Abstract
Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease, has not yet been clarified. Using a pair-feeding model, we determined the effects of a short-term intake of a fat-, fructose- and cholesterol-rich diet (FFC) on the development of early hepatic steatosis and markers of intestinal barrier function in mice treated with and without non-resorbable antibiotics (AB). For four days, C57BL/6J mice were either pair-fed a control diet or a FFC diet ± AB (92 mg/kg body weight (BW) polymyxin B and 216 mg/kg BW neomycin). Hepatic steatosis and markers of inflammation, lipidperoxidation and intestinal barrier function were assessed. Lipid accumulation and early signs of inflammation found in the livers of FFC-fed mice were markedly attenuated in FFC + AB-fed animals. In FFC-fed mice the development of NAFLD was associated with a significant loss of tight junction proteins and an induction of matrix metalloproteinase-13 in the upper parts of the small intestine as well as significantly higher portal endotoxin levels and an induction of dependent signaling cascades in the liver. As expected, portal endotoxin levels and the expression of dependent signaling cascades in liver tissue were almost at the level of controls in FFC + AB-fed mice. However, FFC + AB-fed mice were also protected from the loss of zonula occludens-1 and partially of occludin protein in small intestine. Our data suggest that the development of early diet-induced hepatic steatosis in mice at least in part results from alterations of intestinal barrier function.
Highlights
With a prevalence ranging from ~2% to 44% in the general European population and ~24% among adults in Northern America, non-alcoholic fatty liver disease (NAFLD) is claimed to be the most common liver disease in the world [1,2]
The results ofbut several epidemiological, animal basedfrom studies suggest that general overover-nutrition, changes in dietaryclinical patternsand such as a switch a low fat, polysaccharideand nutrition, and changes in dietary patterns such as a switch from a low fat, polysaccharideand fiber-rich diet to a fat and sugar dominated diet or vice versa may lead to changes of intestinal fiber-rich diet to a fat and sugar dominated diet or vice versa may lead to changes of intestinal microbiota composition and/or intestinal barrier function [22,23] and subsequently the development composition and/or intestinal barrier function
The results of the present study suggest that even in settings of “normal” caloric intake a short-term change of dietary composition towards a more “unhealthy” dietary pattern e.g., a fat, sugar- and cholesterol-rich diet can lead to a loss of tight junction proteins associated with increased lipidperoxidation and matrix metalloproteinase-13 (MMP-13) levels in the small intestine, as well as elevated portal bacterial endotoxin levels and an activation of dependent signaling cascades in the liver and the development of hepatic steatosis
Summary
With a prevalence ranging from ~2% to 44% in the general European population and ~24% among adults in Northern America, non-alcoholic fatty liver disease (NAFLD) is claimed to be the most common liver disease in the world [1,2]. In fructose-fed mice and rats, long-term concomitant treatment with therapeutic doses of antibiotics has been shown to protect animals against the onset of NAFLD or the metabolic syndrome [10,11]. In these studies, protection was associated with lower bacterial endotoxin levels in the portal vein and a less pronounced activation of the TLR-4-dependent signaling cascade in the liver [10,11]. If the beneficial effects of a treatment with therapeutic doses of non-resorbable antibiotics during the onset of NAFLD are associated with changes of intestinal barrier function e.g., protection against the loss of tight junction proteins, or if these effects are only related to the elimination of bacteria from the small and large intestine, has not yet been fully clarified
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