Researchers
 

Prof Michael Muller (UEA)
Dr David Vauzour (UEA)
Dr Naiara Beraza (IFR)
Ms Britt Blokker (UEA)

Prof Müller moved from Wageningen University (the Netherlands) in 2014 to the UEA to become director of the NRP Food and Health Alliance. The Nutrigenomics and Systems Nutrition Group was set up in April 2015 following the setting up of a functional laboratory at the Institute of Food Research.

The group covers a broad area of disciplines including molecular nutrition and physiology, nutrigenomics, molecular hepatology (related to disease mechanisms underlying cholestasis, NASH and hepatic inflammation) and applications of systems biology to integrate (systems nutrition).The group has great expertise in investigating different signalling pathways involved in response of the healthy liver and the gut to nutritional challenges and under conditions of chronic liver injury. We work with a wide variety of experimental models of metabolic syndrome and chronic liver disease and have a range of transgenic animals that allow us to investigate the molecular mechanisms underlying the progression of liver pathologies related e.g. to NAFLD and other chronic liver diseases.  Moreover our expertise in gut physiology provides us with the opportunity to perform integrative research, focusing in defining the key elements that regulate the gut-liver axis. Our expertise in bile acid metabolism and its differential regulation in the liver and the gut is key to develop this research. Our work covers a wide array of chronic and acute liver injury animal models like bile duct ligation-induced cholestatic liver disease, partial hepatectomy to study the regenerative response of the liver, ischemia-reperfusion, mimicking liver transplantation induced stress, and deep experience in different models of dietary challenges to mimic human NASH. Also, we are experts in isolation and further In vitro analysis in primary parenchymal and non-parenchymal cells. We have also a wide experience in working with acute liver damage models (Concanavalin A, LPS, acetaminophen) and to perform further analysis of the liver immune response by flow cytometry analysis and cell sorting and magnetic-beads based separation techniques.  We have also an extensive track record in the applications of multi-omics applications for comprehensive phenotyping and data mining of numerous mouse models. In our research we collaborate with various groups from the NRP (UEA, IFR, The Earlham Institute (EI) and NNUH).

Currently our research is funded by financial support from the UEA, IFR, NRP, BBSRC, Dutch and Spanish funding organizations and the EU.

What we do

We mainly focus on characterising specific molecular mechanisms underlying the dietary and physiological regulation of the gut-brain-liver axis. We investigate certain signalling pathways that control the proper communication between the different elements of this axis during homeostasis and metabolic challenges (e.g. feeding-fasting, high-fat diets, caloric restriction).

Molecular nutrition and systems nutrition: Our work is focusing on the molecular mechanisms underlying the genome-wide effects of in particular fatty acids on immuno-metabolic health and plasticity in organs such as the liver and the small intestine. Most of this work in the past and more recently has focused on the molecular regulation of bile formation and secretion, mechanistic aspects of the involvement of nuclear receptors like PPARs in the genome wide transcriptional control of hepatic fatty acid homeostasis under physiological and pathophysiological conditions (NASH) and the mechanistic aspects of the immune-metabolic interaction between hepatocytes and hepatic immune cells like Kupffer cells in health and disease. To investigate this state-of-the-art physiological, molecular and cell biological methodologies have been used in combination with comprehensive unbiased transcriptomics and pathway mining applications on a series of appropriate (transgenic) mouse models. This pioneering approach had allowed us to increasingly decipher the genome-wide impact of nutrient-sensing transcription factors such as PPARs for immuno-metabolic health of organs like the liver and the gut and to characterize the differential responses of these organs to different dietary fatty acids and other food components. More recently the impact of organ-organ crosstalk has been investigated in an integrated systems approach (e.g. crosstalk between liver/adipose tissue or small intestine/liver) as essential for organ and systemic health and pathophysiological dysregulation of homeostasis. Now, our work is focusing specifically on the interaction of the liver and the small intestine, the genome wide impact of nutrient-sensing transcription factors in response of these organs to nutrients, certain bioactives from in particular plant foods as essential parts of healthy food patterns and the important interaction with the gut microbiota.

Bile acids: A major focus of our work is on the role of bile acids in the interorgan-crosstalk between the gut and the liver. Bile acids (BA) are essential not only to digest fat but also to act as potent signalling molecules, essential for the proper communication between the liver and the gut. Thus, BA and its regulators play a key role in the preservation of liver, gut and gut-liver axis homeostasis. Disruption of BA metabolism is involved in most of chronic liver diseases, and in great proportion, are tightly associated to inflammatory bowel disease; characterised by taxonomic changes in the gut microbiome, bacterial overgrowth, disruption of epithelial barrier integrity leading to alterations in gut permeability. Increased presence of circulating gut bacterial products reach the liver through the enterohepatic circulation, representing an additional ‘hit’ to an already damaged liver, further contributing to the progression of the disease to cirrhosis. We are mainly interested in identifying the molecular mechanisms regulating gut-liver axis response during homeostasis and at early stages of the cellular response to metabolic challenges. This understanding will allow us to propose early diagnostic and/or early interventional strategies to counteract disease progression.

Current projects

  1. Molecular nutrition of dietary lipid and food bioactives in the gut: Here we focus on the role of non-coding RNAs in the regulation of specific aspects of immuno-metabolism in the gut. We are furthermore interested to better understand mechanistically the impact of gut nutrient-sensing mechanisms of nutrition-related gradients for health and disease (PhD project funded by the Norwich Medical School in collaboration with IFR & EI).

  2. Impact of plant food bioactives (dietary polyphenols, such as flavonoids) for the gut-brain axis.

  3. Mechanisms underlying pathological changes in cholestatic liver disease and cirrhosis: To identify and understand the natural cellular response mechanisms to metabolic challenges will allow us to better identify potentially pathological disturbances of gut-liver axis homeostasis. Early detection of alterations in cellular stress response will allow us to propose early diagnostic and/or early interventional strategies to avoid the progression of liver-gut disease (PhD project funded by IFR).

  4. Systems Integration of Omics data & translation from mice to humans: In this project we make use of existing Omics datasets (in particular whole genome transcriptome data of liver and intestinal samples from numerous mouse models including transgenic models (e.g. hepatic acute phase response and intestinal UPR) for combined systems biology analysis and pathway mining approaches (in collaboration with The Earlham Institute).

Recent funding

  1. BBSRC grant (Grant ref. BB/M004449/1).  Enhanced cognition through dietary modulation of neuroinflammation in high risk APOE4 carriers. [Start date: 01-12-14, end date: 31-11-17]: £585k.

  2. Centre of Nutrition Learning and Memory (CNLM)/Abbott Nutrition. Controlled Trial in ‘At Risk’ Humans to Establish the Cognitive Benefits of a Nutrient Mixture and Underlying Mechanisms of Action. [Start date: 01-07-13, end date: 31-06-16] £625k.

  3. MED/NRP Translational Medicine Grant. A proof of concept study to investigate the role of a dietary supplement in the treatment of non-alcoholic steatohepatitis. [Start date: 01-03-13, end date: 31-08-13] £36k

Most of our current research is supported by financial support from the UEA, IFR, NRP, BBSRC, Dutch and Spanish funding organizations and the EU.

Recent publications

      Michael Muller

  1. Rusli F, Boekschoten MV, Zubia AA, Lute C, Müller M, Steegenga WT. A weekly alternating diet between caloric restriction and medium-fat protects the liver from fatty liver development in middle-aged C57BL/6J mice. Mol Nutr Food Res. 2015;59:533-43.
  2. IJssennagger N, Rijnierse A, de Wit N, Jonker-Termont D, Dekker J, Müller M, van der Meer R. Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon. Gut 2012;61:1041-9.
  3. de Wit NJ, Afman LA, Mensink M, Müller M. Phenotyping the effect of diet on non-alcoholic fatty liver disease J Hepatol. 2012;57:1370-3.
  4. Schwarz J, Tomé D, Baars A, Hooiveld GJ, Müller M. Dietary protein affects gene expression and prevents lipid accumulation in the liver in mice PLoS One. 2012;7:e47303.
  5. Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Müller M, Blander JM. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 2011;474:385-9.
  6. Duval C, Thissen U, Keshtkar S, Accart B, Stienstra R, Boekschoten MV, Roskams T, Kersten S, Müller M. Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice. Diabetes. 2010;59:3181-91.

David Vauzour

  1. VAUZOUR D, Noemi Tejera, Colette O’Neill, Valeria Booz, Baptiste Jude, Insa Wolf, Neil Rigby, Jose Manuel Silvan, Peter Curtis, Aedin Cassidy, Sonia de Pascual-Teresa, Gerald Rimbach, Anne Marie Minihane. Anthocyanins do not influence long chain n-3 fatty acid status: Studies in cells, rodents and humans. J Nutr Biochem. 2015, 26(3):211-8.
  2. VAUZOUR D, Pinto JT, Cooper, A and Spencer JP. The neurotoxicity of 5-S-cysteinyldopamine is mediated by the early activation of ERK1/2 followed by the subsequent activation of ASK-1/JNK1/2 pro-apoptotic signalling. Biochem J. 2014, 463: 41–52.
  3. Corona G*, VAUZOUR D*, Hercelin J, Williams CM and Spencer JP. Phenolic acid intake, delivered via moderate Champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation. Antioxid Redox Signal. 2013, 19(14):1676-89. * Joint first author
  4. Rendeiro C, VAUZOUR D, Rattray M, Waffo-Teguo P, Mérillon JM, Butler LT, Williams CM and Spencer JP. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One, 2013. 8(5): e63535. doi:10.1371/journal.pone.0063535.
  5. Rendeiro, C; VAUZOUR, D; Kean, RJ; Butler, LT; Rattray, M; Spencer, JPE and Williams, CM. Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats. Psychopharmacology. 2012, 223(3):319-30.

Naiara Beraza

  1. Fernández-Álvarez S, Gutiérrez-de Juan V, Zubiete-Franco I, Barbier-Torres L, Lahoz A, Parés A, Luka Z, Wagner C, Lu SC, Mato JM, Martínez-Chantar ML, Beraza N. TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency Lab Invest. 2015 Feb;95(2):223-36.
  2. García-Rodríguez JL, Barbier L, Fernandez-Álvarez S, Gutiérrez-de Juan V, Monte MJ, Halilbasic E, Herranz D, Álvarez L, Aspichueta P, García-Marín JJ, Trauner M, Mato JM, Serrano M, Martínez-Chantar ML*, Beraza N*. SIRT1 controls liver regeneration by regulating BA metabolism through FXR and mTOR signaling. Hepatology 2014 May; 59(5):1972-83
  3. Malato Y, Ehedego H, Al-Masaoudi M, Cubero FJ, Bornemann J, Gassler N, Liedtke C, Trautwein C*, Beraza N*. NF-κB Essential Modifier Is Required for Hepatocyte Proliferation and the Oval Cell Reaction After Partial Hepatectomy in Mice. Gastroenterology 2012. Dec;143(6):1597-1608
  4. Gomez-Santos L, Luka Z, Wagner C, Fernandez-Alvarez S, Lu SC, Mato JM, Martinez-Chantar ML, Beraza N.  Inhibition of NK cells protects the liver against acute injury in the absence of GNMT. Hepatology 2012 Aug;56(2):747-59.
  5. Beraza N, Ofner-Ziegenfuss L, Ehedego H, Boekschoten M, Bischoff SC, Müller M, Trauner M, Trautwein C.  Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis. Gut. 2011 Mar;60(3):387-96.

Who we are

Prof. Michael Müller is professor of Systems Nutrition and Nutrigenomics at the University of East Anglia (Norwich/UK) and director of the Food and Health Alliance at the Norwich Research Park. From 2000 – 2013 he was full professor and chair of Nutrition, Metabolism and Genomics at Wageningen University/NL. His group consisted of 1 personal chair, 3 assistant professors, 7 postdocs, 12 PhD students and 5 technicians. From 2003-2009 he was scientific director of the “Netherlands Nutrigenomics Consortium” (21 Million €; 2004-2009; around 40 scientists) within the Top Institute Food & Nutrition. From 2000-2015 he was supervisor and promoter of 26 PhDs. He is (co)author of more than 220 peer-reviewed publications with more than 9000 citations. He has an H-factor of 57 and is a member of the “Faculty of 1000” (Biology/Physiology).  He is a renowned expert in the area of molecular nutrition, nutrigenomics and nutritional systems biology. His work was focusing on the molecular mechanisms underlying genome-wide effects of in particular fatty acids and proteins on metabolic health and plasticity in organs such as the liver, the intestine or the white adipose tissue. His work now is focusing specifically on the interaction of the liver and the small intestine, the genome wide impact of nutrient-sensing transcription factors like PPARS, NRF2, AHR, FXR or SIRT1 in response of these organs to nutrients, certain bioactives from in plant foods as essential parts of healthy food patterns and the interaction with the gut microbiota.

Dr Naiara Beraza research interests are in characterising the molecular mechanism contributing to the progression of chronic liver disease. Further insight in the key regulatory pathways of the metabolic response to injury will allow providing with potential therapeutic approaches to counteract the progression of liver disease to cirrhosis and HCC. Furthermore, her interests are in uncovering the regulatory pathways involved in the regulation of the gut-liver axis with a special focus on the regulation of bile acid metabolism and its impact on gut microbiota, gut permeability and consequently translocation of bacterial products into the liver, that may further contribute to liver injury in the context of chronic disease.

Dr David Vauzour research interest is to develop novel dietary or therapeutic strategies to delay brain ageing, cognitive decline and cardiovascular disease, and involves the fields of oxidative stress, free radical biochemistry, neurodegeneration and the health effects of dietary polyphenols, such as flavonoids. This work has provided further insights into the potential for phytochemicals and their in vivo metabolites to promote human vascular function, decrease (neuro)inflammation, enhance memory, learning and neuro-cognitive performances and to slow the progression of Alzheimer’s and Parkinson’s disease pathophysiology. More recently, Dr Vauzour interests concern the investigation of the aetiological basis of APOE genotype-disease associations, and the impact of this common genotype on disease status.

Get in touch

michael.muller@uea.ac.uk