Obesity promotes Fumonisin B1 toxicity and induces hepatitis

Background and aim: Obesity is a major public health issue worldwide which can leads to chronic and systemic inflammation ultimately resulting to insulin resistance and type 2 diabetes. This chronic inflammatory state contributes to long-term complications, including non-alcoholic fatty liver disease. We hypothesized here that obesity may also enhance the sensitivity to environmental toxins, 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. Methods: The metabolic effects of FB1 in obese and non-obese male C57BL/6J mice was compared. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the final three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water. Results: As 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 transcriptome 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. Conclusion: These results suggested that, in the context of obesity, FB1 toxicity is exacerbated in a way that lead to gut dysbiosis and pronounced liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.