Background Nursing home residents have increased rates of intestinal colonisation with multidrug-resistant organisms (MDROs). We assessed the colonisation and spread of MDROs among this population,... Show moreBackground Nursing home residents have increased rates of intestinal colonisation with multidrug-resistant organisms (MDROs). We assessed the colonisation and spread of MDROs among this population, determined clinical risk factors for MDRO colonisation and investigated the role of the gut microbiota in providing colonisation resistance against MDROs. Methods We conducted a prospective cohort study in a Dutch nursing home. Demographical, epidemiological and clinical data were collected at four time points with 2-month intervals (October 2016-April 2017). To obtain longitudinal data, faecal samples from residents were collected for at least two time points. Ultimately, twenty-seven residents were included in the study and 93 faecal samples were analysed, of which 27 (29.0%) were MDRO-positive. Twelve residents (44.4%) were colonised with an MDRO at at least one time point throughout the 6-month study. Results Univariable generalised estimating equation logistic regression indicated that antibiotic use in the previous 2 months and hospital admittance in the previous year were associated with MDRO colonisation. Characterisation of MDRO isolates through whole-genome sequencing revealed Escherichia coli sequence type (ST)131 to be the most prevalent MDRO and ward-specific clusters of E. coli ST131 were identified. Microbiota analysis by 16S rRNA gene amplicon sequencing revealed no differences in alpha or beta diversity between MDRO-positive and negative samples, nor between residents who were ever or never colonised. Three bacterial taxa (Dorea, Atopobiaceae and Lachnospiraceae ND3007 group) were more abundant in residents never colonised with an MDRO throughout the 6-month study. An unexpectedly high abundance of Bifidobacterium was observed in several residents. Further investigation of a subset of samples with metagenomics showed that various Bifidobacterium species were highly abundant, of which B. longum strains remained identical within residents over time, but were different between residents. Conclusions Our study provides new evidence for the role of the gut microbiota in colonisation resistance against MDROs in the elderly living in a nursing home setting. Dorea, Atopobiaceae and Lachnospiraceae ND3007 group may be associated with protection against MDRO colonisation. Furthermore, we report a uniquely high abundance of several Bifidobacterium species in multiple residents and excluded the possibility that this was due to probiotic supplementation. Show less
Terveer, E.M.; Fallon, M.; Kraakman, M.E.M.; Ormond, A.; Fitzpatrick, M.; Caljouw, M.A.A.; ... ; Fitzpatrick, F. 2020
In this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved... Show moreIn this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved in atherogenesis. We show that continuous enhanced inflammation in hepatocytes increased the hepatic production of VLDL and aggravated atherosclerosis development in hyperlipidemic APOE*3-Leiden (E3L) mice as compared to control E3L mice. Poor lung function, most commonly caused by chronic obstructive pulmonary disease (COPD), is a risk factor for atherosclerosis development. To this end, we investigated whether elastase-induced alveolar wall destruction, a model for COPD, would worsen atherosclerosis development in E3L mice. No difference in atherosclerotic lesion size was observed between mice after elastase or vehicle instillation, indicating that alveolar destruction per se is not responsible for the increased risk for atherosclerosis in COPD patients. Furthermore, we studied the anti-atherosclerotic effects of resveratrol which can be found in red wine and Asian medicinal herbs. Hyperlipidemic E3L.CETP mice were fed a diet without (control) or with resveratrol, atorvastatin, or both. Resveratrol protected against atherosclerosis development, but did not add to the anti-atherogenic effects of atorvastatin. Finally, the clinical implications and future perspectives of these results are discussed. Show less
OBJECTIVE The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-κB (NF-κB) is a... Show moreOBJECTIVE The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-κB (NF-κB) is a central regulator of inflammatory processes, we hypothesized that chronically enhanced hepatic NF-κB activation, through hepatocyte-specific expression of IκB kinase-β (IKKβ) (LIKK), will aggravate atherosclerosis development in APOE*3-Leiden (E3L) mice. METHODS AND RESULTS E3L.LIKK and E3L control littermates were fed a Western-type diet for 24 weeks. E3L.LIKK mice showed a 2.3-fold increased atherosclerotic lesion area and more advanced atherosclerosis in the aortic root with less segments without atherosclerotic lesions (11% vs. 42%), and more segments with mild (63% vs. 44%) and severe (26% vs. 14%) lesions. Expression of LIKK did not affect basal levels of inflammatory parameters, but plasma cytokine levels tended to be higher in E3L.LIKK mice after lipopolysaccharide (LPS) administration. E3L.LIKK mice showed transiently increased plasma cholesterol levels, confined to (V)LDL. This transient character resulted in a mild (+17%) increased cumulative plasma cholesterol exposure. CONCLUSION We conclude that selective activation of NF-κB in hepatocytes considerably promotes atherosclerosis development which is (at least partly) explained by an increased sensitivity to proinflammatory triggers and transiently increased plasma cholesterol levels. Show less
Low-grade inflammation in different tissues, including activation of the nuclear factor kappa B pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular... Show moreLow-grade inflammation in different tissues, including activation of the nuclear factor kappa B pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular diseases (CVDs). In this study, we investigated the relation between chronic hepatocyte-specific overexpression of IkB kinase (IKK)-beta and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK-beta only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IKK-beta specifically in hepatocytes of hyperlipidemic APOE*3-Leiden mice clearly induced hypertriglyceridemia. Mechanistic in vivo studies revealed that the hypertriglyceridemia was caused by increased hepatic VLDL-TG production rather than a change in plasma VLDL-TG clearance. Studies in primary hepatocytes showed that IKK-beta overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK-beta activation and TG production within the hepatocyte. Hepatic lipid analysis and hepatic gene expression analysis of pathways involved in lipid metabolism suggested that hepatocyte- specific IKK-beta overexpression increases VLDL production not by increased steatosis or decreased FA oxidation, but most likely by carbohydrate-responsive element binding protein-mediated upregulation of Fas expression.jlr These findings implicate that specific activation of inflammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK-beta pathway as a possible target to treat hypertriglyceridemia. van Diepen, J. A., M. C. Wong, B. Guigas, J. Bos, R. Stienstra, L. Hodson, S. E. Shoelson, J. F. P. Berbee, P. C. N. Rensen, J. A. Romijn, L. M. Havekes, and P. J. Voshol. Hepatocyte-specific IKK-beta activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. J. Lipid Res. 2011. 52: 942-950. Show less
Low-grade inflammation in different tissues, including activation of the nuclear factor κB (NF-κB) pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular... Show moreLow-grade inflammation in different tissues, including activation of the nuclear factor κB (NF-κB) pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular diseases (CVD). In this study we investigated the relation between chronic hepatocyte-specific overexpression of IKK-β and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK-β only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IκB kinase (IKK-β) specifically in hepatocytes of hyperlipidemic APOE*3-Leiden mice clearly induced hypertriglyceridemia. Mechanistic in vivo studies revealed that the hypertriglyceridemia was caused by increased hepatic VLDL-TG production, rather than a change in plasma VLDL-TG clearance. Studies in primary hepatocytes showed that IKK-β overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK-β activation and TG production within the hepatocyte. Hepatic lipid analysis and hepatic gene expression analysis of pathways involved in lipid metabolism suggested that hepatocyte specific IKK-β overexpression increases VLDL production not by increased steatosis or decreased FA oxidation, but most likely by ChREBP-mediated upregulation of Fas expression. These findings implicate that specific activation of inflammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK-β pathway as a possible target to treat hypertriglyceridemia. Show less
