Short-Term Intake of a Fructose-, Fat- and Cholesterol-Rich Diet Causes Hepatic Steatosis in Mice: Effect of Antibiotic Treatment

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.

Short‐Term Isocaloric Intake of a Fructose‐ but not Glucose‐Rich Diet Affects Bacterial Endotoxin Concentrations and Markers of Metabolic Health in Normal Weight Healthy Subjects

“…Taken together, results of the present study further bolster the hypothesis that dietary fructose may be critical in the development of NAFLD and vascular endothelial dysfunction in humans and that similar to the findings in animal studies9a,38 impairments of intestinal barrier function and an increased translocation of bacterial endotoxin maybe critical herein. Also in line with earlier findings in model organisms,25a results of the present study suggest that at least short‐term glucose may not have these effects on parameters related to liver and vascular endothelial as well as intestinal barrier function.…”

“…In rodents chronic intake of a fructose‐rich diet is associated with the development of vascular dysfunction and hypertension . In addition to chronic extended intake of a fructose‐ and/ or fat‐rich diet, even a short‐term isocaloric change to diets enriched in fructose or fructose‐ and fat can lead to the development of early signs of NAFLD and vascular endothelial dysfunction . These alterations are associated with a loss of tight junction proteins in small intestine and increased endotoxin concentrations in portal plasma 9a.…”

“…In addition to chronic extended intake of a fructose‐ and/ or fat‐rich diet, even a short‐term isocaloric change to diets enriched in fructose or fructose‐ and fat can lead to the development of early signs of NAFLD and vascular endothelial dysfunction . These alterations are associated with a loss of tight junction proteins in small intestine and increased endotoxin concentrations in portal plasma 9a. However, results of short‐term intervention studies in healthy humans show contradictory results regarding the effects of fructose on liver (for overview see ref.…”

All You Can Feed: Some Comments on Production of Mouse Diets Used in Biomedical Research with Special Emphasis on Non-Alcoholic Fatty Liver Disease Research

“…Interestingly, fructose-induced steatosis and damage induced by feeding a diet enriched in 60% fructose for four to eight weeks was more severe in female than in male mice, suggesting that respective diets provoke gender-specific differences during progression of disease [47]. Feeding of fructose in combination with fat and cholesterol for four days was already sufficient to induce hepatic triglyceride accumulation demonstrating that individual "unhealthy" compounds within a diet can be additive or synergistic [138]. Moreover, the feeding of fructose (60%) for four to eight weeks provoked impairment of olfactory epithelium, resulting in reduced olfactory behavioral capacities [139].…”

Helicobacter pylori infection and nonalcoholic fatty liver disease: Time for large clinical trials evaluating eradication therapy

“…Second, antibiotics may per se affect NAFLD, which may distort the effect of RCTs, a potential “artifact” needing careful consideration since the design of the RCTs. Animal data have shown either beneficial or adverse effects antibiotics on NAFLD, which may probably largely differ among different antibiotics. The actions of antibiotics mainly target the intestinal microbiota; to the most, the effects of antibiotics are indirect through affecting the relevant populations of different types of microbiota and gut permeability, whose association with NAFLD is highly emerging .…”