Publications by authors named "Annette Brandt"

21 Publications

  • Page 1 of 1

Effects of different standard and special diets on cognition and brain mitochondrial function in mice.

Nutr Neurosci 2021 Apr 5:1-13. Epub 2021 Apr 5.

Institute of Nutritional Sciences, Laboratory for Nutrition in Prevention and Therapy, Justus-Liebig-University of Giessen, Biomedical Research Center Seltersberg (BFS), Giessen, Germany.

Human nutrition plays an important role in prevention or at least slowing down the progression of age- and diet-related diseases. Thereby, mitochondrial dysfunction represents one common underlying mechanism, which is being investigated in mouse models. However, the influence of the selected diets in preclinical studies on cognition and mitochondrial function has not yet been reported cohesively. Therefore, we present the results of three different studies that addressed this question. First, we investigated the influence of two standard control chow diets and a special diet low in antioxidants over 6 months in aged NMRI mice. Additionally, a 70% high-fat (HF) chow diet as well as a western-style diet (WSD) rich in lard and fructose were examined in C57/BL6 mice. Cognitive performance, mitochondrial function and bioenergetics in the brain were investigated. Moreover, cerebral expression of genes involved in biogenesis and antioxidant defence (citrate synthase, complex I, complex IV, SOD2, Cat1, GPx-1) were quantified. The results show that a modified, low antioxidant diet increased ATP levels in the brain of aged mice, while cognitive functions remained largely unaffected. A HF diet also showed significant effects on ATP levels and gene expression levels of relevant antioxidant markers, while the WSD had marginal effects on mitochondrial function and bioenergetics in the brain. Our results indicate that standard- and special diets have an impact on cognition and mitochondrial function in the brain. Thus, appropriate caution is warranted when selecting a suitable diet for preclinical studies in mice.
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http://dx.doi.org/10.1080/1028415X.2021.1906392DOI Listing
April 2021

Microbiota profiling in aging-associated inflammation and liver degeneration.

Int J Med Microbiol 2021 Mar 29;311(4):151500. Epub 2021 Mar 29.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria. Electronic address:

Background: The number of people above the age of 60 years is raising world-wide being associated with an increase in the prevalence of aging-associated impairments and even diseases. Recent studies suggest that aging is associated with alterations in bacterial endotoxin levels and that these changes may add to low-grade inflammation, the so-called 'inflammaging', and aging-associated liver degeneration. However, mechanisms involved, and especially, the interaction of intestinal microbiota and barrier in the development of aging-associated inflammation and liver degeneration have not been fully understood.

Objective: The aim of the present study was to determine if intestinal microbiota composition changes with age and if these alterations are associated with changes of markers of intestinal barrier function and the development of inflammation and liver degeneration.

Methods: Blood, liver, small and large intestinal tissue of male 2-, 15-, 24- and 30-months old C57BL/6 mice fed standard chow were obtained. Intestinal microbiota composition, expression levels of antimicrobial peptides in small intestine and markers of intestinal barrier function were measured. Furthermore, indices of liver damage, inflammation and expression levels of lipopolysaccharide binding protein (Lbp) as well as of toll-like receptors (Tlr) 1-9 in liver tissue were assessed.

Results: Pairwise comparisons of the microbial community in the small intestine showed differences between 2- and 24-, 15- and 24-, as well as 15- and 30-months old animals while Shannon's diversity, species richness and evenness indexes did not differ in both small and large intestine, respectively, between age groups. Concentrations of nitric oxide were significantly lower in small intestine of 15-, 24- and 30-months old mice compared to 2-months old mice while mRNA expression of the antimicrobial peptides defensin alpha 1 and lysozyme 1 was unchanged. In contrast, in liver tissue, older age of animals was associated with increasing inflammation and the development of fibrosis in 24- and 30-months old mice. Numbers of inflammatory foci and neutrophils in livers of 24- and 30-months old mice were significantly higher compared to 2-months old mice. These alterations were also associated with higher endotoxin levels in plasma as well as an increased mRNA expression of Lbp and Tlr1, Tlr2, Tlr4, Tlr6 and Tlr9 in livers in older mice.

Conclusion: Despite no consistent and robust changes of microbiota composition in small and/or large intestine of mice of different age were observed, our data suggest that alterations of markers of intestinal barrier function in small intestine are associated with an induction of several Tlrs and beginning hepatic inflammation in older mice and increase with age.
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http://dx.doi.org/10.1016/j.ijmm.2021.151500DOI Listing
March 2021

Fortifying Butterfat with Soybean Oil Attenuates the Onset of Diet-Induced Non-Alcoholic Steatohepatitis and Glucose Intolerance.

Nutrients 2021 Mar 16;13(3). Epub 2021 Mar 16.

Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Althanstraße 14/UZAII, A-1090 Vienna, Austria.

The addition of plant oils such as soybean oil (S) to a diet rich in saturated fatty acids is discussed as a possible route to prevent or diminish the development of metabolic disease. Here, we assessed whether a butterfat-rich diet fortified with S affects the development of early non-alcoholic steatohepatitis (NASH) and glucose intolerance. Female C57BL/6J mice were fed a standard-control diet (C); a fat-, fructose-, and cholesterol-rich diet (FFC, 25E% butterfat, 50% (wt./wt.) fructose, 0.16% (wt./wt.) cholesterol); or FFC supplemented with S (FFC + S, 21E% butterfat + 4E% S) for 13 weeks. Indicators of liver damage, inflammation, intestinal barrier function, and glucose metabolism were measured. Lipopolysaccharide (LPS)-challenged J774A.1 cells were incubated with linolenic and linoleic acids (ratio 1:7.1, equivalent to S). The development of early NASH and glucose intolerance was significantly attenuated in FFC + S-fed mice compared to FFC-fed mice associated with lower hepatic - mRNA expression, while markers of intestinal barrier function were significantly higher than in C-fed mice. Linolenic and linoleic acid significantly attenuated LPS-induced formation of reactive nitrogen species and mRNA expression in J774A.1 cells. Our results indicate that fortifying butterfat with S may attenuate the development of NASH and glucose intolerance in mice.
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http://dx.doi.org/10.3390/nu13030959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001628PMC
March 2021

Citrulline supplementation attenuates the development of non-alcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase.

Redox Biol 2021 May 26;41:101879. Epub 2021 Jan 26.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Althanstraße 14, 1090, Vienna, Austria. Electronic address:

Non-alcoholic fatty liver disease (NAFLD) is by now the most prevalent liver disease worldwide. The non-proteogenic amino acid l-citrulline (L-Cit) has been shown to protect mice from the development of NAFLD. Here, we aimed to further assess if L-Cit also attenuates the progression of a pre-existing diet-induced NAFLD and to determine molecular mechanisms involved. Female C57BL/6J mice were either fed a liquid fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C) for 8 weeks to induce early stages of NASH followed by 5 more weeks with either FFC-feeding +/- 2.5 g L-Cit/kg bw or C-feeding. In addition, female C57BL/6J mice were either pair-fed a FFC +/- 2.5 g L-Cit/kg bw +/- 0.01 g/kg bw i.p. N(ω)-hydroxy-nor-l-arginine (NOHA) or C diet for 8 weeks. The protective effects of supplementing L-Cit on the progression of a pre-existing NAFLD were associated with an attenuation of 1) the increased translocation of bacterial endotoxin and 2) the loss of tight junction proteins as well as 3) arginase activity in small intestinal tissue, while no marked changes in intestinal microbiota composition were prevalent in small intestine. Treatment of mice with the arginase inhibitor NOHA abolished the protective effects of L-Cit on diet-induced NAFLD. Our results suggest that the protective effects of L-Cit on the development and progression of NAFLD are related to alterations of intestinal arginase activity and intestinal permeability.
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http://dx.doi.org/10.1016/j.redox.2021.101879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868995PMC
May 2021

Exchanging dietary fat source with extra virgin olive oil does not prevent progression of diet-induced non-alcoholic fatty liver disease and insulin resistance.

PLoS One 2020 3;15(9):e0237946. Epub 2020 Sep 3.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.

Dietary fat is discussed to be critical in the development of non-alcoholic fatty liver disease. Here, we assess the effect of exchanging dietary fat source from butterfat to extra virgin olive oil on the progression of an already existing diet-induced non-alcoholic fatty liver disease in mice. Female C57BL/6J mice were fed a liquid butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% from butterfat) or control diet (C, 12%E from soybean oil) for 13 weeks. In week 9, fat sources of some BFC- and C-fed mice were switched either to 25E% or 12E% olive oil (OFC and CO). Glucose and insulin tolerance tests were performed, and markers of liver damage and glucose metabolism were assessed. After 6 weeks of feeding, BFC-fed mice had developed marked signs of insulin resistance, which progressed to week 12 being not affected by the exchange of fat sources. Liver damage was similar between BFC- and OFC-fed mice. Markers of lipid metabolism and lipid peroxidation in liver and of insulin signaling in liver and muscle were also similarly altered in BFC- and OFC-fed mice. Taken together, our data suggest that exchanging butterfat with extra virgin olive oil has no effect on the progression of non-alcoholic fatty liver disease and glucose tolerance in mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470337PMC
October 2020

Fortifying diet with rapeseed oil instead of butterfat attenuates the progression of diet-induced non-alcoholic fatty liver disease (NAFLD) and impairment of glucose tolerance.

Metabolism 2020 08 1;109:154283. Epub 2020 Jun 1.

Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria. Electronic address:

Background: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enriched diet to a rapeseed oil (RO) enriched diet affects progression of an existing NAFLD and glucose intolerance in mice.

Methods: For eight weeks, female C57Bl/6J mice were either fed a liquid control (C) or a butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% butterfat) to induce early signs of steatohepatitis and glucose intolerance in mice. For additional five weeks mice received either BFC or C or a fat-, fructose- and cholesterol-rich and control diet, in which butterfat was replaced with RO (ROFC and CRO). Markers of glucose metabolism, liver damage and intestinal barrier were assessed.

Results: Exchanging butterfat with RO attenuated the progression of BFC diet-induced NAFLD and glucose intolerance. Beneficial effects of RO were associated with lower portal endotoxin levels and an attenuation of the induction of the toll-like receptor-4-dependent signaling cascades in liver. Peroxisome proliferator-activated receptor γ activity was induced in small intestine of ROFC-fed mice.

Conclusion: Taken together, exchanging butterfat with RO attenuated the progression of diet-induced steatohepatitis and glucose intolerance in mice.
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http://dx.doi.org/10.1016/j.metabol.2020.154283DOI Listing
August 2020

Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis.

Nutrients 2020 Mar 30;12(4). Epub 2020 Mar 30.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Althanstraße 14, UZA II, 1090 Vienna, Austria.

Sodium butyrate (SoB) supplementation has been suggested to attenuate the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined the therapeutic potential of SoB on NAFLD progression and molecular mechanism involved. Eight-week old C57BL/6J mice were pair-fed a fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C). After 8 weeks, some mice received 0.6g SoB/kg bw in their respective diets (C+SoB; FFC+SoB) or were maintained on C or FFC for the next 5 weeks of feeding. Liver damage, markers of glucose metabolism, inflammation, intestinal barrier function and melatonin metabolism were determined. FFC-fed mice progressed from simple steatosis to early non-alcoholic steatohepatitis, along with significantly higher TNFα and IL-6 protein levels in the liver and impaired glucose tolerance. In FFC+SoB-fed mice, disease was limited to steatosis associated with protection against the induction of mRNA and iNOS protein levels in livers. SoB supplementation had no effect on FFC-induced loss of tight junction proteins in the small intestine but was associated with protection against alterations in melatonin synthesis and receptor expression in the small intestine and livers of FFC-fed animals. Our results suggest that the oral supplementation of SoB may attenuate the progression of simple steatosis to steatohepatitis.
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http://dx.doi.org/10.3390/nu12040951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231312PMC
March 2020

Aging-related liver degeneration is associated with increased bacterial endotoxin and lipopolysaccharide binding protein levels.

Am J Physiol Gastrointest Liver Physiol 2020 04 24;318(4):G736-G747. Epub 2020 Feb 24.

Institute of Nutrition, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany.

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were ) to determine how aging affects liver health in mice in the absence of any interventions and ) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP) mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein. Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.
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http://dx.doi.org/10.1152/ajpgi.00345.2018DOI Listing
April 2020

Peritoneal Level of CD206 Associates With Mortality and an Inflammatory Macrophage Phenotype in Patients With Decompensated Cirrhosis and Spontaneous Bacterial Peritonitis.

Gastroenterology 2020 05 23;158(6):1745-1761. Epub 2020 Jan 23.

Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany; Department of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. Electronic address:

Background & Aims: Peritoneal macrophages (PMs) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PMs and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP).

Methods: We isolated PMs from ascites samples of 66 patients with decompensated cirrhosis (19 with SBP) and analyzed them by flow cytometry, quantitative real-time polymerase chain reaction, functional analysis, and RNA microarrays. We used ascites samples of a separate cohort of 111 patients with decompensated cirrhosis (67 with SBP) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor by enzyme-linked immunosorbent assay (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease but without cirrhosis were included as controls.

Results: We used surface levels of CD206 to identify subsets of large PMs (LPM) and small PMs (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPMs vs SPMs from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPMs vs SPMs, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPMs had an inflammatory phenotype, were less susceptible to tolerance induction, and released more tumor necrosis factor than SPMs. LPMs from patients with cirrhosis produced more inflammatory cytokines than LPMs from controls. Activation of PMs by Toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPMs and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPMs in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (>0.53 mg/L) were less likely to survive for 90 days than those with lower levels.

Conclusions: Surface level of CD206 can be used to identify mature, resident, inflammatory PMs in patients with cirrhosis. Soluble CD206 is released from activated LPMs and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
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http://dx.doi.org/10.1053/j.gastro.2020.01.029DOI Listing
May 2020

Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine.

Sci Rep 2019 04 30;9(1):6668. Epub 2019 Apr 30.

Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, 1090, Vienna, Austria.

The antidiabetic drug metformin has been proposed to affect non-alcoholic fatty liver disease (NAFLD) through its effects on intestinal microbiota and barrier function. However, so far most studies focused on long-term effects and more progressed disease stages. The aim of this study was to assess in two experimental settings, if the onset of NAFLD is associated with changes of intestinal microbiota and barrier function and to determine effects of metformin herein. C57Bl/6J mice were fed a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) for four days or six weeks ±300 mg/kg BW/day metformin (Met). Markers of liver health, intestinal barrier function and microbiota composition were assessed. Metformin treatment markedly attenuated FFC-induced NAFLD in both experiments with markers of inflammation and lipidperoxidation in livers of FFC + Met-fed mice being almost at the level of controls. Metformin treatment attenuated the loss of tight junction proteins in small intestine and the increase of bacterial endotoxin levels in portal plasma. Changes of intestinal microbiota found in FFC-fed mice were also significantly blunted in FFC + Met-fed mice. Taken together, protective effects of metformin on the onset of NAFLD are associated with changes of intestinal microbiota composition and lower translocation of bacterial endotoxins.
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http://dx.doi.org/10.1038/s41598-019-43228-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491483PMC
April 2019

Metabolic Abnormalities in Normal Weight Children Are Associated with Increased Visceral Fat Accumulation, Elevated Plasma Endotoxin Levels and a Higher Monosaccharide Intake.

Nutrients 2019 Mar 18;11(3). Epub 2019 Mar 18.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090 Vienna, Austria.

Being overweight has been identified as the main risk factor for the development of metabolic disorders in adults and children. However, recent studies suggest that normal weight individuals are also frequently affected by metabolic abnormalities with underlying mechanisms not yet fully understood. The aim of the present study was to determine if dietary pattern and markers of intestinal permeability, as well as inflammation, differ between normal weight healthy children and normal weight children suffering from metabolic abnormalities. In total, 45 normal weight children aged 5⁻9 years were included in the study, of whom nine suffered from metabolic abnormalities. Anthropometric data, dietary intake and markers of inflammation, as well as intestinal permeability, were assessed in fasting blood samples. Neither BMI nor BMI-SDS differed between groups; however, children with metabolic abnormalities had a significantly larger waist circumference (+~5 cm) and a higher leptin to adiponectin ratio. While plasma leptin levels are significantly higher in normal weight children with metabolic abnormalities, neither TNF α nor sCD14, adiponectin, PAI-1 or IL-6 plasma levels differed between groups. Despite similar total calorie and macronutrient intake between groups, mean total fructose and total glucose intake (resulting mainly from sugar sweetened beverages, fruits and sweets) were higher in children with metabolic abnormalities than in healthy children. Time spent physically active was significantly higher in healthy normal weight children whereas time spent physically inactive was similar between groups. Furthermore, bacterial endotoxin levels were significantly higher in the peripheral plasma of normal weight children with metabolic abnormalities than in healthy normal weight children. Our results suggest that metabolic disorders in normal weight children are associated with a high monosaccharide intake and elevated bacterial endotoxin as well as leptin plasma levels, the latter also discussed as being indicative of visceral adiposity.
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http://dx.doi.org/10.3390/nu11030652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470572PMC
March 2019

Moderate consumption of fermented alcoholic beverages diminishes diet-induced non-alcoholic fatty liver disease through mechanisms involving hepatic adiponectin signaling in mice.

Eur J Nutr 2020 Mar 16;59(2):787-799. Epub 2019 Mar 16.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Althanstraße 14 (UZA II), 1090, Vienna, Austria.

Purpose: Results of some epidemiological studies suggest that moderate alcohol consumption may be associated with a decreased risk to develop NAFLD. Here, the effect of the consumption of moderate beer and diluted ethanol, respectively, on the development of NAFLD were assessed.

Methods: Female C57BL/6J mice were fed a control diet (C-D) or a diet rich in fructose, fat and cholesterol (FFC) enriched isocalorically and isoalcoholically with beer (FFC + B) or plain ethanol (FFC + E) (2.5 g ethanol/kg body weight/day) for 7 weeks. Liver damage was assessed by histology using NAFLD activity score. Markers of inflammation, insulin resistance and adiponectin signaling were measured at mRNA and protein levels. Using J774A.1 cells as a model of Kupffer cells, the effect of alcoholic beverages on adiponectin receptor 1 (Adipor1) was assessed.

Results: Hepatic triglyceride concentration, neutrophil granulocytes, iNOS protein concentrations and early signs of insulin resistance found in FFC-fed mice were significantly attenuated in FFC+ B-fed mice (P < 0.05 for all). These findings were associated with a super-induction of Adipor1 mRNA expression (+ ~ 18-fold compared to all other groups) and a decrease of markers of lipid peroxidation in liver tissue of FFC + B-fed mice when compared to FFC-fed animals. Similar differences were not found between FFC- and FFC+ E-fed mice. Expression of Adipor1 was also super-induced (7.5-fold) in J774A.1 cells treated with beer (equivalent to 2 mmol/L ethanol).

Conclusions: These data suggest that moderate intake of fermented alcoholic beverages such as beer at least partially attenuates NAFLD development through mechanisms associated with hepatic AdipoR1 expression.
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http://dx.doi.org/10.1007/s00394-019-01945-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058579PMC
March 2020

Consumption of decaffeinated coffee protects against the development of early non-alcoholic steatohepatitis: Role of intestinal barrier function.

Redox Biol 2019 02 23;21:101092. Epub 2018 Dec 23.

Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide lacking universally accepted therapies. Studies suggest that coffee consumption is associated with a reduced risk of NAFLD; however, molecular mechanisms and ingredients involved remain to be fully understood. Here, we determined the effects of regular intake of decaffeinated coffee on the development of NAFLD in mice, and molecular mechanisms involved.

Methods: Female C57BL/6J mice (n = 6-7/ group) were pair-fed either a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) +/- decaffeinated coffee (DeCaf, 6 g/kg BW) for 4 days or 6 weeks. Indices of liver damage, hepatic inflammation and parameters of insulin resistance and intestinal permeability as well as nitric oxide system were determined.

Results: Early signs of insulin resistance and non-alcoholic steatohepatitis (NASH) found after 6 weeks of FFC feeding were significantly lower in FFC+DeCaf-fed mice when compared to FFC-fed animals. Moreover, elevation of portal endotoxin levels and loss of tight junction proteins in proximal small intestine found in FFC-fed mice were significantly attenuated in FFC+DeCaf-fed animals. These beneficial effects of DeCaf were associated with a protection against the significant induction of inducible NO-synthase protein levels and 3-nitrotyrosine protein adducts found in proximal small intestine of FFC-fed mice. Similar protective effects of DeCaf were also found in mice fed the FFC diet short-term.

Conclusion: Our results suggest that protective effects of DeCaf on the development of NAFLD are at least in part related to maintaining intestinal barrier function.
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http://dx.doi.org/10.1016/j.redox.2018.101092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313826PMC
February 2019

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.

Mol Nutr Food Res 2019 03 2;63(6):e1800868. Epub 2019 Jan 2.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090, Vienna, Austria.

Scope: Dietary pattern and impairments of intestinal barrier function are discussed to be critical in the development of metabolic impairments. Here, it is determined if an isocaloric exchange of complex carbohydrates with monosaccharides affects markers of intestinal permeability and metabolic health in healthy subjects.

Methods And Results: After a dietary standardization for 4 days, all 12 subjects aged 21-33 years receive an isocaloric fructose- and glucose-enriched diet for 3 days separated by a wash-out phase. Anthropometry, blood pressure, markers of intestinal permeability and metabolic as well as inflammatory parameters are determined in blood samples or isolated peripheral blood mononuclear cells collected at baseline, after standardizations and the monosaccharide interventions, respectively. While anthropometric and inflammatory parameters are not changed, the intake of an isocaloric fructose- but not glucose-enriched diet is associated with a significant increase of bacterial endotoxin plasma levels and alanine aminotransferase activity in serum, while total plasma nitrate/nitrite concentrations are significantly decreased. In peripheral blood mononuclear cells, Toll like receptors 4, 2, and MYD88 mRNA expressions are significantly induced after the fructose-rich but not the glucose-rich diet.

Conclusion: In metabolically healthy subjects, even a short-term intake of a fructose-rich diet can elevate bacterial endotoxin levels and change markers of liver health and vascular endothelial function.
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http://dx.doi.org/10.1002/mnfr.201800868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590154PMC
March 2019

Non-Alcoholic Fatty Liver Disease in Overweight Children: Role of Fructose Intake and Dietary Pattern.

Nutrients 2018 Sep 19;10(9). Epub 2018 Sep 19.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090 Vienna, Austria.

The role of nutrition and diet in the development of non-alcoholic fatty liver disease (NAFLD) is still not fully understood. In the present study, we determined if dietary pattern and markers of intestinal permeability differ between overweight children with and without NAFLD. In addition, in a feasibility study, we assessed the effect of a moderate dietary intervention only focusing on nutrients identified to differ between groups on markers of intestinal barrier function and health status. Anthropometric data, dietary intake, metabolic parameters, and markers of inflammation, as well as of intestinal permeability, were assessed in overweight children ( = 89, aged 5⁻9) and normal-weight healthy controls ( = 36, aged 5⁻9). Sixteen children suffered from early signs of NAFLD, e.g., steatosis grade 1 as determined by ultrasound. Twelve children showing early signs of NAFLD were enrolled in the intervention study ( = 6 intervention, = 6 control). Body mass index (BMI), BMI standard deviation score (BMI-SDS), and waist circumference were significantly higher in NAFLD children than in overweight children without NAFLD. Levels of bacterial endotoxin, lipopolysaccharide-binding protein (LBP), and proinflammatory markers like interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) were also significantly higher in overweight children with NAFLD compared to those without. Total energy and carbohydrate intake were higher in NAFLD children than in those without. The higher carbohydrate intake mainly resulted from a higher total fructose and glucose intake derived from a significantly higher consumption of sugar-sweetened beverages. When counseling children with NAFLD regarding fructose intake (four times, 30⁻60 min within 1 year; one one-on-one counseling and three group counselings), neither alanine aminotransferase (ALT) nor aspartate aminotransferase (AST) activity in serum changed; however, diastolic blood pressure ( < 0.05) and bacterial endotoxin levels ( = 0.06) decreased markedly in the intervention group after one year. Similar changes were not found in uncounseled children. Our results suggest that a sugar-rich diet might contribute to the development of early stages of NAFLD in overweight children, and that moderate dietary counseling might improve the metabolic status of overweight children with NAFLD.
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http://dx.doi.org/10.3390/nu10091329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165138PMC
September 2018

Oral Supplementation of Glutamine Attenuates the Progression of Nonalcoholic Steatohepatitis in C57BL/6J Mice.

J Nutr 2017 11 20;147(11):2041-2049. Epub 2017 Sep 20.

Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany; and

Universally accepted therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) are still lacking. Studies suggest a preventive effect of oral Gln supplementation on the development of NASH; however, whether Gln also has therapeutic potential for pre-existing NASH has not yet been clarified. The aim of the present study was to determine whether Gln prevents the progression of diet-induced NASH in mice. For 8 wk, female C57BL/6J mice (6-8 wk old) were pair-fed a liquid Western-style diet [WSD, 25% of energy from fat, 50% wt:wt fructose, 0.16% wt:wt cholesterol] or control diet (C diet) to induce liver damage. From week 8 to 13, they were pair-fed the C diet or WSD alone or supplemented with l-Gln to provide 2.1 g/kg body weight (C diet + Gln or WSD + Gln). Energy intake was adjusted to the group with the lowest energy intake. Indexes of liver damage and inflammation, intestinal barrier function, and toll-like receptor 4 () signaling in the liver were determined. The liver histology scores significantly increased from 8 to 13 wk (+31%) in WSD-fed mice and were significantly higher than in controls ( ≤ 0.05 for both time comparisons), whereas scores did not differ between C diet-fed and WSD + Gln-fed mice after 13 wk of feeding. The occludin protein concentrations in the small intestinal tissue were similarly reduced in both WSD-fed groups when compared with controls [WSD compared with C diet (-53%) and C diet + Gln (-42%), ≤ 0.05; WSD + Gln compared with C diet + Gln (-34%), ≤ 0.05] after 13 wk, whereas the expression of myeloid differentiation primary response gene 88 mRNA and concentration of inducible nitric oxide synthase and 4-hydroxynonenal protein adducts were significantly higher only in livers of WSD-fed mice ( ≤ 0.05 for the WSD group compared with all other groups; WSD + Gln group compared with the C diet groups: NS). Taken together, our data suggest that oral Gln supplementation protects mice from the progression of pre-existing, WSD-induced NASH.
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http://dx.doi.org/10.3945/jn.117.253815DOI Listing
November 2017

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

Nutrients 2017 Sep 14;9(9). Epub 2017 Sep 14.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090 Vienna, Austria.

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.
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http://dx.doi.org/10.3390/nu9091013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622773PMC
September 2017

The Effect of High-Dose Ionizing Radiation on the Isolated Photobiont of the Astrobiological Model Lichen Circinaria gyrosa.

Astrobiology 2017 02;17(2):154-162

5 Departamento de Observación de la Tierra, Instituto Nacional de Técnica Aeroespacial (INTA) , Madrid, Spain .

Lichen symbioses between fungi and algae represent successful life strategies to colonize the most extreme terrestrial habitats. Consequently, space exposure and simulation experiments have demonstrated lichens' high capacity for survival, and thus, they have become models in astrobiological research with which to discern the limits and limitations of terrestrial life. In a series of ground-based irradiation experiments, the STARLIFE campaign investigated the resistance of astrobiological model organisms to galactic cosmic radiation, which is one of the lethal stressors of extraterrestrial environments. Since previous studies have identified that the alga is the more sensitive lichen symbiont, we chose the isolated photobiont Trebouxia sp. of the astrobiological model Circinaria gyrosa as a subject in the campaign. Therein, γ radiation was used to exemplify the deleterious effects of low linear energy transfer (LET) ionizing radiation at extremely high doses up to 113 kGy in the context of astrobiology. The effects were analyzed by chlorophyll a fluorescence of photosystem II (PSII), cultivation assays, live/dead staining and confocal laser scanning microscopy (CLSM), and Raman laser spectroscopy (RLS). The results demonstrate dose-dependent impairment of photosynthesis, the cessation of cell proliferation, cellular damage, a decrease in metabolic activity, and degradation of photosynthetic pigments. While previous investigations on other extraterrestrial stressors have demonstrated a high potential of resistance, results of this study reveal the limits of photobiont resistance to ionizing radiation and characterize γ radiation-induced damages. This study also supports parallel STARLIFE studies on the lichens Circinaria gyrosa and Xanthoria elegans, both of which harbor a Trebouxia sp. photobiont. Key Words: Astrobiology-Gamma rays-Extremotolerance-Ionizing radiation-Lichens-Photobiont. Astrobiology 17, 154-162.
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http://dx.doi.org/10.1089/ast.2015.1453DOI Listing
February 2017

Simulated Space Radiation: Impact of Four Different Types of High-Dose Ionizing Radiation on the Lichen Xanthoria elegans.

Astrobiology 2017 02;17(2):136-144

1 Institute of Botany, Heinrich-Heine-University (HHU) , Düsseldorf, Germany .

This study addresses the viability of the lichen Xanthoria elegans after high-dose ionizing irradiation in the frame of the STARLIFE campaign. The first set of experiments was intended to resemble several types of galactic cosmic radiation (GCR) as present beyond the magnetic shield of Earth. In the second set of experiments, γ radiation up to 113 kGy was applied to test the limit of lichen resistance to ionizing radiation. Entire thalli of Xanthoria elegans were irradiated in the anhydrobiotic state. After STARLIFE 1, the metabolic activity of both symbionts was quantified by live/dead staining with confocal laser scanning microscopy. The photosynthetic activity was measured after the respective irradiation to assess the ability of the symbiotic green algae to restore photosynthesis after irradiation. The STARLIFE campaign complements the results of the LIFE experiments at the EXPOSE-E facility on the International Space Station by testing the model organism Xanthoria elegans on its resistance to hazardous radiation that might be accumulated during long-term space exposure. In addition, the photosynthetic activity of metabolically active lichen was investigated after X-ray irradiation up to 100 Gy (3.3 Gy/min). Since previous astrobiological experiments were mostly performed with anhydrobiotic lichen, these experiments will broaden our knowledge on the correlation of physiological state and astrobiological stressors. Key Words: Astrobiology-Extremotolerance-Gamma rays-Ionizing radiation-Lichens-Viability. Astrobiology 17, 136-144.
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http://dx.doi.org/10.1089/ast.2015.1455DOI Listing
February 2017

Treatment with alpha-galactosylceramide protects mice from early onset of nonalcoholic steatohepatitis: Role of intestinal barrier function.

Mol Nutr Food Res 2017 05 22;61(5). Epub 2017 Feb 22.

Institute of Nutrition, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University of Jena, Jena, Germany.

Scope: The role of invariant natural killer T cells in the development of nonalcoholic steatohepatitis (NASH) has not yet been fully understood. Here, the effect of the invariant natural killer T-cell activator alpha-galactosylceramide (αGalCer) on the development of nonalcoholic fatty liver disease and intestinal barrier function was assessed in a mouse model of early Western-style diet (WSD) induced NASH.

Methods And Results: Female C57BL/6J mice were either fed a liquid control diet or a liquid fructose-enriched WSD for 6 wk while being treated three times weekly with αGalCer (2 μg intraperitoneal) or vehicle. Indices of liver damage, glucose metabolism, and intestinal permeability were measured. Treatment with αGalCer markedly suppressed hepatic fat accumulation and inflammation while not affecting fasting glucose. The protective effects of αGalCer were associated with a protection against the increased translocation of bacterial endotoxins and the decreased protein levels of tight junction proteins occludin and zonula occludens 1 found in vehicle-treated mice while being fed a WSD.

Conclusion: Taken together, our data suggest that the protective effects of αGalCer against the development of a diet-induced NASH in mice are associated with a protection against the increased translocation of intestinal bacterial endotoxins associated with the development of NASH.
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http://dx.doi.org/10.1002/mnfr.201600985DOI Listing
May 2017

Characterisation of Growth and Ultrastructural Effects of the Xanthoria elegans Photobiont After 1.5 Years of Space Exposure on the International Space Station.

Orig Life Evol Biosph 2016 Jun 2;46(2-3):311-21. Epub 2015 Nov 2.

Institute of Botany, Heinrich-Heine-University (HHU), Universitaetsstr. 1, 40225, Duesseldorf, Germany.

The lichen Xanthoria elegans has been exposed to space and simulated Mars-analogue environment in the Lichen and Fungi Experiment (LIFE) on the EXPOSE-E facility at the International Space Station (ISS). This long-term exposure of 559 days tested the ability of various organisms to cope with either low earth orbit (LEO) or Mars-analogue conditions, such as vacuum, Mars-analogue atmosphere, rapid temperature cycling, cosmic radiation of up to 215 ± 16 mGy, and insolation of accumulated doses up to 4.87 GJm(-2), including up to 0.314 GJm(-2) of UV irradiation. In a previous study, X. elegans demonstrated considerable resistance towards these conditions by means of photosynthetic activity as well as by post-exposure metabolic activity of 50-80% in the algal and 60-90% in the fungal symbiont (Brandt et al. Int J Astrobiol 14(3):411-425, 2015). The two objectives of the present study were complementary: First, to verify the high post-exposure viability by using a qualitative cultivation assay. Second, to characterise the cellular damages by transmission electron microscopy (TEM) which were caused by the space and Mars-analogue exposure conditions of LIFE. Since the algal symbiont of lichens is considered as the more susceptible partner (de Vera and Ott 2010), the analyses focused on the photobiont. The study demonstrated growth and proliferation of the isolated photobiont after all exposure conditions of LIFE. The ultrastructural analysis of the algal cells provided an insight to cellular damages caused by long-term exposure and highlighted that desiccation-induced breakdown of cellular integrity is more pronounced under the more severe space vacuum than under Mars-analogue atmospheric conditions. In conclusion, desiccation-induced damages were identified as a major threat to the photobiont of X. elegans. Nonetheless, a fraction of the photobiont cells remained cultivable after all exposure conditions tested in LIFE.
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http://dx.doi.org/10.1007/s11084-015-9470-1DOI Listing
June 2016