Decoding the human microbiome using data science

The human microbiota is thought to have a tremendous influence on human health and diseases. Although it was virtually impossible to study them until a few years ago, next generation sequencing technologies have enabled us to access and characterize the microbiota in a culture-free manner. Cross-sectional studies have shown associations between changes in human gut microbiota and several diseases. For most of these associations though, whether the relationship is causality or reverse causality still remains to be elucidated. This is only the beginning of a new trend to elucidate the role of host-associated microbiota in diseases, and bioinformatics is becoming increasingly important in this endeavor. Over the last 15 years, my research has focused on analyzing human microbiome data to improve our understanding of their importance in human health. In this talk, I will present examples of our discoveries in (i) higher level trends in human microbiome composition, (ii) microbiome-derived diagnostic biomarkers for colorectal cancer, and (iii) resilience of healthy gut microbiome against antibiotic treatment. Finally, I will show some examples from our approaches to integrate microbiome multi-omics data to enable understanding at the molecular level.


Jean-Louis Guéant, MD, PhD, DSc and specialized in Hepato-Gastroenterology is Professor of Biochemistry-Molecular Biology (PU-PH CE2). In the University Regional Hospital of Nancy, he is Head of the Department of Biochemistry-Molecular Biology and Nutrition and has a clinical activity in the department of Hepato-Gastroenterology, National Reference Center of inherited Metabolic Diseases. He is Director of UMR-S Inserm 1256 “Nutrition-Genetics-Environmental Exposure” at the University of Lorraine and coordinator of the Federation of Clinical Research ARRIMAGE.In France, he is President of the section of Medical Biochemistry-Molecular Biology, Physiology, Cell Biology and Nutrition of the National Committee of Universities, President of the National Commission of Medical Biology, and Member of the National Academy of Medicine. He has organized four international congresses since 2010 and is regularly invited to international conferences as speaker and session chair. He is member of the editorial board of Hum Genet, Nutrients and Vitamins and Hormones. His scientific production includes 450 articles in Pub Med, with publications in N Engl J Med, Nature Comm, The Lancet, PNAS, Ann Intern Med, Cell Rep Medicine, Gastroenterology, Gut, J Hepatology, Nucleic acid Research, J Allergy Clin Immunol, Blood, etc… He ranked as top world expert in the items vitamin B12 deficiency and Methionine synthase in expertscape . He has described key mechanisms of digestive transport and metabolism of vitamin B12 and folate, the influence of the one carbon metabolism on the epigenome, cellular stress, energy metabolism and fetal programming in rare and complex metabolic diseases and a new type of B12 rare metabolic disease produced by an epimutation in the MMACHC gene promoter and named “Epi-cblC.”  He has also dissected genetic predictors of allergic drug reactions, He has received the Distinguish Scientist Award of the Sigrid Juselius Foundation, the AGAF award of American Gastroenterological Association, and the “Prix Elise Cailleret” of the French National Academy of Medicine.

More about Jean LOUIS GUEANT;

Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B12 metabolism

Methyl-Cobalamin (Cbl) derives from dietary vitamin B12 and acts as cofactor of methionine synthase (MS) in mammals. MS encoded by MTR catalyzes the remethylation of homocysteine to generate methionine and tetrahydrofolate, which fuel methionine and cytoplasmic folate cycles, respectively. Methionine is the precursor of S-adenosyl methionine (SAM), the universal methyl donor of transmethylation reactions. Impaired MS activity results from inadequate dietary intake or malabsorption of B12 and inborn errors of Cbl metabolism (IECM). The mechanisms at the origin of the high variability of clinical presentation of impaired MS activity are classically considered as the consequence of the dysruption  of folate cycle and related synthesis of purines and pyrimidines and the decreased synthesis of endogenous methionine and SAM. Since one decade, data on cellular and animal models of B12 deficiency and IECM have highlighted other key pathomechanisms, including altered interactome of MS with methionine synthase reductase, MMACHC and MMADHC, endoplasmic reticulum stress, altered cell signaling and genomic/epigenomic dysregulations. Decreased MS activity increases catalytic protein phosphatase 2A (PP2A) and produces imbalanced phosphorylation/methylation  of nucleocytoplasmic RNA binding proteins, including ELAVL1/HuR protein, with subsequent nuclear sequestration of mRNAs and dramatic alteration of gene expression, including SIRT 1. Decreased SAM and SIRT1 activity induce ER stress through impaired SIRT1-deacetylation of HSF1 and hypomethylation/hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), which deactivate nuclear receptors and lead to impaired energy metabolism and neuroplasticity.  The reversibility of these pathomechanisms by SIRT1 agonists opens promising perspectives in the treatment of IECM outcomes resistant to conventional supplementation  therapies.

About Rejko KRUGER

Biopic – Prof. dr med Rejko  KRÜGER

KRÜGER Rejko (Professor Dr. med.) is Professor of Neuroscience at the Luxembourg Centre for Systems Biomedicine of the University of Luxembourg and Director of Transversal Translational Medicine at the Luxembourg Institute of Health. His clinical and experimental research on Parkinson’s disease is supported by an Excellence Grant (PEARL) from the Fonds National de Recherche (FNR). He joined University of Luxembourg in June 2014 after serving nine years as Associate Professor for Neurology at the University of Tübingen and as Head of the Laboratory for Functional Neurogenomics at the Hertie-Institute for Clinical Brain Research in Tübingen, Germany. His clinical and research experience extends over 20 years with a special interest focus in the genetics of neurodegenerative diseases, which has resulted in more than 200 scientific publications thus far (>30.000 citations, h-index 60). He coordinates the National Center for Excellence in Research on Parkinson’s disease (NCER-PD), funded by the FNR. Furthermore, he sees patients with Movement Disorders at the Centre Hospitalier de Luxembourg. He is currently a reviewer for various high impact factor international journals and funding agencies. Prof. Krüger is regularly invited to international conferences in the area of Parkinson’s disease and Movement Disorders and in 2019 faculty member at the World Parkinson’s Conference (Kyoto, Japan) and Congress of the Movement Disorders Society (Nice, France). Since 2017, the Ministry of Health is supporting Prof. Krüger to lead integrated healthcare concepts for neurodegenerative diseases in Luxembourg: the “Programme Démence Prévention” (an initiative to prevent dementia) and ParkinsonNet Luxembourg (a care network of health care professionals for Parkinson’s disease).

More about Rejko KRUGER;

From genes to therapy – emerging concepts for personalized medicine and clinical decision support in Parkinson’s disease’.

To date, no causative treatments are available for common neurodegenerative diseases like Parkinson’s disease (PD). Previously failed trials did not account for the clinical and pathophysiological heterogeneity of PD. Genetics of PD provided first insight into the complexity of this most common neurodegenerative movement disorder and delineated relevant subgroups of patients, who share an underlying molecular pathology. Novel patient-based models from monogenic forms of PD allowed to dissect mechanisms of neurodegeneration and define prototypes for stratification of the more common sporadic form of PD. These strategies hold promise to translate into novel disease-modifying compounds for more targeted therapies using mechanism-based interventions in subgroups of PD patients. Moreover, due to the rapid evolution of novel technologies, e.g. next generation sequencing technologies or device-assisted registrations of clinical symptoms of PD. This is linked with a dramatic increase in multiscale high quality data characterizing PD at different levels and enables novel strategies for patient stratification and identification of markers for therapeutic outcome, that can be translated into clinical decision support, e.g. genetic predictors of therapeutic outcomes in PD. The implementation of these novel strategies and technologies allows for a more direct participation of patients in ongoing research and integrated care efforts and strengthen patient’s autonomy and responsibility for future research.


About Tiago OUTEIRO

The Outeiro Lab

Tiago Outeiro graduated in Biochemistry at the University of Porto and was an Erasmus student at the University of Leeds in the UK. Prof. Outeiro did his PhD thesis at the Whitehead Institute for Biomedical research – MIT and worked as a Research Scientist at FoldRx Pharmaceuticals as a Research Scientist and Consultant. Prof. Outeiro was a Postdoctoral Research Fellow in the Department of Neurology of the Massachusetts General Hospital – Harvard Medical School where he focused on the study of Neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Prof. Outeiro directed the Cell and Molecular Neuroscience Unit at IMM, Lisbon, from 2007 to 2014, and is currently Full Professor and the Director of the Department of Experimental Neurodegeneration at the University Medical Center Goettingen, in Germany. Prof. Outeiro holds a joint Professor position at Newcastle University in the UK. Prof. Outeiro has authored >280 research articles in international journals and participates in various international boards and in collaborative projects with the aim of identifying the molecular basis of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. He has been awarded multiple prizes and grants in Germany, from the European Union, and from other international funding agencies.

Unravelling the molecular mechanisms of Parkinson’s disease and related synucleinopathies

Protein misfolding and aggregation are common events in a wide variety of neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease (PD). Aging is the major known risk factor for the development of neurodegenerative diseases, but mutations in several genes are associated with familial forms. In PD, aggregation of alpha-synuclein (ASYN) in Lewy bodies and the loss of dopaminergic neurons from the substantia nigra, are typical pathological hallmarks. Our limited understanding of the molecular mechanisms underlying protein aggregation and neurodegeneration has complicated the development of novel therapeutic approaches. In our studies, we exploit different model organisms and employ diverse molecular approaches to unravel the molecular basis of neurodegenerative disorders. We are using novel cellular models where central aspects associated with ASYN dysfunction are recapitulated and we are now using powerful imaging approaches to investigate how different types of protein-protein interactions influence conformational changes in ASYN and how those relate to the initial oligomerization events associated with its toxicity. Altogether, our approaches will contribute for the development of novel strategies for therapeutic intervention in protein misfolding disorders.

Advances in (Epi)Genetic Epidemiology: from population to personalized risk.

The technique and discoveries of genome-wide association studies (GWASs) have revolutionized the field of genetic epidemiology prompting the development and application of a range of new tools offering new insights into old questions. Since the first successful GWAS in 2007 many genetic markers (so called single nucleotide polymorphisms or SNPs) have been identified for almost every common disease or trait. Those discovered SNPs themselves can be combined in multi-SNP genetic risk scores. This integrated measure of genetic susceptibility offers an ideal opportunity to investigate to what extent the development of the disease or trait depends on the environment (i.e., gene-environment interaction). The advent of genome-wide methylation arrays (or epigenome-wide association studies or EWAS) has provided yet another tool to investigate gene-environment interaction in complex traits as the epigenome provides an interface between the environment and the genome and can be influenced by dietary, lifestyle, behavioral, and social factors. The current presentation will review these methodological advances and illustrate the promise of genetic and epigenetic risk scores for personalized risk prediction ultimately impacting prevention of our common complex diseases.