Cereulide

The incidence of both type 1 and type 2 diabetes mellitus is increasing and although environmental pollutants are thought to play a major role, their specific contributions remain elusive. One food toxin, cereulide, is of particular interest, since it is ubiquitous in our environment, and the beta cell has been shown to be especially susceptible to cereulide toxicity in a number of studies.

Cereulide toxin

Cereulide is a toxin produced by certain strains of Bacillus cereus, that acts as a potassium ionophore on the inner mitochondrial membrane, thereby uncoupling oxidative phosphorylation [1]. As it is highly resistant to heat, acidity and proteolysis, cereulide is difficult to eradicate from the food chain and to neutralize in the digestive tract. Moreover, the highly lipophilic character of cereulide suggests possible bioaccumulation in human tissues [2]. Cereulide is well known to cause acute and possibly fatal emetic food poisoning, with an estimated lethal dose of 8 μg/kg body weight [3]. Acute toxicity usually involves liver and gut, but cereulide has been detected in also in the spleen and plasma of intoxicated patients [4], which supports the hypothesis that cereulide enters both portal and systemic circulation. Low concentrations of cereulide (4 ng/g food) are however frequently found in take-away rice and pasta dishes, but has been detected even in infant foods and vegetables [5]. Although large scale prevalence data for the cereulide toxin itself are lacking, repeated exposure to nanogram levels of cereulide through food is probable, although the effects of chronic or low concentration exposure is largely unknown.

Cereulide and beta cell death

Several in vitro studies have reported a lethal toxicity of cereulide to the beta cell. Exposure to 1 ng/ml purified cereulide, or cereulide-containing bacterial extracts caused cell death in fetal porcine islets of Langerhans in culture [6]. Similarly low concentrations have reported to cause cell death in murine islets in culture, as well as in mouse (MIN6) and rat (INS-1E) insulin secreting beta cell lines [7][8]. Beta cells seem to be much more sensitive to killing by cereulide, as other mammalian cells were unaffected at these low exposure levels. Most likely, this is a consequence of the beta cell’s dependency on aerobic glycolysis through its mitochondria, which is the target of cereulide toxicity. Beta cells have very low Monocarboxylate transporters 1 (Mct1) expression to prevent insulin release in response to circulating pyruvate. As a result beta-cells cannot switch to anaerobic glycolysis, and depend solely on aerobic glycolysis for their energy supply. Initial statements reported that cereulide causes necrotic cell death, but recent studies observed pyknotic nuclei, chromatin condensation, caspase activation and cytochrome c release into the cytoplasme, supporting the hypothesis that cereulide causes apoptotic cell death.

Cereulide and beta cell function

Cereulide has been shown to depolarize the inner mitochondrial membrane, to cause swelling of the mitochondria, and to reduce respiration. As mitochondrial ATP production is a key element for glucose-stimulated insulin production, cereulide’s mitochondriotoxic properties not only cause beta cell death, but also dysfunction, at even lower concentrations. In vitro glucose stimulated insulin secretion assay showed a significant reduction in the fraction of insulin secreted by MIN6 cells after 24 h exposure to only 0.15 ng/ml cereulide. Insulin secretion was completely inhibited by 0.5 ng/ml in MIN6 cells and whole mouse islets, and insulin content of murine and porcine islets decreases at a concentration of 0.5 - 1.0 ng/ml [6,8].

Cereulide and other metabolic target tissues

As mentioned before, cereulide also has toxic effects on liver tissue, as proven both in human cases and animal studies, but hepatic damage seems to occur at higher doses and the effects are reversible [9]. So far, there are no reports on low grade liver or adipose tissue inflammation, which are important contributors to insulin resistance in type 2 diabetes. Recently, also intestinal toxicity has been studied and altered enterocyte metabolism was observed in vitro [10].

Conclusion

In vitro studies in different beta cell models have shown that the beta cell is highly susceptible to the mitochondriotoxic effects of cereulide. Extremely low concentrations of cereulide inhibit the beta cell’s secretory capacity and induce beta cell death, key traits in diabetes pathophysiology. Although, cereulide can enter the circulation and is known to cause acute toxicity in humans, the true relevance of chronic low exposure remains uncertain. Until further studies yield clear results, conscientious food hygiene and storage are mandatory.

References

  1. ^ Kawamura-Sato K, Hirama Y, Agata N, Ito H, Torii K, et al. (2005) Quantitative analysis of cereulide, an emetic toxin of Bacillus cereus, by using rat liver mitochondria. Microbiol Immunol 49: 25–30.

  2. ^ Andersson MA, Hakulinen P, Honkalampi-Hämäläinen U, Hoornstra D, Lhuguenot J-C, et al. (2007) Toxicological profile of cereulide, the Bacillus cereus emetic toxin, in functional assays with human, animal and bacterial cells. Toxicon Off J Int Soc Toxinology 49: 351–367. doi:10.1016/j.toxicon.2006.10.006.

  3. ^ Naranjo M, Denayer S, Botteldoorn N, Delbrassinne L, Veys J, et al. (2011) Sudden Death of a Young Adult Associated with Bacillus cereus Food Poisoning. J Clin Microbiol 49: 4379–4381. doi:10.1128/JCM.05129-11.

  4. ^ Shiota M, Saitou K, Mizumoto H, Matsusaka M, Agata N, et al. (2010) Rapid Detoxification of Cereulide in Bacillus cereus Food Poisoning. PEDIATRICS 125: e951–e955. doi:10.1542/peds.2009-2319.

  5. ^ Delbrassinne L, Andjelkovic M, Dierick K, Denayer S, Mahillon J, et al. (2012) Prevalence and levels of Bacillus cereus emetic toxin in rice dishes randomly collected from restaurants and comparison with the levels measured in a recent foodborne outbreak. Foodborne Pathog Dis 9: 809–814. doi:10.1089/fpd.2012.1168.

  6. ^ Virtanen SM, Roivainen M, Andersson MA, Ylipaasto P, Hoornstra D, et al. (2008) In vitro toxicity of cereulide on porcine pancreatic Langerhans islets. Toxicon Off J Int Soc Toxinology 51: 1029–1037. doi:10.1016/j.toxicon.2008.01.019.

  7. ^ Hoornstra D, Andersson MA, Teplova VV, Mikkola R, Uotila LM, et al. (2013) Potato crop as a source of emetic Bacillus cereus and cereulide induced mammalian cell toxicity. Appl Environ Microbiol. doi:10.1128/AEM.00201-13.

  8. ^ Vangoitsenhoven R (n.d.) Foodborne cereulide causes beta-cell dysfunction and apoptosis. PLoS ONE 2014: accepted.

  9. ^ Yokoyama K, Ito M, Agata N, Isobe M, Shibayama K, et al. (1999) Pathological effect of synthetic cereulide, an emetic toxin of Bacillus cereus, is reversible in mice. FEMS Immunol Med Microbiol 24: 115–120.

  10. ^ Rajkovic A, Grootaert C, Butorac A, Cucu T, De Meulenaer B, et al. (2014) Sub-Emetic Toxicity of Bacillus cereus Toxin Cereulide on Cultured Human Enterocyte-Like Caco-2 Cells. Toxins 6: 2270–2290. doi:10.3390/toxins6082270.

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