Serotonin reuptake transporter deficiency promotes liver steatosis and impairs intestinal barrier function in obese mice fed a Western‐style diet

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Background Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western‐style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high‐fat and high‐sugar diets. Methods 6–8 weeks old male serotonin reuptake transporter knockout mice (SERT −/− ) and wild‐type controls (SERT +/+ ) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. Key Results SERT −/− mice showed increased weight gain compared with SERT +/+ mice when fed a WSD ± F for 12 weeks ( p < 0.05), whereby SERT −/− mice exhibited reduced energy (−21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis ( p < 0.05), enhanced levels of endotoxin in portal vein plasma ( p < 0.05), and increased liver expression of Tnf and Myd88 ( p < 0.05), when mice were fed a WSD ± F. Finally, SERT −/− mice, when compared with SERT +/+ mice, had a decreased mRNA expression of Muc2 ( p < 0.01), Ocln ( p < 0.05), Cldn5 ( p = 0.054) and 7 ( p < 0.01), Defa5 ( p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO‐1 ( p < 0.01) and DEFA5 protein ( p < 0.0001) were decreased. Conclusion and Inferences Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction.