Obesity promotes Fumonisin B1 toxicity and induces hepatitis

Dopavogui, L.; Regnier, M.; Polizzi, A.; Ponchon, Q.; Smati, S.; Klement, W.; Lasserre, F.; Lukowicz, C.; Lippi, Y.; Fougerat, A.; Bertrand-Michel, J.; Naylies, C.; Canlet, C.; Debrauwer, L.; Gamet-Payrastre, L.; Dauriat, C.; Casas, J.; Croubels, S.; De Baere, S.; Burger, H. M.; Chassaing, B.; Ellero-Simatos, S.; Guillou, H.; Oswald, I. P.; LOISEAU, N.

doi:10.1101/2022.07.22.500801

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bioRxiv · 10.1101/2022.07.22.500801

Obesity promotes Fumonisin B1 toxicity and induces hepatitis

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Abstract

Background and aimObesity is a major public health issue worldwide. Obesity is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. This toxin provokes severe mycotoxicosis in animals, which leads to hepatotoxicity and alterations in the immune response and intestinal barrier permeability. We investigated here whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. MethodsThe metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the last three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water. ResultsAs expected, HFD feeding induced significant body weight gain, glucose intolerance, and hepatic steatosis. FB1-exposed mice displayed a higher sphinganine/sphingosine ratio, a well-known FB1 biomarker of exposure, due to inhibition of ceramide synthases activity by FB1. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. ConclusionThese results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

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Dopavogui, L., Regnier, M., Polizzi, A., Ponchon, Q., Smati, S., Klement, W., Lasserre, F., Lukowicz, C., Lippi, Y., Fougerat, A., Bertrand-Michel, J., Naylies, C., Canlet, C., Debrauwer, L., Gamet-Payrastre, L., Dauriat, C., Casas, J., Croubels, S., De Baere, S., Burger, H. M., Chassaing, B., Ellero-Simatos, S., Guillou, H., Oswald, I. P., LOISEAU, N.. 2022-07-22. Obesity promotes Fumonisin B1 toxicity and induces hepatitis. https://doi.org/10.1101/2022.07.22.500801

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