caco-2 cells. J Biochem Mol Toxicol. 23(4):233-43.

Bouhet S, Oswald IP. (2005). The effects of mycotoxins, fungal food

contaminants, on the intestinal epithelial cell-derived innate immune response.

Vet Immunol Immunopathol. 108(1-2):199-209.

Bouhet S, Oswald IP. (2007). The intestine as a possible target for fumonisin

toxicity. Mol Nutr Food Res. 51(8):925-31.

Caloni et al., (2002). Evaluation of Fumonisin B(1) and its metabolites

absorption and toxicity on intestinal cells line Caco- 2. Toxicon.

40(8):1181-188.

Caloni et al., (2006). Aflatoxin M1 absorption and cytotoxicity on human

intestinal in vitro model. Toxicon. 47(4):409-15.

Creppy et al., (2004). Synergistic effects of fumonisin B1 and ochratoxin A: are

in vitro cytotoxicity data predictive of in vivo acute toxicity? Toxicology.

201(1-3):115-23.

Diesing et al., (2010). Mycotoxin deoxynivalenol (DON) mediates biphasic

cellular response in intestinal porcine epithelial cell lines IPEC- 1 and

IPEC-J2. Toxicol Lett. In press.

Kasuga et al., (1998). In vitro effect of deoxynivalenol on the differentiation

of human colonic cell lines Caco- 2 and T84. Mycopathologia. 142(3):161-7.

Kouadio et al., (2005). Comparative study of cytotoxicity and oxidative stress

induced by deoxynivalenol, zearalenone or fumonisin B1 in human intestinal cell

line Caco-2. Toxicology. 213(1-2):56-65.

Kouadio et al., (2007). Effects of combinations of Fusarium mycotoxins on the

inhibition of macromolecular synthesis, malondialdehyde levels, DNA methylation

and fragmentation, and viability in Caco- 2 cells. Toxicon. 49(3):306-17.

Lambert et al., (2007). Ochratoxin A displaces claudins from detergent resistant

membrane microdomains. Biochem Biophys Res Commun. 358(2):632-6.

Mahfoud et al., (2002). pH-dependent interaction of fumonisin B1 with

cholesterol: physicochemical and molecular modeling studies at the air-water

interface. J Agric Food Chem. 50(2):327-31.

Mahfoud et al., (2002). The mycotoxin patulin alters the barrier function of the

intestinal epithelium: mechanism of action of the toxin and protective effects

of glutathione. Toxicol Appl Pharmacol. 181(3):209-18.

Maresca et al., (2001). The mycotoxin ochratoxin A alters intestinal barrier and

absorption functions but has no effect on chloride secretion. Toxicol Appl

Pharmacol. 176(1):54-63.

Maresca et al., (2002). The mycotoxin deoxynivalenol affects nutrient absorption

in human intestinal epithelial cells. J Nutr. 132(9):2723-31.

Maresca et al., (2008). Both direct and indirect effects account for the pro-

inflammatory activity of enteropathogenic mycotoxins on the human intestinal

epithelium: stimulation of interleukin-8 secretion, potentiation of interleukin-

1beta effect and increase in the transepithelial passage of commensal bacteria.

Toxicol Appl Pharmacol.228(1):84-92.

Maresca M, Fantini J. (2010) Some food-associated mycotoxins as potential risk

factors in humans predisposed to chronic intestinal inflammatory diseases.

Toxicon. 56(3):282-94.

Mattsson (2007). Mixtures in the real world: the importance of plant

McLaughlin et al., (2004). Ochratoxin A increases permeability through tight

junctions by removal of specific claudin isoforms. Am J Physiol Cell Physiol.

287(5):C1412-7.

McLaughlin et al., (2009). The mycotoxin patulin, modulates tight junctions in

caco- 2 cells. Toxicol In Vitro. 23(1):83-9.

Pestka (2010). Deoxynivalenol: mechanisms of action, human exposure, and

toxicological relevance. Arch Toxicol. 84(9):663-79.

Pinton et al., (2009). The food contaminant deoxynivalenol, decreases intestinal

barrier permeability and reduces claudin expression. Toxicol Appl Pharmacol.

237(1):41-8.

Pinton et al., (2010). Deoxynivalenol Impairs Porcine Intestinal Barrier

Function and Decreases the Protein Expression of Claudin- 4 through a

Mitogen-Activated Protein Kinase-Dependent Mechanism. J Nutr. 140(11):1956-62.

Razafimanjato et al. (2010). The food-associated fungal neurotoxin ochratoxin A

inhibits the absorption of glutamate by astrocytes through a decrease in cell

surface expression of the excitatory amino- acid transporters GLAST and

GLT-1.Neurotoxicology. 31(5):475-84.