Publications by authors named "Ina Bergheim"

92 Publications

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

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.

Cell Mol Gastroenterol Hepatol 2021 12;11(4):909-933. Epub 2020 Nov 12.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany. Electronic address:

Background & Aims: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF.

Methods: To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6 mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF.

Results: Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6 mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6 mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6 mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6C inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response.

Conclusions: Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF.
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http://dx.doi.org/10.1016/j.jcmgh.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900526PMC
November 2020

Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

Mol Metab 2020 12 8;42:101076. Epub 2020 Sep 8.

Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands.

Objective: Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown.

Methods: We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on (I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points.

Results: We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression.

Conclusions: Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated.

Ntr Registration: 4488.
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http://dx.doi.org/10.1016/j.molmet.2020.101076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536740PMC
December 2020

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

Validation of Malnutrition Screening Tools in Liver Cirrhosis.

Nutrients 2020 May 3;12(5). Epub 2020 May 3.

Department of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria.

Malnutrition in liver cirrhosis is frequently underestimated. To determine if a patient is at risk of malnutrition, several screening tools have been established. However, most of them are not validated for patients with liver cirrhosis. Therefore, we compared the RFH-NPT (Royal Free Hospital Nutritional Prioritizing Tool) as the validated gold standard for malnutrition screening in cirrhosis patients with GMS (Graz Malnutrition Screening), NRS-2002 (Nutritional Risk Screening) and MNA-SF (Mini Nutritional Assessment-Short Form). Based on common validity criteria for screening tools, only the MNA-SF showed fair correlation (12/15 points) with the RFH-NPT, whereas NRS-2002 and GMS performed worse (6/15 points). Taken together, our results suggest that NRS-2002 and GMS are not suitable for screening of malnutrition in cirrhosis patients. A cirrhosis-specific screening tool like RFH-NPT should be used to assess malnutrition and to identify those at risk of malnutrition.
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http://dx.doi.org/10.3390/nu12051306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285209PMC
May 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

Adipokines and Endotoxemia Correlate with Hepatic Steatosis in Non-Alcoholic Fatty Liver Disease (NAFLD).

Nutrients 2020 Mar 5;12(3). Epub 2020 Mar 5.

Metabolic Liver Research Program, I. Department of Medicine, University Medical Centre of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131 Mainz, Germany.

(1) Background The etiology of non-alcoholic fatty liver disease (NAFLD) is multifactorial. Dietary composition has been implicated as a factor modulating intestinal barrier and could affect disease severity. The aim of this study was to evaluate dietary intake and markers of intestinal permeability in patients with NAFLD. (2) Methods We enrolled 63 patients with NAFLD and compared them to age-matched controls. (3) Results: body mass index (BMI) and leptin to adiponectin ratio-the latter being an indicator of abdominal fat accumulation-correlated with the degree of hepatic steatosis being accompanied with rising levels of fasting insulin. Furthermore, endotoxin plasma levels and markers of inflammation were significantly higher in NAFLD compared to controls and increased with the severity of hepatic steatosis. Despite comparable intake of total energy and macronutrients, intake of fiber was lower in all patients with NAFLD compared to controls and were negatively related to disease severity. (4) Conclusions: Taken together, results of the present study suggest that fiber intake in patients is negatively related to steatosis degree and bacterial endotoxin levels, further suggesting that dietary fiber intake may be a target in NAFLD treatment (NCT: 02366052 and 03482284).
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http://dx.doi.org/10.3390/nu12030699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146245PMC
March 2020

Sarcopenia and Liver Cirrhosis-Comparison of the European Working Group on Sarcopenia Criteria 2010 and 2019.

Nutrients 2020 Feb 20;12(2). Epub 2020 Feb 20.

Department of Internal Medicine Division of Gastroenterology und Hepatology Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.

The European Working group on Sarcopenia in Older People recently updated the diagnostic criteria for sarcopenia. It is yet unclear how these modified criteria influence the rate of diagnosis in high risk populations, such as liver cirrhosis. We therefore assessed if the new diagnostic criteria for sarcopenia impacts on sarcopenia prevalence in liver cirrhosis. Within two years 114 cirrhotic patients were prospectively enrolled in the study. Sarcopenia was determined by muscle strength (handgrip strength), muscle mass (lumbal muscle index) and muscle performance (gait speed). Using the 2019 definition, the rate of pre-sarcopenia was significantly lower (30.7% versus 3.5%) due to the different starting points (2010 muscle mass, 2019 muscle strength) and cut-off values (muscle strength). The change in diagnostic criteria for sarcopenia drastically influences the rate of pre-sarcopenia diagnosis in cirrhotics. To evaluate, which diagnostic criteria should be chosen to diagnose sarcopenia in liver cirrhosis patients, prospective studies are needed.
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http://dx.doi.org/10.3390/nu12020547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071440PMC
February 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

Positive effect of an electrolyzed reduced water on gut permeability, fecal microbiota and liver in an animal model of Parkinson's disease.

PLoS One 2019 10;14(10):e0223238. Epub 2019 Oct 10.

School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.

There is growing awareness within the scientific community of the strong connection between the inflammation in the intestine and the pathogenesis of Parkinson's disease (PD). In previous studies we developed a PD animal model exposing pup rats to permethrin (PERM) pesticide. Here, we intended to explore whether in our animal model there were changes in gut permeability, fecal microbiota and hepatic injury. Moreover, we tested if the co-treatment with an electrolyzed reduced (ERW) was effective to protect against alterations induced by PERM. Rats (from postnatal day 6 to 21) were gavaged daily with PERM, PERM+ERW or vehicle and gut, liver and feces were analyzed in 2-months-old rats. Increased gut permeability, measured by FITC-dextran assay, was detected in PERM group compared to control and PERM+ERW groups. In duodenum and ileum, concentration of occludin was higher in control group than those measured in PERM group, whereas only in duodenum ZO-1 was higher in control than those measured in PERM and PERM+ERW groups. Number of inflammatory focis and neutrophils as well as iNOS protein levels were higher in livers of PERM-treated rats than in those of PERM+ERW and control rats. Fecal microbiota analysis revealed that Lachnospira was less abundant and Defluviitaleaceae more abundant in the PERM group, whereas the co-treatment with ERW was protective against PERM treatment since the abundances in Lachnospira and Defluviitaleaceae were similar to those in the control group. Higher abundances of butyrate- producing bacteria such as Blautia, U.m. of Lachnospiraceae family, U.m. of Ruminococcaceae family, Papillibacter, Roseburia, Intestinimonas, Shuttleworthia together with higher butyric acid levels were detected in PERM+ERW group compared to the other groups. In conclusion, the PD animal model showed increased intestinal permeability together with hepatic inflammation correlated with altered gut microbiota. The positive effects of ERW co-treatment observed in gut, liver and brain of rats were linked to changes on gut microbiota.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223238PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786615PMC
March 2020

Changes in Oral Microbial Ecology of C57BL/6 Mice at Different Ages Associated with Sampling Methodology.

Microorganisms 2019 Aug 22;7(9). Epub 2019 Aug 22.

Institute of Animal Science, University of Hohenheim, 70599 Stuttgart, Germany.

The mouth is an important niche for bacterial colonization. Previous research used mouth microbiota to predict diseases like colon cancer and inflammatory bowel disease (IBD). It is still unclear how the sampling methodology influences microbial characterization. Our aim was to determine if the sampling methods, e.g., cotton swab or tissue biopsy, and the age influence the oral microbial composition of mice. Microbial DNA was extracted using a commercial kit and characterized targeting the 16s rRNA gene from mouth swabs and tissue biopsies from 2 and 15 months old C57BL/6 male mice kept in the same SPF facility. Our results show statistical different microbial community of the different ages, type of sampling, and the two fixed factors age x type of sample (-value <0.05). At the genus level, we identified that the genera , , and either increase or decrease in abundance depending on sampling and age. Additionally, the abundance of , and some unclassified was affected by the sampling method. While swab and tissue biopsies both identified the common colonizers of oral microbiota, cotton swabbing is a low-cost and practical method, validating the use of the swab as the preferred oral sampling approach.
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http://dx.doi.org/10.3390/microorganisms7090283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780121PMC
August 2019

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

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis.

Gut 2019 08 14;68(8):1477-1492. Epub 2019 Mar 14.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Objective: There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout model resembling human primary sclerosing cholangitis (PSC).

Design: Male , crossed with hepatocyte-specific deletion of caspase-8 ( /Casp8) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of -associated intestinal dysbiosis was studied by microbiota transfer experiments.

Results: mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.

Conclusions: MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
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http://dx.doi.org/10.1136/gutjnl-2018-316670DOI Listing
August 2019

Nutritional Intake and the Risk for Non-Alcoholic Fatty Liver Disease (NAFLD).

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

RA Molecular Nutritional Science, Department of Nutritional Sciences, University of Vienna, Althanstr.14, 1090 Vienna, Austria.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising worldwide, and it is estimated that approximately one billion individuals may be afflicted with NAFLD globally [...].
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http://dx.doi.org/10.3390/nu11030588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470721PMC
March 2019

Beneficial Effects of Vitamin D Treatment in an Obese Mouse Model of Non-Alcoholic Steatohepatitis.

Nutrients 2019 Jan 3;11(1). Epub 2019 Jan 3.

Division of Hepatology, University Hospital Würzburg, 97080 Würzburg, Germany.

Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut⁻liver axis.
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http://dx.doi.org/10.3390/nu11010077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356425PMC
January 2019

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

Selenium-binding protein 1 (SELENBP1) is a marker of mature adipocytes.

Redox Biol 2019 01 10;20:489-495. Epub 2018 Nov 10.

Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.

Selenium-binding protein 1 (SELENBP1) has recently been reported to catalyse the oxidation of methanethiol, an organosulfur compound produced by gut microbiota. Two of the reaction products of methanethiol oxidation, hydrogen peroxide and hydrogen sulphide, serve as signalling molecules for cell differentiation. Indeed, colonocyte differentiation has been found to be associated with SELENBP1 induction. Here, we show that SELENBP1 is induced when 3T3-L1 preadipocytes undergo terminal differentiation and maturation to adipocytes. SELENBP1 induction succeeded the up-regulation of known marker proteins of white adipocytes and the intracellular accumulation of lipids. Immunofluorescence microscopy revealed predominant cytoplasmic localisation of SELENBP1 in 3T3-L1 adipocytes, as demonstrated by co-staining with the key lipogenic enzyme, acetyl-CoA-carboxylase (ACC), located in cytosol. In differentiating 3T3-L1 cells, the mTOR inhibitor rapamycin and the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) likewise suppressed SELENBP1 induction, adipocyte differentiation and lipid accumulation. However, lipid accumulation per se is not linked to SELENBP1 induction, as hepatic SELENBP1 was down-regulated in high fructose-fed mice despite increased lipogenesis in the liver and development of non-alcoholic fatty liver disease (NAFLD). In conclusion, SELENBP1 is a marker of cell differentiation/maturation rather than being linked to lipogenesis/lipid accumulation.
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http://dx.doi.org/10.1016/j.redox.2018.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249406PMC
January 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

Iso-alpha acids from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation, and fibrosis.

Lab Invest 2018 12 8;98(12):1614-1626. Epub 2018 Aug 8.

Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. Iso-alpha acids (IAAs), hop-derived bitter compounds in beer, have been shown to beneficially affect different components of the metabolic syndrome such as insulin resistance and dyslipidemia. However, IAAs have not yet been studied in the context of chronic liver disease. Here we analyzed the effect of IAA on the pathogenesis of NAFLD. Once, we applied IAA to mice in combination with a NAFLD-inducing Western-type diet (WTD), and observed that IAA significantly inhibited WTD-induced body weight gain, glucose intolerance, and hepatic steatosis. Fitting to this, IAA dose-dependently inhibited cellular lipid accumulation in primary human hepatocytes (PHH) in vitro. Reduced expression of PPAR-gamma and key enzymes of lipid synthesis as well as increased expression of PPAR-alpha, indicative for increased lipid combustion, were identified as underlying mechanisms of reduced hepatocellular steatosis in vitro and in vivo. Analysis of hepatic HMOX1 expression indicated reduced oxidative stress in IAA-treated mice, which was paralleled by reduced activation of the JNK pathway and pro-inflammatory gene expression and immune cell infiltration. Furthermore, IAA reduced hepatic stellate cell (HSC) activation and pro-fibrogenic gene expression. Similarly, IAA also dose-dependently reduced oxidative stress and JNK activation in steatotic PHH, inhibited HSC activation, and reduced proliferation and pro-fibrogenic gene expression in already activated HSC in vitro. In conclusion, IAAs inhibit different pathophysiological steps of disease progression in NAFLD. Together with previous studies, which demonstrated the safety of even long-term application of IAA in humans, our data suggest IAA as promising therapeutic agent for the prevention and treatment of (non)alcoholic (fatty) liver disease.
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http://dx.doi.org/10.1038/s41374-018-0112-xDOI Listing
December 2018

Relations of gut liver axis components and gut microbiota in obese children with fatty liver: A pilot study.

Clin Res Hepatol Gastroenterol 2018 09 10;42(4):387-390. Epub 2018 Jul 10.

Pediatrics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via Allende, 84081 Baronissi (Sa), Italy; University Hospital "San Giovanni di Dio e Ruggi d'Aragona", 84131 Salerno, Italy; European Laboratory of Food Induced Intestinal Diseases (ELFID), University of Naples Federico II, 80100 Naples, Italy.

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http://dx.doi.org/10.1016/j.clinre.2018.03.015DOI Listing
September 2018

Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis.

Cell Death Dis 2018 01 19;9(2):51. Epub 2018 Jan 19.

Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-β-a potent pro-fibrogenic cytokine-leads to disease progression. Our aim was to elucidate the crosstalk of TGF-β and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-β and cell fate was determined. Fluidigm RNA analyses revealed transcriptional effects that regulate survival and apoptosis. Mechanistic insights were derived from enzyme/pathway inhibition experiments and modulation of oxidative stress levels. To substantiate findings, animal model specimens and human liver tissue cultures were investigated.

Results: On its own, ethanol had no effect on hepatocyte apoptosis, whereas TGF-β increased cell death. Combined treatment led to massive hepatocyte apoptosis, which could also be recapitulated in human HCC liver tissue treated ex vivo. Alcohol boosted the TGF-β pro-apoptotic gene signature. The underlying mechanism of pathway crosstalk involves SMAD and non-SMAD/AKT signaling. Blunting CYP2E1 and ADH activities did not prevent this effect, implying that it was not a consequence of alcohol metabolism. In line with this, the ethanol metabolite acetaldehyde did not mimic the effect and glutathione supplementation did not prevent the super-induction of cell death. In contrast, blocking GSK-3β activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-β. This study provides novel information on the crosstalk between ethanol and TGF-β. We give evidence that ethanol directly leads to a boost of TGF-β's pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.
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http://dx.doi.org/10.1038/s41419-017-0071-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833779PMC
January 2018

An iso-α-acid-rich extract from hops (Humulus lupulus) attenuates acute alcohol-induced liver steatosis in mice.

Nutrition 2018 Jan 27;45:68-75. Epub 2017 Jul 27.

Institute of Nutrition, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, Jena, Germany; Department of Nutritional Sciences, Molecular Nutritional Science, University Vienna, Vienna, Austria. Electronic address:

Objective: Results of in vitro and in vivo studies suggest that consumption of beer is less harmful for the liver than consumption of spirits. It also has been suggested that secondary plant compounds derived from hops such as xanthohumol or iso-α-acids may have beneficial effects on the development of liver diseases of various etiologies. The aim of this study was to determine whether iso-α-acids consumed in doses achieved by "normal" beer consumption have beneficial effects on health.

Methods: Female C57 Bl/6 J mice, pretreated for 4 d with an iso-α-acid-rich extract (∼30% iso-α-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol (6 g/kg body weight intragastric) or an iso-caloric maltodextrin solution. Markers of liver damage, toll-like receptor-4 signaling, and lipid peroxidation were determined. Furthermore, the effect of isohumulone on the lipopolysaccharide-dependent activation of J774 A.1 macrophages, used as a model of Kupffer cells, was determined.

Results: In the liver, acute ethanol administration led to a significant accumulation of fat (∼10-fold), which was accompanied by significantly higher inducible nitric oxide synthase protein level, elevated nitric oxide production, and increased plasminogen activator inhibitor 1 protein concentration when compared to controls. In mice pretreated with iso-α-acids, these effects of alcohol were markedly attenuated. Pretreatment of J774 A.1 macrophages with isohumulone significantly attenuated lipopolysaccharide-induced mRNA expression of inducible nitric oxide synthase and interleukin-6 as well as the release of nitric oxide.

Conclusion: Taken together, iso-α-acids markedly attenuated the development of acute alcohol-induced damage in mice.
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http://dx.doi.org/10.1016/j.nut.2017.07.010DOI Listing
January 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