The human milk oligosaccharide 2'-fucosyllactose alleviates liver steatosis, ER stress, and insulin resistance by reducing hepatic diacylglycerols and improving gut permeability in obese Ldlr-/-Leiden mice

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2 '-fucosyllactose are thought to primarily improve gut health and it...

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Veröffentlicht in:Frontiers in Nutrition 2022-06, Vol.9
Hauptverfasser: Gart, E., Salic, K., Morrison, M.C., Giera, M., Attema, J., Ruiter, C. de, Caspers, M., Schuren, F., Bobeldijk-Pastorova, I., Heer, M., Qin, Y., Kleemann, R.
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Zusammenfassung:Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2 '-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2 '-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2 '-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2 '-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2 '-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2 '-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2 '-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2 '-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2 '-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2 '-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2 '-fucosyllactose to correct dysmetabolism and insulin resistance.
DOI:10.3389/fnut.2022.904740