Publications by authors named "Natasa Giallourou"

20 Publications

  • Page 1 of 1

Sex Disparities and Neutralizing-Antibody Durability to SARS-CoV-2 Infection in Convalescent Individuals.

mSphere 2021 08 25;6(4):e0027521. Epub 2021 Aug 25.

Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2 months after infection or the reason for the discrepancy in COVID-19 disease and sex. Using convalescent-phase sera collected from 101 COVID-19-recovered individuals 21 to 212 days after symptom onset with 48 additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations of individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to 6 months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex and in individuals with cardiometabolic comorbidities. In this study, we found that neutralizing antibody responses in COVID-19-convalescent individuals vary in magnitude but are durable and correlate well with receptor binding domain (RBD) Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardiometabolic comorbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2 which supports the growing literature on sex discrepancies regarding COVID-19 disease morbidity and mortality, as well as functional neutralizing antibody responses to SARS-CoV-2.
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http://dx.doi.org/10.1128/mSphere.00275-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386415PMC
August 2021

Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals.

medRxiv 2021 Feb 3. Epub 2021 Feb 3.

Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities.

Significance: In this study we found that neutralizing antibody responses in COVID-19 convalescent individuals vary in magnitude but are durable and correlate well with RBD Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time, that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardio-metabolic co-morbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.02.01.21250493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872367PMC
February 2021

Enteropathogenic Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations, and Increased Intestinal Permeability in a Murine Model.

Front Cell Infect Microbiol 2020 17;10:595266. Epub 2020 Dec 17.

Center for Global Health, Division of Infectious Disease and International Health, University of Virginia School of Medicine, Charlottesville, VA, United States.

Enteropathogenic  (EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC or mutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues. Metabolomic changes were also observed in EPEC infected mice with changes in tricarboxylic acid (TCA) cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. The mutant colonized the mice with no weight loss or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.
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http://dx.doi.org/10.3389/fcimb.2020.595266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773950PMC
June 2021

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis.

J Clin Invest 2020 08;130(8):4019-4024

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

The microbiome provides resistance to infection. However, the underlying mechanisms are poorly understood. We demonstrate that colonization with the intestinal bacterium Clostridium scindens protects from Entamoeba histolytica colitis via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte progenitors (GMPs) and resulted in increased intestinal neutrophils with subsequent challenge with E. histolytica. Introduction of C. scindens alone was sufficient to expand GMPs in gnotobiotic mice. Adoptive transfer of bone marrow from C. scindens-colonized mice into naive mice protected against amebic colitis and increased intestinal neutrophils. Children without E. histolytica diarrhea also had a higher abundance of Lachnoclostridia. Lachnoclostridia C. scindens can metabolize the bile salt cholate, so we measured deoxycholate and discovered that it was increased in the sera of C. scindens-colonized specific pathogen-free and gnotobiotic mice, as well as in children protected from amebiasis. Administration of deoxycholate alone increased GMPs and provided protection from amebiasis. We elucidated a mechanism by which C. scindens and the microbially metabolized bile salt deoxycholic acid alter hematopoietic precursors and provide innate protection from later infection with E. histolytica.
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http://dx.doi.org/10.1172/JCI133605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410058PMC
August 2020

Effects of improved water, sanitation, and hygiene and improved complementary feeding on environmental enteric dysfunction in children in rural Zimbabwe: A cluster-randomized controlled trial.

PLoS Negl Trop Dis 2020 02 14;14(2):e0007963. Epub 2020 Feb 14.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.

Background: Environmental enteric dysfunction (EED) may be an important modifiable cause of child stunting. We described the evolution of EED biomarkers from birth to 18 months in rural Zimbabwe and tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF), on EED.

Methodology And Findings: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial was a 2x2 factorial cluster-randomised trial of improved IYCF and improved WASH on child stunting and anaemia at 18 months of age. 1169 infants born to HIV-negative mothers provided plasma and faecal specimens at 1, 3, 6, 12, and 18 months of age. We measured EED biomarkers that reflect all domains of the hypothesized pathological pathway. Markers of intestinal permeability and intestinal inflammation declined over time, while markers of microbial translocation and systemic inflammation increased between 1-18 months. Markers of intestinal damage (I-FABP) and repair (REG-1β) mirrored each other, and citrulline (a marker of intestinal epithelial mass) increased from 6 months of age, suggesting dynamic epithelial turnover and regeneration in response to enteric insults. We observed few effects of IYCF and WASH on EED after adjustment for multiple comparisons. The WASH intervention decreased plasma IGF-1 at 3 months (β:0.89, 95%CI:0.81,0.98) and plasma kynurenine at 12 months (β: 0.92, 95%CI:0.87,0.97), and increased plasma IGF-1 at 18 months (β:1.15, 95%CI:1.05,1.25), but these small WASH effects did not translate into improved growth.

Conclusions: Overall, we observed dynamic trends in EED but few effects of IYCF or WASH on biomarkers during the first 18 months after birth, suggesting that these interventions did not impact EED. Transformative WASH interventions are required to prevent or ameliorate EED in low-income settings.
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http://dx.doi.org/10.1371/journal.pntd.0007963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046282PMC
February 2020

Characterizing the metabolic perturbations induced by activity-based anorexia in the C57Bl/6 mouse using H NMR spectroscopy.

Clin Nutr 2020 08 6;39(8):2428-2434. Epub 2019 Dec 6.

Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK.

Background & Aims: Anorexia nervosa (AN) is a severe psychological and potentially life-threatening eating disorder. The activity-based anorexia (ABA) mouse model is commonly used to investigate physiological abnormalities associated with this disorder. Characterizing the holistic biochemical alterations induced by anorexia is essential to understanding AN pathophysiology as well as to define biomarkers for prognosis.

Methods: To unravel the adaptive biochemical mechanisms occurring in this model in response to self-starvation, the urinary, plasma and fecal metabolic phenotypes of mice under different experimental conditions were compared. This included control mice with and without physical activity (CT and CTPA mice), a group with limited food access (LFA), and a group with both limited food access and physical activity (ABA). Using H nuclear magnetic resonance (NMR) spectroscopy, several biochemical perturbations were observed.

Results: Physical activity altered the abundance of 14 fecal metabolites, including those involved in gut microbial metabolism and proteolysis. Food restriction disrupted a wide range of metabolic pathways including gut microbial metabolism, proteolysis and fatty acid breakdown (24 urinary and 6 plasma metabolites). The combined impact of food restriction and physical activity resulted in the same pattern of metabolic disruption (24 urine, 6 plasma).

Conclusions: This work defined the metabolic signatures of ABA mice and provides novel insights into biological adaptations of mice in response to both food restriction and physical activity. These results should be further confirmed in AN patients.
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http://dx.doi.org/10.1016/j.clnu.2019.10.026DOI Listing
August 2020

A murine model of diarrhea, growth impairment and metabolic disturbances with infection and the role of zinc deficiency.

Gut Microbes 2019 3;10(5):615-630. Epub 2019 Feb 3.

Center for Global Health, Division of Infectious Diseases and International Health, University of Virginia , Charlottesville , USA.

is one of the major enteric pathogens worldwide. We present a murine model of infection and investigate the role of zinc deficiency (ZD). C57BL/6 mice fed either standard chow (HC) or ZD diets were pretreated with an antibiotic cocktail and received strain 2457T orally. Antibiotic pre-treated ZD mice showed higher colonization than non-treated mice. ZD mice showed persistent colonization for at least 50 days post-infection (pi). -infected mice showed significant weight loss, diarrhea and increased levels of fecal MPO and LCN in both HC and ZD fed mice. preferentially colonized the colon, caused epithelial disruption and inflammatory cell infiltrate, and promoted cytokine production which correlated with weight loss and histopathological changes. Infection with (critical for type 3 secretion system) did not cause weight loss or diarrhea, and had decreased stool shedding duration and tissue burden. Several biochemical changes related to energy, inflammation and gut-microbial metabolism were observed. Zinc supplementation increased weight gains and reduced intestinal inflammation and stool shedding in ZD infected mice. In conclusion, young antibiotic-treated mice provide a new model of oral infection, with ZD promoting prolonged infection outcomes.
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http://dx.doi.org/10.1080/19490976.2018.1564430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748602PMC
December 2019

Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity.

Free Radic Biol Med 2018 12 17;129:504-519. Epub 2018 Oct 17.

Molecular Physiology Laboratory, Centre for Atherothrombotic & Metabolic Disease, Hull York Medical School, United Kingdom. Electronic address:

Obesity leading to hyperlipidaemia and atherosclerosis is recognised to induce morphological and metabolic changes in many tissues. However, hyperlipidaemia can occur in the absence of obesity. The impact of the latter scenario on skeletal muscle and liver is not understood sufficiently. In this regard, we used the Apolipoprotein E-deficient (ApoE) mouse model, an established model of hyperlipidaemia and atherosclerosis, that does not become obese when subjected to a high-fat diet, to determine the impact of Western-type diet (WD) and ApoE deficiency on skeletal muscle morphological, metabolic and biochemical properties. To establish the potential of therapeutic targets, we further examined the impact of Nox2 pharmacological inhibition on skeletal muscle redox biology. We found ectopic lipid accumulation in skeletal muscle and the liver, and altered skeletal muscle morphology and intramuscular triacylglycerol fatty acid composition. WD and ApoE deficiency had a detrimental impact in muscle metabolome, followed by perturbed gene expression for fatty acid uptake and oxidation. Importantly, there was enhanced oxidative stress in the skeletal muscle and development of liver steatosis, inflammation and oxidative protein modifications. Pharmacological inhibition of Nox2 decreased reactive oxygen species production and protein oxidative modifications in the muscle of ApoE mice subjected to a Western-type diet. This study provides key evidence to better understand the pathophysiology of skeletal muscle in the context of hyperlipidaemia and atherosclerosis and identifies Nox2 as a potential target for attenuating oxidative stress in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.10.422DOI Listing
December 2018

Inferring Metabolic Mechanisms of Interaction within a Defined Gut Microbiota.

Cell Syst 2018 09 5;7(3):245-257.e7. Epub 2018 Sep 5.

Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Department of Medicine, Division of Infectious Diseases & International Health, University of Virginia, Charlottesville, VA, USA; Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA. Electronic address:

The diversity and number of species present within microbial communities create the potential for a multitude of interspecies metabolic interactions. Here, we develop, apply, and experimentally test a framework for inferring metabolic mechanisms associated with interspecies interactions. We perform pairwise growth and metabolome profiling of co-cultures of strains from a model mouse microbiota. We then apply our framework to dissect emergent metabolic behaviors that occur in co-culture. Based on one of the inferences from this framework, we identify and interrogate an amino acid cross-feeding interaction and validate that the proposed interaction leads to a growth benefit in vitro. Our results reveal the type and extent of emergent metabolic behavior in microbial communities composed of gut microbes. We focus on growth-modulating interactions, but the framework can be applied to interspecies interactions that modulate any phenotype of interest within microbial communities.
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http://dx.doi.org/10.1016/j.cels.2018.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166237PMC
September 2018

A prebiotic intervention study in children with autism spectrum disorders (ASDs).

Microbiome 2018 08 2;6(1):133. Epub 2018 Aug 2.

Health Sciences Research Centre, Life Sciences Department, Whitelands College, University of Roehampton, London, SW15 4JD, UK.

Background: Different dietary approaches, such as gluten and casein free diets, or the use of probiotics and prebiotics have been suggested in autistic spectrum disorders in order to reduce gastrointestinal (GI) disturbances. GI symptoms are of particular interest in this population due to prevalence and correlation with the severity of behavioural traits. Nowadays, there is lack of strong evidence about the effect of dietary interventions on these problems, particularly prebiotics. Therefore, we assessed the impact of exclusion diets and a 6-week Bimuno® galactooligosaccharide (B-GOS®) prebiotic intervention in 30 autistic children.

Results: The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites.

Conclusions: To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects. A combined dietary approach resulted in significant changes in gut microbiota composition and metabolism suggesting that multiple interventions might be more relevant for the improvement of these aspects as well as psychological traits.

Trial Registration: NCT02720900 ; registered in November 2015.
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http://dx.doi.org/10.1186/s40168-018-0523-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091020PMC
August 2018

Metabolic targets of watercress and PEITC in MCF-7 and MCF-10A cells explain differential sensitisation responses to ionising radiation.

Eur J Nutr 2019 Sep 31;58(6):2377-2391. Epub 2018 Jul 31.

Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.

Purpose: Watercress is a rich source of phytochemicals with anticancer potential, including phenethyl isothiocyanate (PEITC). We examined the potential for watercress extracts and PEITC to increase the DNA damage caused by ionising radiation (IR) in breast cancer cells and to be protective against radiation-induced collateral damage in healthy breast cells. The metabolic events that mediate such responses were explored using metabolic profiling.

Methods: H nuclear magnetic resonance spectroscopy-based metabolic profiling was coupled with DNA damage-related assays (cell cycle, Comet assay, viability assays) to profile the comparative effects of watercress and PEITC in MCF-7 breast cancer cells and MCF-10A non-tumorigenic breast cells with and without exposure to IR.

Results: Both the watercress extract and PEITC-modulated biosynthetic pathways of lipid and protein synthesis and resulted in changes in cellular bioenergetics. Disruptions to the redox balance occurred with both treatments in the two cell lines, characterised by shifts in the abundance of glutathione. PEITC enhanced the sensitivity of the breast cancer cells to IR increasing the effectiveness of the cancer-killing process. In contrast, watercress-protected non-tumorigenic breast cells from radiation-induced damage. These effects were driven by changes in the cellular content of the antioxidant glutathione following exposure to PEITC and other phytochemicals in watercress.

Conclusion: These findings support the potential prophylactic impact of watercress during radiotherapy. Extracted compounds from watercress and PEITC differentially modulate cellular metabolism collectively enhancing the therapeutic outcomes of radiotherapy.
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http://dx.doi.org/10.1007/s00394-018-1789-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689287PMC
September 2019

A novel mouse model of Campylobacter jejuni enteropathy and diarrhea.

PLoS Pathog 2018 03 23;14(3):e1007083. Epub 2018 May 23.

Division of Infectious Disease and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States of America.

Campylobacter infections are among the leading bacterial causes of diarrhea and of 'environmental enteropathy' (EE) and growth failure worldwide. However, the lack of an inexpensive small animal model of enteric disease with Campylobacter has been a major limitation for understanding its pathogenesis, interventions or vaccine development. We describe a robust standard mouse model that can exhibit reproducible bloody diarrhea or growth failure, depending on the zinc or protein deficient diet and on antibiotic alteration of normal microbiota prior to infection. Zinc deficiency and the use of antibiotics create a niche for Campylobacter infection to establish by narrowing the metabolic flexibility of these mice for pathogen clearance and by promoting intestinal and systemic inflammation. Several biomarkers and intestinal pathology in this model also mimic those seen in human disease. This model provides a novel tool to test specific hypotheses regarding disease pathogenesis as well as vaccine development that is currently in progress.
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http://dx.doi.org/10.1371/journal.ppat.1007083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988333PMC
March 2018

Enhanced exercise and regenerative capacity in a mouse model that violates size constraints of oxidative muscle fibres.

Elife 2016 08 5;5. Epub 2016 Aug 5.

School of Biological Sciences, University of Reading, Reading, United Kingdom.

A central tenet of skeletal muscle biology is the existence of an inverse relationship between the oxidative fibre capacity and its size. However, robustness of this relationship is unknown. We show that superimposition of Estrogen-related receptor gamma (Errγ) on the myostatin (Mtn) mouse null background (Mtn(-/-)/Errγ(Tg/+)) results in hypertrophic muscle with a high oxidative capacity thus violating the inverse relationship between fibre size and oxidative capacity. We also examined the canonical view that oxidative muscle phenotype positively correlate with Satellite cell number, the resident stem cells of skeletal muscle. Surprisingly, hypertrophic fibres from Mtn(-/-)/Errγ(Tg/+) mouse showed satellite cell deficit which unexpectedly did not affect muscle regeneration. These observations 1) challenge the concept of a constraint between fibre size and oxidative capacity and 2) indicate the important role of the microcirculation in the regenerative capacity of a muscle even when satellite cell numbers are reduced.
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http://dx.doi.org/10.7554/eLife.16940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975572PMC
August 2016

Effects of domestic processing methods on the phytochemical content of watercress (Nasturtium officinale).

Food Chem 2016 Dec 1;212:411-9. Epub 2016 Jun 1.

Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland.

The impact of conventional cooking and processing methods on total phenols, antioxidant activity, carotenoids and glucosinolates of watercress was evaluated. Boiling significantly decreases phenolic content, antioxidant activity and recoverable glucosinolates, however it increases the carotenoid concentrations of watercress as compared to the raw vegetable. Cooking by microwaving and steaming maintains the majority of phytochemicals in comparison to the fresh material, suggesting that they should be used as the preferred methods of watercress preparation. Boiling of watercress should be avoided to ensure maximum ingestion of watercress-derived beneficial phytochemicals.
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http://dx.doi.org/10.1016/j.foodchem.2016.05.190DOI Listing
December 2016

Effect of a long-term high-protein diet on survival, obesity development, and gut microbiota in mice.

Am J Physiol Endocrinol Metab 2016 Jun 29;310(11):E886-99. Epub 2016 Mar 29.

Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark; BGI-Shenzhen, Shenzhen, China,

Female C57BL/6J mice were fed a regular low-fat diet or high-fat diets combined with either high or low protein-to-sucrose ratios during their entire lifespan to examine the long-term effects on obesity development, gut microbiota, and survival. Intake of a high-fat diet with a low protein/sucrose ratio precipitated obesity and reduced survival relative to mice fed a low-fat diet. By contrast, intake of a high-fat diet with a high protein/sucrose ratio attenuated lifelong weight gain and adipose tissue expansion, and survival was not significantly altered relative to low-fat-fed mice. Our findings support the notion that reduced survival in response to high-fat/high-sucrose feeding is linked to obesity development. Digital gene expression analyses, further validated by qPCR, demonstrated that the protein/sucrose ratio modulated global gene expression over time in liver and adipose tissue, affecting pathways related to metabolism and inflammation. Analysis of fecal bacterial DNA using the Mouse Intestinal Tract Chip revealed significant changes in the composition of the gut microbiota in relation to host age and dietary fat content, but not the protein/sucrose ratio. Accordingly, dietary fat rather than the protein/sucrose ratio or adiposity is a major driver shaping the gut microbiota, whereas the effect of a high-fat diet on survival is dependent on the protein/sucrose ratio.
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http://dx.doi.org/10.1152/ajpendo.00363.2015DOI Listing
June 2016

Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse.

Skelet Muscle 2015 7;5:38. Epub 2015 Dec 7.

School of Biological Sciences, University of Reading, Reading, RG6 6UB UK.

Background: Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet.

Methods: Pregnant as well as virgin myostatin null mice and age matched wild type animals were raised on a high fat diet for up to 10 weeks. The effect of the diet was tested on skeletal muscle, liver and fat. Quantitate PCR, Western blotting, immunohistochemistry, in-vivo and ex-vivo muscle characterisation, metabonomic and lipidomic measurements were from the four major cohorts.

Results: We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization.

Conclusions: Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling.
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http://dx.doi.org/10.1186/s13395-015-0063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671215PMC
December 2015

Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation.

PLoS One 2015 25;10(3):e0120524. Epub 2015 Mar 25.

School of Biological Sciences, University of Reading, Whiteknights campus, Reading, United Kingdom.

Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120524PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373938PMC
March 2016

Choline inadequacy impairs trophoblast function and vascularization in cultured human placental trophoblasts.

J Cell Physiol 2014 Aug;229(8):1016-27

Division of Nutritional Science, Cornell University, Ithaca, New York.

Maternal choline intake during gestation may influence placental function and fetal health outcomes. Specifically, we previously showed that supplemental choline reduced placental and maternal circulating concentrations of the anti-angiogenic factor, fms-like tyrosine kinase-1 (sFLT1), in pregnant women as well as sFLT1 production in cultured human trophoblasts. The current study aimed to quantify the effect of choline on a wider array of biomarkers related to trophoblast function and to elucidate possible mechanisms. Immortalized HTR-8/SVneo trophoblasts were cultured in different choline concentrations (8, 13, and 28 µM [control]) for 96-h and markers of angiogenesis, inflammation, apoptosis, and blood vessel formation were examined. Choline insufficiency altered the angiogenic profile, impaired in vitro angiogenesis, increased inflammation, induced apoptosis, increased oxidative stress, and yielded greater levels of protein kinase C (PKC) isoforms δ and ϵ possibly through increases in the PKC activators 1-stearoyl-2-arachidonoyl-sn-glycerol and 1-stearoyl-2-docosahexaenoyl-sn-glycerol. Notably, the addition of a PKC inhibitor normalized angiogenesis and apoptosis, and partially rescued the aberrant gene expression profile. Together these results suggest that choline inadequacy may contribute to placental dysfunction and the development of disorders related to placental insufficiency by activating PKC.
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http://dx.doi.org/10.1002/jcp.24526DOI Listing
August 2014
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