Mechanism elucidated: how smell perception influences food intake

A research team led by Giovanni Marsicano, a Inserm Research Director at Unit 862 (NeuroCentre Magendie, Bordeaux), has succeeded in elucidating how the endocannabinoid system controls food intake through its effects on the perception of smells. These results are due to appear in the journal Nature Neuroscience on 9 February 2014.

Nature-Neuro Nose_illustration

© Charlie Padgett

In animals, as in humans, hunger mechanisms are known to stimulate food intake. Hunger triggers a set of mechanisms that encourage feeding, for example by increasing sensory perceptions such as the sense of smell. The researchers have now succeeded in revealing what links hunger and increased smell perception in the brain, and the resulting urge to eat.

The researchers have discovered how this mechanism is initiated in the endocannabinoid system in mice. This system interconnects receptors located in the brain and involved in different sensations such as euphoria, anxiety, or even pain, that are also sensitive to cannabinoid substances, such as cannabis.

The researchers discovered that the CB1 cannabinoid receptors control a circuit that connects the olfactory bulb (the region in the nervous system that initially handles olfactory information, located above the nose) to the olfactory cortex (higher structures of the brain). When the sensation of hunger is felt, it triggers the activity of the cannabinoid receptors, which in turn activate the olfactory circuit, which then becomes more responsive.

It is therefore this biological mechanism that brings about the increased sensitivity to smell during hunger, explaining one of the reasons for food intake and attraction to food.

The researchers expect that the circuit involved in the olfactory system is altered in obese or anorexic patients, and that sensitivity to smell may be more or less strong compared to normal. Elucidation of the biological mechanism will allow better management of these types of pathologies.

This work was funded by ERC (European Research Council).

ERC: France, the leading country for life sciences in Europe

The European Research Council (ERC) has just awarded Consolidator Grants to 19 French projects in life sciences, thereby placing France at the head of European countries submitting proposals in this area. 

The specific “Consolidator Grant” call, which is part of the final ERC call in the EU’s Seventh Framework Programme for Research, rewards the best researchers with 7-12 years’ experience since completing their PhD. Recipients receive an average grant of €1.84 million, up to a maximum of €2.75 million, for a period of up to 5 years.

This new funding will enable promising researchers to build their own research teams and develop their most innovative ideas. “In light of these results, Aviesan members have proven their excellence in life sciences at international level. This announcement strengthens our hopes of success for our researchers in the next Framework Programme, ‘Horizon 2020,’ open since January 2014,” notes Prof. André Syrota, Chairman of Aviesan, with satisfaction.

These results confirm the excellent position of France in Europe with respect to life sciences, with France consistently placed in the top three: the number of recipients of ERC “Starting Grants” (young independent researchers), and “Advanced Grants” (established researchers) who have decided to conduct their project in France, for the entire FP7, is 108 and 72, respectively, for the life sciences.

See details of results on the European Research Council (ERC) website.

The 19 recipients of ERC Consolidator Grants in life sciences (LS) in France:

Eric Bapteste
Evolution Paris Seine, CNRS, Université Pierre et Marie Curie (UPMC), Paris
Sequence similarity networks: a promising complement to the phylogenetic framework to study evolutionary biology

Déborah Bourc’His
Developmental Biology and Genetics, Institut Curie, CNRS, Inserm, Paris
Epigenetic Control of Mammalian Reproduction

Pierre Bruhns
Antibodies in Therapy & Pathology, Institut Pasteur, Inserm, Paris
Role of myeloid cells, their mediators and their antibody receptors in allergic shock (anaphylaxis) using humanized mouse models and clinical samples

Olivier David
Grenoble Institut des Neurosciences (GIN), Inserm, Université Joseph Fourier, CHU Grenoble, Grenoble
Functional Brain Tractography

Sonia Garel
Biology Institute, Ecole Normale Supérieure (IBENS), Inserm, CNRS, Collège de France, Paris
Neural and Immune Orchestrators of Forebrain Wiring

Jean-Marc Goaillard
Ion Channel and Synaptic Neurobiology Laboratory (UNIS), Inserm, Aix-Marseille University, Marseille
Biophysical networks underlying the robustness of neuronal excitability

Mohamed-ali Hakimi
Adaptation and Pathogenesis of Microorganisms (LAPM), CNRS, Université Joseph Fourier (UJF), Grenoble
Toxoplasma gondii secretes an armada of effector proteins to co-opt its host cell transcriptome and microRNome to promote sustained parasitism

Olivier Hamant
Reproduction et développement des plantes (RDP), INRA, ENS Lyon, CNRS, Lyon
Mechanical signals in plants: from cellular mechanisms to growth coordination and patterning

Abderrahman Khila
Institut de Génomique Fonctionnelle de Lyon (IGFL), CNRS, ENS Lyon, Université Claude Bernard Lyon 1, INRA, Lyon
RNA-mediated Transcriptional Gene Silencing in Humans

Rosemary Kiernan
Institute of Human Genetics (IGH), CNRS, Montpellier
RNA-mediated Transcriptional Gene Silencing in Humans

Federico Mingozzi
Research Center for Myology, Université Pierre et Marie Curie (UPMC), Inserm, CNRS, Paris
Molecular Signatures and Modulation of immunity to Adeno-Associated Virus vectors

Antonin Morillon
Dynamics of Genetic Information: Fundamental Basis and Cancer, CNRS, Institut Curie, Université Pierre et Marie Curie (UPMC), Paris
Dark matter of the human transcriptome: Functional study of the antisense Long Noncoding RNAs and Molecular Mechanisms of Action

Hélène Morlon
Applied Mathematics Centre (CMAP), CNRS, Ecole Polytechnique, Palaiseau
From 01/01/2014: Biology Institute, Ecole Normale Supérieure (IBENS), CNRS, ENS Paris, Inserm, Paris
Phylogenetic ANalysis of Diversification Across the tree of life

Mario Pende
Research Centre for Growth and Signalling, Inserm, Paris
mTOR pathophysiology in rare human diseases

Benjamin Prud’Homme
Developmental Biology Institute of Marseille, CNRS, Aix-Marseille University
Evolution of a Drosophila wing pigmentation spot, a sexual communication system

Bénédicte Françoise Py
Centre International de Recherche en Infectiologie (CIRI), CNRS, Université Lyon 1 Claude Bernard, ENS Lyon, Inserm, Lyon
Regulation of inflammasome activity through NLRP3 ubiquitination level

David Robbe
Mediterranean Institute of Neurobiology (INMED), Inserm, Marseille
Neuronal Dynamics of the Basal Ganglia and the Kinematics of Motor Habits

Maria Carla Saleh
Virology, CNRS, Institut Pasteur, Paris
Dynamics of the RNAi-mediated antiviral immunity

Michael Weber
Biotechnology and Cell Signalling (BSC) CNRS, University of Strasbourg, Strasbourg
Identification of novel functions and regulators of DNA methylation in mammals

Leukemia: mode of action of a targeted treatment clarified

The mechanism of senescence – or premature cell ageing – can have an anticancer effect. This new work, conducted by Hugues de Thé and his team (Paris Diderot University/ Inserm/ CNRS/ AP-HP), was published in Nature Medicine on 12 January 2014. It reveals that targeted treatments for acute promyelocytic leukaemia, a rare form of blood cancer, cause a cascade of molecular events leading to cellular senescence and recovery. This action model could be activated in other types of cancers. 

The PML/RARA* protein causes the proliferation of cancer cells in patients affected by acute promyelocytic leukaemia. Existing targeted treatments combining a hormone – retinoic acid – and a poison – arsenic – result in permanent recovery for the majority of patients, without us having a precise understanding of their action on cancer cells. Previous work by Prof Hugues de Thé’s team has shown that the combination of arsenic and retinoic acid causes destruction of the PML/RARA protein and the elimination of leukaemic stem cells. It remained to understand the link between these two events.

This new research contributes the factors needed to understand the recovery. It demonstrates the unexpected involvement of a cascade of events leading to senescence. The aim of the treatment is to reach this final ageing stage of the cells in order to render them incapable of multiplying.

During this targeted treatment researchers showed that the p53** protein, arbiter between cell death and survival, triggers senescence through the involvement of PML nuclear bodies. These spherical structures are present in normal cells but are disorganised by PML/RARA in leukaemia. The treatment reorganises them (see figure below), activating p53 and triggering senescence. In this cascade of events (treatment, PML/RARA degradation, reformation of nuclear bodies, p53 activation), only one link has to be missing to block all the therapeutic effects.


Leukaemic cells before (left) and after treatment (right). The blue represents DNA in the nucleus; the red is nuclear corpus PML. These one are reorganised by the treatment targeting PML/RARA. © Photos provided by Prof Hugues de Thé

It is this phenomenon that enables the elimination of diseased cells and leads to total recovery of the patient, using only combined retinoic acid/arsenic treatment. The absence of chemotherapy avoids many severe side effects.

This understanding of the cellular and molecular mechanism of recovery from acute promyelocytic leukaemia opens prospects for activating this same PML/p53 pathway in other types of cancers.

This work was financed by the French Ligue contre le cancer [cancer research charity], the French Fondation ARC pour la recherche sur le cancer [ARC Foundation for Cancer Research] and the European Research Council (ERC).

* Acute promyelocytic leukaemia is caused by the modification of two genes, RAR and PML, leading to the development of cancer cells;
** the gene coding for p53 protein plays an essential role in cell proliferation under normal conditions and in maintaining the integrity of the cell genome.

A good outcome for the CHILD-INNOVAC project: successful test in humans of a nasal vaccine against pertussis

The CHILD-INNOVAC European research programme, coordinated by Inserm, has enabled the development of an innovative vaccine that can be administered intranasally, to combat pertussis, which has shown a resurgence in developed countries in recent years. The research consortium, headed by Camille Locht, Director of the Centre for Infection and Immunity of Lille (a joint Unit involving Inserm, CNRS, Institut Pasteur de Lille and University of Lille Nord de France), today published promising results from Phase I clinical trials of the vaccine in human subjects in the online journal PLOS ONE

Researchers from the CHILD-INNOVAC European project, which brought together 10 European partners*, evaluated the efficacy and safety of a new concept in intranasal vaccination against pertussis. They also carried out clinical trials in humans, which provided conclusive results. 

Pertussis is a wrongly “forgotten” disease, according to Camille Locht, a Research Director at Inserm and Director of Scientific Affairs of the Institut Pasteur de Lille. The disease currently affects several tens of millions of individuals, and kills approximately 300,000 children annually worldwide. The associated morbidity and mortality are increasing throughout the world. Its resurgence has become a matter for major concern since 2010 in some developed countries, such as the USA, Australia, the UK, the Netherlands and France. 

The CHILD-INNOVAC project is more specifically focused on combating two major respiratory pathogens: Bordetella pertussis (the bacterium that causes whooping cough) and respiratory syncytial virus (which causes bronchiolitis in infants). These pathogens mainly affect infants aged 0 to 6 months, who are poorly protected by the vaccines presently available. The project also provides proof of concept that this vaccine may be applied to other respiratory infections.

The researchers from the CHILD-INNOVAC project have succeeded in testing in humans, for the first time, a live bacterial vaccine, genetically attenuated and specially designed for intranasal administration to combat major respiratory pathogens. “This original method of administration will make the vaccine accessible to greater numbers of people at a smaller cost,” explains the project coordinator, Camille Locht.

CHILD-INNOVAC: a European success
The main success of this European project is the achievement of a vaccine for which the immunogenicity and safety could be tested in humans in only two and a half years (compared with 5-7 years for most projects of this type). This is a very short time, which Camille Locht explains is due to “the skills and motivation of the consortium, which brought together experts in their respective areas of specialisation from seven European countries. It was possible to relay the data in a flexible and efficient manner at the different stages of the project.” The project received a budget of €5 million, awarded by the European Commission under FP7. 

The Phase I trials in humans allowed the immunogenicity and safety of the vaccine to be measured in comparison with a placebo, under double-blind conditions. They took place in Sweden, which has the most “naive” population with respect to vaccination against pertussis, given that vaccination was abandoned in that country for several years, for reasons of inefficacy. 
The main objective of these trials was to record all possible adverse events, namely cough, sneezing, nasal discharge, effects on general health, etc. These measurements were examined by an independent data monitoring committee.
The second objective was to assess colonisation of the nasal mucosa by the vaccine, and the triggering of an immune response. 
It was possible to test three different doses of the vaccines: a low, intermediate and high dose. 
Results obtained after monitoring the vaccinated subjects for 6 months, and analysing 60,000 data points, showed that the vaccine induced no adverse events compared with the placebo, even at the high dose. The vaccine colonised the nasal mucosa best at the high dose. Moreover, immune responses were triggered in all subjects whom the vaccine had colonised. “It is of special interest that a single nasal administration was able to induce an immune response that was maintained for at least 6 months, i.e. for the duration of the study,” comments Camille Locht. 

The next step will involve administering higher volumes in an effort to increase the level of colonisation of the nasal mucosa by the vaccine. Camille Locht and his collaborators also hope to improve the stability of vaccine over time, with a view to industrial development in the near future. 

Inserm Transfert, in charge of the valorization of the IP portfolio related to the BPZE-based technology, recently entered into an agreement with a biotech partner to further develop the technology.

Further information


The CHILD-INNOVAC project was aimed at developing innovative intranasal vaccines against the two main respiratory pathogens, pertussis and respiratory syncytial virus (RSV). The project has provided prototypes for polyvalent vaccines that can be administered intranasally, based on attenuated B. pertussis. The immunity induced by the BPZE1 vaccine was studied in detail, together with its genetic and biological stability and safety.
CHILD-INNOVAC began in 2008, and was supported by the EU (FP7) for 4 years. It was coordinated by Inserm, along with 27 other European projects. The project involved 10 partners, including 2 private companies and 8 laboratories, based in 7 European countries:

Inserm (coordinator), France:
Inserm Transfert, France:
Université Libre de Bruxelles, Belgium:
Innogenetics, Belgium:
National University of Ireland, Maynooth:
Istituto Superiore Di Sanità, Italy:
Swedish Institute for Communicable Disease Control:
Netherlands Vaccine Institute
National Institute for Public Health and the Environment, the Netherlands:
Imperial College of Science, Technology and Medicine, England: http:/

EUCelLEX Project: assessment of the social issues raised by the use of regenerative medicine in Europe

The European EUCelLEX Project (Cell-based regenerative medicine: new challenges for EU legislation and governance), coordinated by Inserm for a three-year period, funding to the tune of €500,000 from the European Union. The project consists in a full examination of the application of the European rules regarding cell banks together with current practices in respect of the therapeutic use of human cells in the different countries concerned. The purpose is to submit the data obtained to the European Commission for it to draw up legislative measures in line with medical advances in this field. On 4 December the nine research teams in Europe and Canada met at the Political Sciences Research Centre in Paris (CEVIPOF) for the launching of the project. 

Biobanks: the future of regenerative medicine

Today, human biological specimens are seen as resources essential to advances in the life sciences and medicine. The analytical data obtained enable a better understanding of the various diseases and also make it possible to propose the appropriate treatment, notably in the field of regenerative medicine[1]. Gathering, storing, processing and distributing them are all done by the biobanks – key players in the transfer of scientific knowledge to clinical practice. These biological databanks will enable researchers to identify new clinical biomarkers and develop new therapeutic approaches such as regenerative medicine. In this field, research into stem cells continues to be promising, stimulating as it does the body’s self-healing ability.

Need for a legal definition of the use of human biological specimens at European level

From 2004 to 2006, the European Union adopted three directives governing cells and human tissues in order to standardise their acquisition, their storage and their use for therapeutic purposes. These directives apply specifically to tissue and cell banks, including cord blood strains and cells used for regenerative medicine. However, they were used in very different ways from one country to another. “At present, the European legal texts concerning the use of stem cells for research by the players in the public and private sectors are not such as to enable the efficient sharing of these resources in Europe, which may impede advances in research,“ explains Emmanuelle Rial-Sebbag, coordinator of the EUCelLEX Project.

Furthermore, scientific developments in the use of human cells centre around new legal and institutional issues. More particularly, the development of research infrastructures at European level (BBMRI-ERIC, FCrin[2]) means re-examining the relevance of all this in the light of rapidly expanding clinical practice which also has to take public health issues into account. Thus today, the areas of examination can be seen to be expanding, and hence the inadequacy of European legislation regarding cell research. It should added that certain parts of the process of translating basic knowledge, up to and including the marketing of new products, are unequally regulated, either by the national laws of the member states or by Europe.

The EUCelLEX Project objectives

It is within this context that the EUCelLEX Project’s chief objective is to examine current legislation concerning the therapeutic use of somatic cells, in both the public and private sectors and in a number of European countries.

To this end, the project aims to assess the relevance of current European legislation in order to provide the data needed to establish a European framework for the use of stem cells of every type (embryo, adult and IPS cells from cord blood) in the light of recent scientific, legal and institutional developments in Europe. To obtain a complete picture of the European situation, the legal study will be complemented by an examination of current clinical practices together with the many ethical recommendations throughout Europe. Starting with the observation that the entire translational process, from research to the marketing of a product, is only partially covered by the EU rules, the teams will need to examine the heterogeneous nature of the legislation due to the freedom of action allowed to the member states.

Initially, each of the partners in the project will need to examine the legislation and the policies in their respective countries governing the use of stem cells at both national and European level.

They will then compare current legislation with the practices that are due to develop stem cells in the near future, more especially in the research infrastructures to highlight the deficiencies and propose sustainable solutions. Special interest will also be paid to emerging such as “cell tourism” or the use of unproved therapies. For example, in some European countries doctors propose to use regenerative medicine techniques which have yet to be scientifically validated and which do not meet the safety criteria imposed by both French and European legislation.

The ultimate objective is to make recommendations to the European Commission so as to facilitate the use of stem cells for clinical purposes in a stabilised legal context.

Thus the results of the project will enable innovation in research and help the European to implement specific legislation in this field.


The 4 phases of the EUCelLEX Project:

1. Information gathering on the legal implementation of the directive on tissues and cells, with the focus on current European legislation and the regulations set forth at national level.

2. Integration of this knowledge into a wider analytical context covering the entire field, focusing on stem cells and the cord blood banks.

3. Make an in-depth analysis of the legislation, the literature, case law and the gathering of opinions on the various ethical aspects.

4. Create tools for the participation of the professional people involved and he key players in the questions raised by the use of stem cells.

The research partners in the EUCelLEX consortium, based throughout Europe and in Canada, will use their scientific, legal and ethical skills to highlight the issues raised by the use of stem cells for the medicine of tomorrow.


EUCelLEX – Cell-based regenerative medicine: new challenges for EU legislation and governance

(Reference : 601806)

The EUCelLEX Project is to be launched on 4 December 2013 and will be aided by the European Union (FP7) for a period of three years. It is coordinated by Inserm and involves nine partners based in seven European countries and Canada:

Inserm (coordinator), France:
Leibniz University, Germany:
Central European University, Budapest, Hungary:
Legal Pathway, Netherlands
Oxford University, England:
Medical University of Graz, Austria:
National Political Sciences Foundation, France:
KU Leuven, Belgium:
McGill University, Canada:


[1] Regenerative medicine is a multidisciplinary field of research whose clinical applications are based on the repair, replacement or regeneration of cells, tissues or organs in order to restore an impaired function, irrespective of the cause, including congenital anomalies, diseases, traumas and ageing. It uses a combination of several technological approaches designed to replace traditional grafts.

[2] Biobanking and Biomolecular Resources Research Infrastructure – European Research Infrastructure Consortium, French Clinical Research Infrastructure Network

Cancer treatment: a step towards personalized chronotherapy

Cancer chronotherapy consists in administering treatment at an optimal time. Because the body is governed by precise biological rhythms, the efficacy of anti-cancer drugs can be doubled and their toxicity reduced five-fold depending on the exact timing of their administration. However, important differences in biorhythms exist between individuals, which chronotherapy has not been able to take into account until now. An international study conducted on mice and coordinated by researchers from Inserm, CNRS and Université Paris-Sud[1] has paved the way towards personalized chronotherapy treatments. In an article published in the journal Cancer Research, the team has shown that the timing of optimal tolerance to irinotecan, a widely used anti-cancer drug, varies by 8 hours depending on the sex and genetic background of mice. They then developed a mathematical model that makes it possible to predict, for each animal, the optimal timing for administering the drug. They now hope to test this model on other drugs used in chemotherapy.

The body’s metabolism follows a 24 hour rhythm, driven by the circadian clock. Consequently, at certain precise times of the day or night, a given drug may prove to be more toxic to cancer cells and less aggressive to healthy cells. Cancer chronotherapy, discovered some twenty years ago by Francis Lévi, seeks to improve the efficacy of chemotherapy treatments. His research has shown that this efficacy can be doubled, depending on the time at which they are administered. Furthermore, it is precisely at this optimal time that the drugs prove to be five times less toxic to the body.

However, research points to the need for personalizing chronotherapy. Indeed, biorhythms can change from one person to the next. For example, although the optimal timing is the same for 50% of patients, the remaining 50% are either ahead of or behind this time. The team headed by Lévi wanted to elucidate the factors that affect these differences in biorhythms.

To do this, the researchers studied the toxicity of irinotecan, an anti-cancer drug widely used in the treatment of cancer of the colon and pancreas, as a function of the timing of its administration in four strains of male and female mice. For the first time, they were thus able to observe that the time of best tolerance to treatment varied by up to eight hours from one group of rodents to the next, depending on their sex and genetic background.

The researchers then worked on developing a method able to predict this optimal drug timing independently of sex and genetic background. To do this, they measured the expression of 27 genes in the liver and colon over 24 hours and then analyzed these measurements using a methodology derived from systems biology. In this way, the researchers were able to construct and validate a mathematical model to precisely predict the timing at which irinotecan is less toxic to the body using the expression curve of two genes, known as Rev-erbα and Bmal1, which regulate the metabolism and proliferation of cells.

The researchers are now aiming to validate this model on other drugs used in chemotherapy. In addition to gene expression, they would also like to find other physiological parameters related to the biological clock that could help predict the optimal timing of treatments for each patient. This work should make it possible to enhance the efficacy and tolerance of such treatments as well as considerably improve the quality of life of patients.

This project was funded in particular by the European Union (7th Framework Programme for Research and Technological Development) and ERASYSBIO+, the European consortium of funding bodies, ministries and project management agencies

[1] Coordinated by the Unité Rythmes Biologiques et Cancers (Inserm/Université Paris-Sud), this work also involved the Institut de Biologie de Valrose (CNRS/Inserm/Université de Nice Sophia Antipolis), the Laboratoire des Signaux et Systèmes (CNRS/Supélec/Université Paris-Sud) and the Milan Institute of Pharmacology.

FIBRO-TARGETS – Europe banks on cardiac fibrosis as a therapeutic target in heart failure

The European Union commits funds to the FIBRO-TARGETS (Targeting cardiac fibrosis for heart failure treatment) research consortium, to be coordinated by Inserm over a four-year period. The objective of the project is to determine the underliying mechanisms in myocardial interstitial fibrosis contributing to the development of heart failure. Unravelling the mechanisms of cardiac fibrosis will lead to the discovery of therapeutic target candidates for various cardiac diseases. FIBRO-TARGETS brings together eleven European expert teams from six different countries both from public research institutes and European biotechs. This is the second EU funding in heart failure for Inserm; the first one was launched last February: HOMAGE (for Heart OMics in AGEing – which aims to validate specific biomarkers of heart failure).
All 11 partners convened in Amsterdam on September 3rd,  for the kickoff of the FIBRO-TARGETS project.

Centre d'Investigation Clinique Plurithématique (CIC-P) Pierre D

© Inserm / P. Delapierre

Beyond and in addition to a diseased heart muscle, myocardial interstitial fibrosis (MIF) is one of the key mechanisms of cardiac remodelling. Cardiac fibrosis contributes to cardiac tissue stiffness. It results from the excessive accumulation of proteins that make up the extracellular matrix. As a consequence, diastolic and systolic cardiac functions are altered which, over time, results in symptomatic heart failure (HF), with breathlessness, fluid congestion, oedema and fatigue.

Heart failure is a serious disease since it is often irreversible. It is estimated that more than 6.5 million people suffer from heart failure in Europe.

 It is the leading cause of hospitalization for patients over the age of 65. The incidence is increasing at an alarming rate because of an aging population and the burden of cardiovascular risk factors (diabetes, obesity and high blood pressure). Early interventions targeting key mechanisms, including myocardial interstitial fibrosis, could slow down progression to heart failure.

Using the large amount of data amassed by the FIBRO-TARGETS consortium, myocardial interstitial fibrosis was identified as a major therapeutic target for the prevention and treatment of heart failure. The FIBRO-TARGETS project therefore aims to accurately identify the main mechanisms involved in MIF and to define therapeutic approaches that target these mechanisms. Cardiac fibroblasts (specific cells in cardiac muscle) make up between 60 – 70 % of all cardiac cells and are the main source of the extracellular matrix proteins responsible for fibrosis. Since these mechanisms have been identified, direct intervention can be performed on fibroblast proliferation and on the composition of extracellular matrix using molecules with potential therapeutic benefits: preventing, repairing or slowing down cardiac remodelling.

“In addition, until now, the only means of quantifying fibrosis was a biopsy, an invasive and inaccurate method used to estimate the total degree of cardiac fibrosis. Over the last ten years, cardiac imaging has allowed to perform accurate anatomic and functional assessments of the myocardium (the muscular tissue of the heart).

Relevant to this project, it is also possible to describe mechanistic phenotypes, including myocardial interstitial fibrosis, using circulating biomarkers”

explains Professor Faiez Zannad, researcher at Inserm unit U1116, Centre d’Investigation Clinique P. Drouin Inserm 9501 in Nancy, and coordinator of the FIBRO-TARGETS and HOMAGE projects.

The FIBRO-TARGETS project objectives are first to confirm the main biological mechanisms involved in myocardial interstitial fibrosis. The next step will be to experimentally validate new molecules and targeted therapeutic strategies that aim to improve the quality of the cellular matrix and limit myocardial interstitial fibrosis. This will allow to propose potential clinical scénarios with the objective to treat heart failure. Finally, the targets could be used as biomarkers to predict, monitor and describe the response to myocardial interstitial fibrosis treatments.

To meet these objectives, the European researchers will undertake experimental physiological and pharmacological studies, as well as molecular biology and pharmaceutical chemistry studies, in an attempt to clarify the mechanisms involved in cardiac interstitial fibrosis using existing in-vitro and in vivo models, and/or models developed during the project. They will also validate the relevance of new therapeutic approaches developed during the project. The second step is a translational research aiming at stratifying patients that are most likely to respond to an anti-fibrotic targeted therapy, eventually leading to a personalized pharmacotherapy. Patients will be classified into groups according to profiles determined using imaging and circulating markers describing the new proposed targets.

The FIBRO-TARGETS project results will help resolve one of the 21st century’s major health problems that affects elderly people in particular.

Rich or poor in intestinal bacteria: we are not all equal when it comes to obesity-related conditions

Researchers working on the European METACARDIS (Metagenomics in Cardiometabolic Diseases) Project, coordinated by Inserm, have published in the magazine Nature the first results of the investigation into the composition of the intestinal flora of obese patients. They observed that these individuals were deficient in intestinal bacteria (in both quantity and diversity) and were at greater risk of developing cardio-metabolic diseases. At the same time, they managed to improve the composition of the intestinal flora through a specific diet. In future, it will soon be possible to develop a simple test to identify people at risk and offer them a suitable preventive solution.

Centre Biomédical recherche et de valorisation

© Inserm

The obesity epidemic affected about 400 million adults in 2005; it will affect 700 million people in 2015 and the numbers will continue to increase. The causes are partially environmental (a more sedentary lifestyle, changes in eating habits, etc.) and partially genetic. Obesity linked to mutations represents a minority of cases. More and more data indicate that the variations in our “other genome”, the microbiome, i.e. the total genome of all the micro-organisms in our body, do more in the development of obesity than variations or polymorphism in the human genome.

Researchers working on the European METACARDIS project participated in two studies whose results have initiated the development and creation of individual treatments for patients suffering from cardio-metabolic disorders, including cardio-vascular diseases and metabolic diseases associated with obesity.

Two types of individuals, depending on the bacterial composition of the digestive tract

The first stage of the METACARDIS project is the study of patient cohorts constituted during previous European or national programmes (the European projects MetaHIT and Micro-Obes supported by the French National Research Agency; > 200 subjects), who provided instant access to much clinical, medical and environmental data as well as biological samples.

An initial study was performed on the MetaHIT cohort, which consisted of 292 Danish adults 123 of them non-obese and 169 obese. The researchers analysed the intestinal bacterial genome of these individuals, using a new technique known as quantitative metagenomics. According to the results, it appears that the two groups of individuals can be differentiated by the richness of the bacteria they carry and the abundance of certain species of intestinal bacteria. One quarter of the people in the cohort were bacteria “poor”, while three-quarters possessed intestinal flora that were “rich” in bacteria. It is the first time that such a distinction has been highlighted in the population. Furthermore, the distinction did not depend on the corpulence of the individuals, because non-obese people were found in both groups, even though the bacteria-deficient group contained more obese people (80%).

Increased risk of complications associated with obesity

When comparing the two groups, researchers discovered that those who were deficient in intestinal bacteria were at greater risk than those who were bacteria-rich of developing complications linked to obesity such as type II diabetes, lipidic and hepatic problems and increased inflammatory factors in the blood, of the type frequently observed in these conditions.

Species of bacteria limit weight gain

Researchers also observed that obese people in the bacteria-deficient group gained more weight over time than individuals in the other group. In bacteria-poor individuals, eight specific species of bacteria were present in low numbers, or were even absent altogether. These species may have a protective role in preventing weight gain and in the long run their detection will open the way to the development of new probiotics that will help to combat weight gain.

Only six species of bacteria make it possible to differentiate between “poor” and “rich”

The second study, conducted by researchers in the METACARDIS consortium on the MicroObes cohort, focused on a cohort of 49 obese or overweight French adults. This confirmed the results of the first study. There were similarities in the bacteria-poor and rich communities between the French and Danish populations. Furthermore, on the basis of only six species of bacteria that were particularly representative in these communities, it was possible to distinguish between bacteria-rich communities and bacteria-poor communities with 95% accuracy. These results could lead to the devising of a simple method for determining which type of microbial intestinal community lives inside an individual. The purpose of METACARDIS is, on the one hand, to confirm, in a larger European cohort, the importance of these bacterial markers and on the other hand to develop a simple diagnostic test to identify individuals who are at greatest risk of becoming obese, associated with co-morbidity.

A diet that helps to enrich the microbiota

The French study also investigated the impact of a protein- and fibre-rich, low calorie diet on the genetic diversity of the intestinal microbiota. After six weeks, the diet not only produced the expected improvement in the clinical characteristics of the individuals studied, but also increased the richness of intestinal bacteria in the bacteria-poor communities. Researchers were thus able to correlate the increase in bacterial richness with weight loss, a reduction in the mass of fat and in cardio-metabolic risk factors. The way is open not only for the diagnosis of at-risk individuals but also for intervention through targeted nutritional recommendations. The inflammatory level of the blood and fatty tissue was not reduced by the diet as efficaciously in individuals who were species-poor as in those who were species-rich. Other interventions, perhaps involving medication, need to be invented to tackle this problem.

The METACARDIS consortium will pursue its research for another five years in order to better specify the various forms of obesity which vary greatly from one person to another and to detect people at risk from metabolic and cardiovascular complications so as to do more to prevent these complications and treat them in a targeted fashion. Consequently any early changes in the microbiota looks like the right route to pursue since it would be accessible through changes in the diet” explains Prof. Karine Clément, the METACARDIS coordinator. In fact, the ultimate aim of the project is to devise preventive medicines for chronic conditions as an alternative to the curative medicines that are becoming less and less affordable financially for industrialised societies.

The METACARDIS project, coordinated by Inserm and launched last December, represents the first systematic study to correlate intestinal flora and cardio-metabolic conditions in humans. The project is bringing together groups of European doctors and multidisciplinary researchers as well as experts in biotechnology and those from industry can access the latest technologies to promote the development of new preventive and treatment strategies for cardio-metabolic conditions. The teams include the INSERM 872 Unit headed by Karine Clément and Dominique Gauguier at the “Les Cordeliers Research Centre”, the “ICAN” University Hospital Institute headed by Serge Hercberg and INSERM Unit 557 “Nutritional Epidemiology” run by Hervé Blottière, Joël Doré and Dusko Ehrlich of the INRA.

The 12 partners in the METACARDIS project:

Inserm, France

INRA, France

Imperial College London, United Kingdom

University of Copenhagen, Denmark

European Molecular Biology Laboratory, Germany

University of Gothenburg, Sweden

Flemish Institute for Biotechnology, Belgium

Assistance Publique – Hôpitaux de Paris, France

University of Leipzig, Germany

Danone Research, France

Cargill, France

Chalmers University of Technology, Sweden

INSERM Transfert, France

Biobyte Solutions, Germany


The Health and Care of Pregnant Women and Babies in Europe in 2010

Second European Perinatal Health Report released by the Euro-Peristat project

The burden of mortality and morbidity in the perinatal period – pregnancy, childbirth, and the postpartum – remains a major concern in Europe. Over 5 million women deliver babies in European countries every year. A healthy pregnancy and infancy confers long-lasting benefits by preventing death and disability in childhood, and reducing risks of adult chronic diseases such as diabetes and hypertension.

The European Perinatal Health Report released by the Euro-Peristat project is the most comprehensive report on the health and care of pregnant women and babies in Europe and brings together data from 2010 from 26 European Union member states, plus Iceland, Norway and Switzerland. Euro-Peristat takes a new approach to health reporting. Rather than simply comparing countries on single indicators such as infant mortality, our report paints a fuller picture by presenting data about mortality, low birthweight and preterm birth alongside data about health care and maternal characteristics that can affect the outcome of pregnancy. It also illustrates differences in the ways that data are collected and explains how these can affect comparisons between countries.

The first Euro-Peristat report, with data for 2004, was published in 2008. It found wide differences between the countries of Europe in indicators of perinatal health and care. Documenting these differences is important because it shows that gains are possible in most countries, provides information about alternative ways of providing care, and raises important questions about the effectiveness of national healthcare policies and the role of evidence in maternity care. This second report provides the opportunity to see whether these gains have been achieved and whether inequalities between the countries of Europe have narrowed.

The 250-page European Perinatal Health Report is a major feat of collaboration between researchers and official statisticians in Europe. It also contains data from two other European projects: Surveillance of Cerebral Palsy in Europe (SCPE) and European Surveillance of Congenital Anomalies (EUROCAT).The Euro-Peristat project is cofinanced by the Health Programme of the European Union’s Directorate General for Health and Consumers which also provides funding for SCPE and EUROCAT.

Report highlights


Fetal, neonatal, and infant mortality fell across-the-board in Europe between 2004 and 2010, but these declines were not equally distributed.

  • Fetal, neonatal and infant mortality rates declined by approximately 20%.
  • Declines were most pronounced in countries with higher mortality rates in 2004 (including Denmark, Italy, and the Netherlands for fetal mortality and Estonia, Latvia, and Lithuania for neonatal mortality).
  • Fetal, neonatal and infant mortality rates also fell in some countries with very low mortality in 2004 (including Slovenia, Finland, the Czech Republic and Austria), a decline showing that further decreases are possible.

Declines in mortality did not narrow the wide differences between European countries.

  • Fetal mortality rates at or after 28 weeks of gestation ranged from under 2.0 per 1000 live births and stillbirths in the Czech Republic and Iceland to 4.0 or more per 1000 in France, Latvia, the region of Brussels in Belgium, and Romania. The countries of the United Kingdom also had relatively high fetal mortality rates.
  • Neonatal mortality rates ranged from 1.2 per 1000 live births in Iceland and 1.5 per 1000 in Finland and Sweden to 4.5 per 1000 in Malta and 5.5 per 1000 in Romania.
  • Infant mortality rates ranged from 2.3 per 1000 live births in Iceland and Finland to 5.5 in Malta, 5.7 in Latvia, and 9.8 in Romania.

Preterm birth rates stayed the same or declined in many countries. Previous reports, including a new study issued by the Euro-Peristat group (see below) have found increases in overall preterm birth rates over the past 15 years. In contrast, our data for 2010 suggest that increases may have stopped in some countries. Understanding why these rates have stabilised or decreased in some countries can help shape health policies in countries where rates continue to rise.

European congenital anomaly registries (in the EUROCAT network) recorded a total prevalence of major congenital anomalies of 25.5 per 1000 births for 2006-2010. The prevalence among live births was 20.9 per 1000 births. Extrapolating to the EU-27, this represents approximately 112 000 affected live births. Although most fetuses affected by a congenital anomaly survive the first year of life, these anomalies are a major contributor to fetal and neonatal deaths. The total perinatal mortality rate associated with congenital anomaly was 0.81 per 1000 births. Rates of termination of pregnancy for fetal anomaly varied between regions and countries from 0 to 10.5 per 1000 births. The decade through 2010 saw shallow declines in the prevalence of non-chromosomal anomalies including neural tube defects and congenital heart defects and an increase in some congenital anomalies including Down syndrome and Gastroschisis.

Cerebral palsy affects one newborn in 500 per year. Population-based registries across Europe have shown a decrease in cerebral palsy rates in children born with very low birth weight or moderate gestational age.

Maternal deaths are rare in Europe, but under-reporting is widespread. The maternal mortality ratio (MMR) ranges from under 3 per 100 000 (in Estonia, Italy, Austria, and Poland) to over 10 per 100 000 live births (Latvia, Hungary, Slovenia, Slovakia, and Romania). Although considerable variation arises from the very small numbers of deaths involved, there is good evidence that maternal deaths derived from routine statistical systems are under-reported. This must be investigated particularly for countries where ratios are very low.


Some risk factors for poor perinatal outcome increased, while others decreased. Levels of risk vary greatly between countries.

  • Multiple pregnancies: Multiple pregnancy rates differ widely throughout Europe, ranging from lows of 9 to 13 per 1000 women with live births or stillbirths in Romania, Latvia, Lithuania, and Poland to more than 20 per 1000 in Brussels, the Czech Republic, Denmark, Cyprus, Spain, and Malta. However, rates rose in 20 of the 23 countries that provided data on this indicator in both time periods. Babies from multiple births are 10 times more likely than singletons to be delivered preterm and as a result have higher risks of neonatal and infant death.
  • Maternal age: Since 2004, the average age of women giving birth in Europe has risen, but the proportions of mothers 35 years and older vary between countries from 10.9% in Romania to 34.7% in Italy. Births to mothers aged under 20 are uncommon (2% or lower in many countries), but in some countries, they account for over 5% of births (United Kingdom, Hungary, Latvia, Malta, Slovakian, and Romania.
  • Smoking during pregnancy: Our data show a decline over time in countries for which these data were available. In many countries, however, more than 10% of women continue to smoke during pregnancy. Countries with highest proportions of smokers were:  Spain (data from Catalonia – 14.4%), France (17.7%), and some UK countries, including Scotland (19%), Wales (16%), Northern Ireland (15%). Eleven countries had no data on this indicator.
  • Underweight, overweight and obesity: Data on maternal prepregnancy body mass index were collected for the first time in this report although 18 countries did not have these data. In many countries, more than 10% of pregnant women were obese, with highs in Wallonia in Belgium (13.6%), Germany (13.7%), and Scotland (20.6%).


Caesarean section rates increased in most countries between 2004 and 2010. With the exception of Finland and Sweden, where rates declined, increases were widespread ranging from under 0.2% in Italy to over 7% in Lithuania, Slovakia, and Poland. In general, increases were most marked in the countries of central and eastern Europe and in Germany and Austria.

Practices related to caesarean section have not converged over time. Rates in 2010 ranged from 52.2% in Cyprus, 38.0% in Italy, 36.9% in Romania and 36.3% in Portugal to below 20% in the Netherlands, Slovenia, Finland, Sweden, Iceland, and Norway. Differences in population risk factors for caesarean section, such as maternal age and parity do not suffice to explain these wide differences. Among countries with high proportions of older mothers Italy and Portugal had high caesarean section rates while the Netherlands and Finland had lower rates.

Variations in obstetric practices raise questions about the role of scientific evidence in clinical decision making. In addition to caesarean, other aspects of clinical practice also varied widely. For example, episiotomy rates ranged from 5% to 70% of vaginal deliveries, yet current evidence does not support routine use of this procedure. Rates were around 70% in Cyprus, Poland, Portugal, and Romania and ranged from 43-58% in Wallonia and Flanders in Belgium and in Spain. The lowest rates – between 5 and 7% – were reported in Denmark, Sweden, and Iceland.

Up to 5 to 6% of births in some countries may occur after use of some form of assisted reproductive techniques (ART), although the use of the less invasive procedures is under-reported in most data systems or not reported at all. Births after in vitro fertilisation (IVF) accounted for 2 to 4% of all births. Many countries are implementing policies to prevent multiple pregnancies in assisted conception, and the decrease in twin rates observed in some countries – such as Denmark, the Netherlands and Norway – may be the result of these policies. In contrast, the substantial increases in twin birth rates observed in Italy, Malta, Luxembourg, Brussels in Belgium and the Czech Republic could result from more widespread use of ART without clear practice guidelines.

While the proportion of births in larger maternity units has increased in many countries, the size of maternity units still varies widely. Overall, few births occurred in maternity units with fewer than 500 births in 2010, but this proportion was higher in some countries (16.1% in Germany, 17.6% in Estonia, 18.3% in Switzerland, and 61.9% in Cyprus). At the other end of the spectrum, in Denmark, Ireland, Latvia, Slovenia, Sweden, England and Scotland, over one quarter of births take place in maternity units with 5000 or more deliveries per year.


European countries face common challenges related to the health and care of mothers and babies as shown by the results of this and the previous Euro-Peristat report. By making its perinatal health indicators widely available to health planners, clinicians, researchers and users, Euro-Peristat seeks to promote evidence-based actions to improve maternal and child health. Yet to build a truly sustainable system, further actions are needed to:

Improve national capacity for perinatal health reporting by ensuring that each country can provide the full set of Euro-Peristat indicators using appropriate definitions as well as by improving ascertainment of very preterm births and maternal deaths. Wider linkage of data sources, building on methods already in use in Europe, could yield immediate gains for perinatal health monitoring in many countries.

Reinforce European collaborations to produce and use these data. The Euro-Peristat network has published 20 articles in peer-reviewed journals based on these data. Other researchers have also used the Euro-Peristat data for research on perinatal health in their own countries. We expect that these new data from 2010 – which allow exploration of time trends in maternal and infant health–to further highlight the value of having comparable data from the countries in Europe.

Notes to editors:

  • On May 27th, the Euro-Peristat project released the European Perinatal Health Report: The health and care of pregnant women and their babies in 2010. It can be downloaded free of charge as a PDF from
  • Funding: Support comes from the European Union’s Health Programme
  • The Euro-Peristat project is coordinated by the Institut de la santé et de la recherche médicale (INSERM) in Paris. Data collection is coordinated by TNO, the Netherlands

Liver disease: understanding it will enable the provision of better treatment

A certain number of patients hospitalised for cirrhosis complications soon develop a syndrome characterised by acute liver failure and/or the failure of other vital organs (ACLF)[1]. This syndrome had no specific diagnostic criteria hitherto. In this prospective study, led by Dr Richard Moreau, INSERM Research Director (Mixed Research Unit 773 “Centre de Recherche biomédicale Bichat-Beaujon”; INSERM/Université Paris Diderot) who is also a practitioner attached to the Hepatology Department of the Beaujon Hospital (AP-HP), researchers studied a cohort of 1343 patients from 12 European countries. The results, published in the learned journal Gastroenterology, describe, for the first time, the specific profile of sufferers from this syndrome that is associated with cirrhosis. This also makes it possible to more clearly define the actual rules of attribution of the organs in those most severely affected, for whom there is a high risk of early death.

Cirrhosis is an irreversible liver disease. It is characterised by chronic inflammation that destroys the liver cells and produces anarchic regeneration in the form of nodules. The disease causes the liver to lose function and is accompanied by multiple complications. When these complications manifest (bleeding in the digestive tract, bacterial infection, accumulation of liquid in the abdomen, etc.), this is known as decompensated cirrhosis and the patients are hospitalised.

A certain number of these patients quickly develop a syndrome characterised by acute liver failure and/or failure of other vital organs1 (ACLF – acute-on-chronic liver failure). The syndrome is associated with a high risk of death at one month and no diagnostic criteria were clearly established hitherto that might make it possible to describe the condition.

Through a consortium[1], the researchers in Mixed Research Unit 773 “Centre de Recherche biomédicale Bichat-Beaujon” (INSERM/Université Paris Diderot), analysed data from 1343 patients hospitalised due to acute cirrhosis complications between February and September 2011 in 29 Hepatology Departments in 12

European countries[2]. This enabled them to define robust diagnostic criteria for ACLF, indicating that one-third of the patients enrolled in the study had developed this syndrome.

The researchers noted that, compared to patients not suffering from ACLF, those who developed acute failure of an organ or organs were younger, were most frequently prey to alcoholism, suffered from a larger number of bacterial infections and had higher levels of white blood cells, as well as other markers of organ inflammation.

Quite unexpectedly, failure was most severe in patients without a previous history of cirrhosis complications. A high number of organ malfunctions (liver, kidneys, brain) were observed in these patients, including white blood cells in the blood and a mortality rate within one month of admission to hospital that was15 times greater than in patients who had a previous history.

“The identification of the criteria to define acute failure of an organ or organs enabled us to show that this is a separate syndrome from cirrhosis complications. In addition to organ failure and the high associated mortality, the development of the disease depends on the patient’s age and medical history”, explains Richard Moreau, INSERM Director of Research, and the Principal Investigator for the study.

We hope to be able to better identify those at risk of early death in order to improve their treatment. Furthermore, these results could lead to improving the current rules for assigning organs for grafting in the severest cases”, he concludes.


 Crédit photo : ©Fotolia

Liver and cirrhosis

The liver is a vital organ whose main functions are the storage and production of glucose as well as the synthesis and breakdown of other substances (triglycerides, cholesterol, lipoproteins, coagulation factors).
There are about 700,000 cases of cirrhosis in France, of which 30% are at the severe stage, resulting in 10,000 to 15,000 deaths a year. Diagnosis is on average at the age of 50. Not everyone at risk of cirrhosis develops the disease. In fact, it only manifests in 10% to 20% of cases.
The only current treatment for cirrhosis is a liver transplant. The first eligible patients are those whose life expectancy at three months is the lowest. Each year, around 1,000 patients receive liver transplants in France.

Please consult the information on the 


[1]    Consortium known as CLIF (“Chronic Liver Failure”) including French researchers and their European colleagues; Richard Moreau is the main investigator in the first study conducted under the aegis of this Consortium.

[2] France, Belgium, United Kingdom, Italy, Spain, Germany, Netherlands, Ireland, Switzerland, Austria, Denmark, Czech Republic


[1]    Acute-on-chronic liver failure affecting the kidneys, brain, lungs and/or circulatory system